Bangladesh endocrine society guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum

Shahjada Selim; Md Faruque Pathan; Muhammad Hafizur Rahman; Mohammad Saifuddin; Nazmul Kabir Qureshi; Ahmed Salam Mir; Faria Afsana; Tahniyah Haq; A. B. M. Kamrul-Hasan; S. M. Ashrafuzzaman

doi:10.4103/bjem.bjem_2_23

CLINICAL PRACTICE GUIDELINES

Year : 2023 | Volume : 2 | Issue : 1 | Page : 1-19

Bangladesh endocrine society guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum

Shahjada Selim¹, Md Faruque Pathan², Muhammad Hafizur Rahman³, Mohammad Saifuddin⁴, Nazmul Kabir Qureshi⁵, Ahmed Salam Mir⁶, Faria Afsana⁷, Tahniyah Haq¹, A. B. M. Kamrul-Hasan⁸, S. M. Ashrafuzzaman⁹
¹ Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
² BIRDEM Academy, Dhaka Medical College and Hospital, Dhaka, Bangladesh
³ Department of Endocrinology, United Hospital Ltd, Dhaka Medical College and Hospital, Dhaka, Bangladesh
⁴ Department of Endocrinology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
⁵ National Healthcare Network, Uttara Executive Centre, Dhaka, Bangladesh
⁶ Department of Endocrinology, Bangladesh Institute of Health Science, Dhaka, Bangladesh
⁷ Department of Endocrinology, BIRDEM General Hospital, Dhaka, Bangladesh
⁸ Department of Endocrinology, Mymensingh Medical College, Mymensingh, Bangladesh
⁹ Department of Endocrinology, Ibrahim Medical College, Dhaka, Bangladesh

Date of Submission	16-Jan-2023
Date of Acceptance	24-Jan-2023
Date of Web Publication	27-Feb-2023

Correspondence Address:
Shahjada Selim
Associate Professor, Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjem.bjem_2_23

Abstract

Background: In Bangladesh, patients with thyroid disorders are managed in accordance with the recognized guidelines and based on expert experience, as comprehensive national guidelines are currently lacking. The Bangladesh Endocrine Society (BES), as a professional body, has been working to develop guidelines for the last couple of years. Most recently, BES formulated practical recommendations for the management of thyroid disorders during pregnancy, which will be termed the “Guideline on Thyroid Disorders in Pregnancy in Bangladesh 2022,” Methods: The BES formed a task force comprising experts in this field to formulate the practical recommendations for the management of thyroid disorders during pregnancy under several sections. The members of this task force comprehensively reviewed the available evidence for the specific conditions. Three well-known databases (Google Scholar, PubMed, and Scopus) were searched to determine the evidence. The task force members were well trained on reviewing the documents and methods of evidence synthesis. Each section of the recommendation was drafted by one member and subsequently reviewed. There was no barrier to the date or type of article published in the aforementioned databases except for articles published other than English. Due to the scarcity of intervention studies, ideas and findings of observational studies, case studies and expert recommendations were considered during the formulation of the guidelines. All members and affiliated persons declared no competing interest, and it was managed and communicated by the President of the BES. Results: The current guidelines for the management of thyroid disease in pregnancy include recommendations about the screening of thyroid function in pregnancy, planning pregnancy in women with thyroid disorders, interpretation of thyroid function tests, management of hypothyroidism and hyperthyroidism in pregnancy, management of thyroid nodules and thyroid emergencies throughout pregnancy, postpartum care, and directions of future research. Conclusions: Our utmost efforts were centered on developing evidence-based recommendations to inform all the levels of clinicians of Bangladesh for the easy understanding and decision-making processes in the management of thyroid disorders in pregnancy and afterward. While we care most to prepare the guideline, all recommendations are the opinion of society and admit the scope of making individualized decisions for the optimal care of patients.

Keywords: BES guideline, hyperthyroidism, hypothyroidism, thyroid disorder in pregnancy

How to cite this article:
Selim S, Pathan MF, Rahman MH, Saifuddin M, Qureshi NK, Mir AS, Afsana F, Haq T, Kamrul-Hasan AB, Ashrafuzzaman SM. Bangladesh endocrine society guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Bangladesh J Endocrinol Metab 2023;2:1-19

How to cite this URL:
Selim S, Pathan MF, Rahman MH, Saifuddin M, Qureshi NK, Mir AS, Afsana F, Haq T, Kamrul-Hasan AB, Ashrafuzzaman SM. Bangladesh endocrine society guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Bangladesh J Endocrinol Metab [serial online] 2023 [cited 2023 Mar 29];2:1-19. Available from: https://www.bjem.org/text.asp?2023/2/1/1/370601

Purpose and Scope of the Guideline

Thyroid disorders in pregnancy are frequent and considered one of the public health problems in Bangladesh. Despite no exact statistics, the number is not minimal and commonly encountered problems in the day-to-day clinical practice. The purpose of the guidelines and recommendations is to summarize the available evidence to support health-care professionals in decision-making in the management of thyroid disorders in pregnancy. The Bangladesh Endocrine Society (BES), a registered professional body, has been publishing its recommendations for the last few years. As a part of its continuing educational activities, it formed a task force comprising experts in this field to formulate practical recommendations in all possible problems faced by the clinic during the management of patients with thyroid diseases during pregnancy. The current guidelines for the management of thyroid disease in pregnancy include recommendations about the screening of thyroid function in pregnancy, planning a pregnancy in women with thyroid disorders, interpretation of thyroid function tests in pregnancy, management of hypothyroidism and hyperthyroidism in pregnancy, management of thyroid nodules and thyroid emergencies throughout pregnancy, postpartum care and directions of future research. Although the formulation of the guideline was based on the best scientific evidence, it does not nullify the scope of making individualized decisions for the optimal care of the patients. Rather, BES declared all recommendations made by the expert body as an opinion intended for optimal care paradigms for patients with these disorders.

Methods

As no such guidelines are available in Bangladesh, the BES has made an initiative to formulate guidance to manage patients with thyroid disorders in pregnancy. A number of consultative meetings were held, and it was decided that the guideline would be named the “Guideline on Thyroid Disorders in Pregnancy in Bangladesh 2022.” To prepare the first edition of the guideline, a taskforce chair was appointed, and then he appointed the necessary experts. Experts and experienced physicians in this field with a long tract history of successful patient handling were included. Necessary inputs were also taken from specialists with complementary expertise, for example, pediatrics, obstetricians, gynecologists, and epidemiologists. The task force members were educated and well trained about the methods of evidence synthesis, database searching, and required expertise. A total of three databases were searched up to March 2022. Published literature was searched in Google Scholar, PubMed, and Scopus with the following key words: “Thyroid disease and pregnancy, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules in pregnancy, thyroid function tests in pregnancy, pregnancy planning in thyroid diseases, Postpartum thyroid disorders,” etc., Randomized controlled trials were prioritized. Unfortunately, due to the lack of a sufficient number of trials in Bangladesh, the task force considered observational studies, case studies, and expert opinions to formulate the final recommendations. Before starting the work, all task force members declared no competing interest to prepare the guideline, and it was continually followed up by the president of the Bangladesh Endocrine Society. A small group was made to search and review the documents in each section. Prior to that, written and verbal instructions were provided to all task force members about the critical appraisal of the documents and rationale for formulating the strength of recommendations and making an initial draft. Rigorous review and modifications were made by the members of the short team. Then, the recommendations were presented to all taskforce members for additional comments, observations, and revision requests. All decisions were made based on the consensus of all task force members. Dispute was solved by multiple consultations of the team members, and the final decision was made by the chair of the taskforce. Therefore, these recommendations are a combination of expert opinions and narrative summary of the available evidence regarding the management of pregnant females with thyroid diseases.

Section-1.0: Screening of thyroid function in pregnancy

Normal thyroid function is essential for the successful maintenance of normal pregnancy as well as optimal fetal development. Worldwide, hypofunction of the thyroid gland is common in women with pregnancy.^[1] Overt hypothyroidism (OH) and subclinical hypothyroid were therefore found to be significantly higher in females during pregnancy in all parts of the world, including South Asia.^[2],[3],[4] Among the thyroid disorders, hypothyroidism is encountered more frequently in the clinical settings. Major barriers to treat patients are the disease nature, as most of the patients remain asymptomatic over a period of time and a number of patients live with OH with very minimal symptoms. Consequently, they felt no drive to seek care, and most of the women visiting the physicians were during the perpartum period with evidence of complications.^{[5],[6],[7],[8]} An increased chance of adverse events is suggestive of hypothyroidism in women during pregnancy, and it can even have a significant impact on neuro-psychological development in children later in life.^[8],[9],[10] Even marginal hypofunction can be associated with fetal loss, preterm delivery, prematurity, and cognitive dysfunction in children.^[11],[12] As it is difficult to differentiate clinically between women with normal thyroid function and women with subclinical and OH initially, it is logical to screen thyroid function in early gestation or even plan preconception care to prevent adverse outcomes in both mother and fetus. Hence, BES recommended the screening of all women who are pregnant irrespective of gestational age and who are planning to conceive.

Why to screen

Women with hypothyroidism suffer an increased risk of adverse pregnancy outcomes in OH, subclinical hypothyroidism (SCH), and even isolated hypothyroxinemia.^{[5],[6],[7],[8],[9],[10],[11],[12]} Offspring of hypothyroid mothers can have neuropsychological and cognitive dysfunction and congenital malformation.^[9],[10]

Whom to screen

Most of the guidelines advocate that women with the following criteria be offered to screen for thyroid dysfunction^{[8],[13],[14],[15],[16],[17],[18]} [Table 1].

Table 1: Screening criteria

Click here to view

When to screen

There is continuing debate among experts regarding whether we should go for universal screening or target base high-risk individuals in terms of benefit outcome and cost-effectiveness. To date, there is no consensus about universal screening. Most of the guidelines, including the American Association of Clinical Endocrinology, American College of Obstetricians and Gynecologists, American Thyroid Association (ATA), and International Society of Endocrinology, advocate screening for target cases in high-risk groups.^{[8],[15],[16],[17],[18],[19],[20],[21]} Conversely, many experts consider SCH, asymptomatic hypothyroidism, isolated hypothyroxinemia, and their outcomes opined for universal screening. The opinion was proposed to not miss 30%–55% of women, the diagnosis of whom could be missed by a target screening approach. The authors who are in favor of universal screening advocate it to detect early and higher numbers of cases and have the potential to prevent valuable pregnancy loss and reduce adverse events in comparison to targeted screening.^[21]

Recommendations

Considering the high prevalence of both overt and SCH and the iodine deficiency status of our population, universal screening is recommended
Preconception screening is recommended for those who were previously diagnosed and/or already on thyroid replacement therapy. Here, FT3, FT4 and thyroid stimulating hormone (TSH) are all recommended in patients with family history and bad obstetrics history with miscarriage
Should be with a full thyroid profile to elucidate the role of thyroid function in their primary and secondary fertility
Preconception screening of undiagnosed cases and education of previously treated cases are recommended, and this will help to identify subfertility
Preconception counseling, appropriate iodine replacement, and L-thyroxine replacement are recommended, and follow-up should be performed according to trimester-specific levels.

Section 2.0: Preconception in women with thyroid disorders

Thyroid function is closely interlinked with worse maternal and fetal outcomes. The outcome could be improved if we can maintain optimal thyroid function. Hence, for the expected best possible pregnancy outcomes, thyroid function is required to be optimized during the preconception period. This is usually done by appropriate screening, rational management, and pragmatic counseling. Thus, the evaluation of endocrine functional status should be taken as an integral part of preconception management.^[22]

The most common thyroid disorders among women of reproductive age include hypothyroidism, hyperthyroidism, and thyroid nodules. In untreated cases of thyroid disorders, there are heightened risks of subfertility, infertility, poor obstetric history, and suboptimal pregnancy outcomes.^[23]

Hypothyroidism

Screening for thyroid disorders using a sensitive and accurate TSH assay and FT4 is indicated for all women as part of preconception counseling. Testing for thyroid antibodies (anti-thyroglobulin [Tg] and thyroid peroxidase antibodies [TPOAb]) is recommended for select cases only where there is a therapeutic dilemma.^[24] The presence of very high thyroid autoimmunity (89.0%) has been reported from Bangladesh, with a higher proportion of participants being positive for anti-TPO antibodies (82.5%) than anti-Tg antibodies (55.2%). In addition, women with a history of postpartum thyroiditis or postpartum depression should be screened for thyroid status at preconception.

There is insufficient evidence to recommend screening for thyroid antibodies in euthyroid women with a poor obstetric history or in women undergoing in vitro fertilization (IVF). As there is no benefit in the treatment of isolated maternal hypothyroxinemia, universal FT4 screening during preconception is not recommended. Thyroid ultrasonography and scans are not indicated as part of routine preconception workup to diagnose the case.

While the ATA suggests that there is insufficient evidence to recommend for or against TSH preconception testing in women at high risk for hypothyroidism, they do recommend that all pregnant women be verbally screened at the initial prenatal visit for any history of thyroid dysfunction and/or use of thyroid hormone (levothyroxine [LT4]) or antithyroid medications.

Due to the high prevalence of subclinical hypothyroidism (SCH), decreasing iodine sufficiency, and lack of universal iodized salt use in South-East Asia, biochemical screening for thyroid disorders should be a mandatory part of preconception care.^[25] It must also be noted that TSH estimation is more economical and easily available than TPOAb testing in most South Asian countries including Bangladesh.

OH and SCH should be managed with LT4 (category A drug), and TSH levels should be optimized to <2.5 mIU/L before conception.^[4] Lower preconception TSH values (within the nonpregnant reference range) reduce the risk of TSH elevation during the first trimester. Selected TPOAb-negative patients with mild SCH may be kept under close follow-up without LT4 supplementation, particularly for that women who had bad obstetrics history. Such women should be monitored for progression to OH with monthly serum TSH and FT4 until 16–20 weeks of gestation and at least once between 26 and 32 weeks of gestation.

Women who are already receiving LT4 should be counseled to increase their dose of LT4 by approximately 25%–30% if they miss a menstrual cycle or note a positive home pregnancy test and should consult with the both obstetricians and endocrinologist. A simple way of ensuring this adjustment is to increase LT4 from once daily dosing to a total of nine doses per week (29% increase).^[26]

Iodine nutrition

To encounter iodine deficiency-related hypothyroidism in a few endemic areas of Bangladesh, care must be taken for women who are planning to conceive. As screening is relatively expensive, all women must be counseled to use iodized salt in the preconception, as well as other phases of life. Iodized salt contains >15 PPM of iodine (added as potassium iodate, KIO3) per 100 g. Salt contains 150μg of iodine, which is sufficient to meet physiological requirements. The use of iodine-containing multivitamin/mineral and selenium preparations is not routinely recommended to use during preconception or pregnancy.

According to the ATA, a minimum of 250 μg iodine daily suggests that sustained iodine intake from diet and dietary supplements exceeding 500–1100 μg daily should be avoided due to concerns about the potential for fetal hypothyroidism.^[26],[27]

Hyperthyroidism

All the available antithyroid drugs (ATDs) are classified as category D in pregnancy. In the preconception period, hyperthyroidism should be managed and stabilized with methimazole or carbimazole, and the therapy needs to be switched to propylthiouracil as soon as pregnancy is confirmed. Methimazole or carbimazole can be used as an alternative, but patients should be aware that there is a very low risk of congenital defects of the fetus, such as aplasia cutis and esophageal/choanal atresia^[24] of using the drug. Radioactive iodine is contraindicated. If necessary, it should be outweighed the benefits and risks. When administered, it should be performed at least 6 months before conception to minimize the risks. While thyrotoxic women should be rendered euthyroid before attempting pregnancy, subclinical hyperthyroidism does not need pharmacological management in the preconception phase or in pregnancy.

Thyroid nodules

Thyroid nodules should be evaluated, diagnosed, and managed appropriately before conception. Thyroid ultrasonography and fine-needle aspiration cytology (FNAC) may be performed if thyroid nodular disease is detected during the preconception phase.^[28] Management depends upon the nature of the nodule and the overall functional status of the women.

Recommendations

TSH assay is recommended for all women who planned for pregnancy irrespective of age
Evaluation of serum TSH concentration is recommended for all women seeking care for infertility
Evaluation of thyroid autoimmunity by measuring antithyroid antibodies is recommended for all women seeking care for infertility, particularly for those who have a history of previous pregnancy loss(s)
Levothyroxine (LT4) treatment is recommended for subfertile women with OH who desire pregnancy
Women with SCH intended for IVF or intracytoplasmic sperm injection should be treated with LT4. The treatment goal was to achieve a TSH concentration <2.5 mIU/L
Iodized salt intake should be promoted to all women at preconception and/or throughout the life period, with particular emphasis on women living in endemic areas where endemic goiter is most frequent.

Section 3.0: Interpretation of thyroid function tests in pregnancy

Thyroid physiology in pregnancy

Pregnancy is associated with significant but reversible physiological changes in maternal thyroid physiology that need to be considered during the interpretation of thyroid function tests.

The estrogen concentrations rise in pregnancy. It induces increased hepatic synthesis of thyroxine-binding globulin (TBG) and enhances sialylation of TBG, which decreases its metabolic clearance rate.^[22] Consequently, it increases TBG concentrations, which leads to increased total thyroxine (TT₄) and triiodothyronine (TT₃) levels in maternal serum, but the free thyroxine (FT4) and triiodothyronine (FT₃) fractions remain normal.^[22],[23] The TBG level begins to increase by 7 weeks of gestation, reaches a plateau at approximately 16 weeks of gestation, and remains ∼2-fold higher until term. Similarly, levels of total T4 and T3 rise from 7 weeks of gestation, increase ∼50% during the first half of pregnancy, plateau at ∼16–20 weeks of gestation and then remain high until delivery [Figure 1].^[24],[25]

Figure 1: The pattern of changes in serum concentrations of thyroid function studies and hCG according to gestational age. The shaded area represents the normal range of thyroid-binding globulin, total thyroxine, thyroid-stimulating hormone or free T4 in the nonpregnant woman.^[23] TBG: Thyroid-binding globulin, T4: Thyroxine, TSH: Thyroid-stimulating hormone, hCG: Human chorionic gonadotropin. (Adapted and modified from Brent GA (23)

Click here to view

The family of glycoprotein hormones, which include both human chorionic gonadotropin (hCG) and TSH, have a common alpha subunit and a unique beta subunit. There is also considerable homology between the beta subunits of hCG and TSH. As a result, hCG acts as a weak TSH receptor agonist.^[26] The placenta produces hCG in the 1^st week after conception, and the levels peak at week 10 and then decrease and reach a plateau by week 20.^[24] Increased levels of hCG directly stimulate the TSH receptor and increase thyroid hormone production, which in turn results in reduced and sometimes suppressed serum TSH.

The fetus depends entirely on transplacental passage of maternal thyroid hormone in the 1^st trimester, but fetal thyroid hormone production begins at approximately the 12^th week of gestation and is under control of the pituitary at approximately the 20^th week.^[27] Maternal glomerular-filtration rate increases in pregnancy, resulting in increased renal clearance of iodine.^[28] In late gestation, transplacental passage of iodide and placental metabolism of thyroid hormones increases fetal iodine supply.^[29] All these factors cause relative maternal iodine deprivation and stimulation of the maternal thyroid. In iodine-sufficient areas, the thyroid typically increases approximately 10% in size during pregnancy. However, in iodine-deficient areas, the gland typically increases from 20% to 40% in size during pregnancy.^[30] This leads to increased production of T4 and T3 during pregnancy.

Thyroid function tests in pregnancy

TSH concentrations decrease transiently during the first trimester of pregnancy and increase thereafter (without attaining prepregnancy levels), with similar but inverse changes in serum FT4 and FT3.^[31]

Thyroid function tests should be interpreted using population-based, trimester-specific reference ranges for TSH and assay methods and trimester-specific reference ranges for serum free T4. Reference ranges should be defined in healthy TPOAb-negative pregnant women with optimal iodine intake and without thyroid illness.^[8]

A downward shift of both the upper and lower TSH reference ranges is seen in pregnancy, with a lower limit of ∼0.1–0.2 mIU/L and an upper limit of ∼0.5–1.0 mIU/L, with the lowest decrease in the 1^st trimester and then a gradual rise in the 2^nd and 3^rd trimesters, but still below the nonpregnant reference range.^[8] However, the extent of this change varies significantly between different races and ethnic groups. Several reports and guidelines have been published recommending varied TSH cutoffs in different studies. The ATA 2011 guideline followed by the Endocrine Society clinical practice guideline 2012 gave stricter TSH cutoffs of 0.1 −2.5 mIU/L in the first trimester, 0.2−3.0 mIU/L in the second trimester, and 0.3−3 mIU/L in the third trimester.^[13],[32] However, recommendations of using higher cutoff values were also suggested by several systematic reviews and meta-analyses. The 97.5^th percentile of TSH for the first trimester using different analytical methods was found in two groups: According to the Architect, Beckman, and Immulite platforms, it was approximately 3.0 mIU/L, while according to Centaur and Roche, it was close to 4 mIU/L.^[33] Ethnicity may also have a significant effect on TSH and FT4 reference limits in pregnancy. On reviewing the literature, ATA then revised the guidelines in 2017, recommending the upper cutoff limit 0.5 mIU/L less than the preconception TSH value or as 4.0 mIU/L, whereas the local population-specific reference range is not available.^[8] Considering recent international and Indian data, Indian endocrinologists conclude that the recent 2017 recommendation of ATA of a revised URL for TSH of 4.0 mIU/L is high and should instead be 3.0 mIU/L in the first trimester and 3.5 in the second and third trimesters until they are able to generate more nationally representative data for trimester-specific TSH values.^[34] In Bangladesh, representative data on TSH levels in pregnancy are currently lacking. In general, FT4 and FT3 levels increase slightly during the 1^st trimester and subsequently decrease as pregnancy progresses. However, the interpretation of free thyroid hormone levels in pregnancy is more challenging. Most studies reported a progressive decrease in measured free T4 during pregnancy.^{[35],[36],[37]} However, direct free T4 measurements may be unreliable in some patients due to changes in binding proteins during pregnancy. Measurement of free T4 in the dialysate or ultrafiltrate of serum samples using liquid chromatography/tandem mass spectrometry appears to be the most reliable, and when this method is used, free T4 concentrations were shown to decrease modestly with advancing gestational age, particularly between the first and second trimesters.^[38],[39] This assay is relatively expensive and not universally available. Other free T4 assays (and probably free T3 assays) frequently fail to meet performance standards in pregnant patients, owing to increases in TBG and decreases in albumin concentrations that cause the immunoassay to be unreliable.^[36] To compensate, assay kits should provide different free T4 normal ranges for pregnant patients, usually lower than those of nonpregnant patients.^[25] Considering this, all of the guidelines warned against the uncritical use of FT4 results in pregnancy.

Conversely, the measurement of TT4 and the calculated FT4 index (FTI) showed the expected inverse relationship with TSH.^[36] This finding suggests that TT4 measurement may be superior to FT4 measurement in pregnancy. As mentioned before, the TT4 concentration increases from 7 to 16 weeks of gestation, ultimately reaching ∼50% above the prepregnancy level and is then sustained through pregnancy. Therefore, a clinically acceptable upper reference range determination can be calculated by increasing the nonpregnant limit to 50%. However, this limit can only be used after 16 weeks of gestation. If a T4 measurement is required before that time (i. e., 7–16 weeks of pregnancy), a calculation can be made for the upper reference range based on increasing the nonpregnant upper reference limit by 5% per week, beginning at 7 weeks. For example, at 11 weeks of gestation (4 weeks beyond week 7), the upper reference range for T4 is increased by 20% (4 × 5%).^[24]

The ATA recommended the measurement of TT4 and calculation of the FTI as preferable to FT4 immunoassays, although some have argued that this is misguided and regressive. The Endocrine Society guidelines also suggested either FT4 (multiplying the nonpregnant range by 1.5 for the second and third trimesters), whereas the European guidelines recommended either TT4 or FT4 measurement with locally established trimester-specific reference ranges.

Trimester-specific reference ranges for FT4 are not available in our country. TT4 measurements are superior and more reliable than FT4 measurements, especially during the 2^nd and 3^rd trimester of pregnancy.

Section 4.0: Management of hypothyroidism in pregnancy

Primary maternal hypothyroidism is the increase in serum TSH levels above the trimester-specific normal range during pregnancy. Central hypothyroidism (low FT4 but low normal or low TSH) is very rare. Primary hypothyroidism is generally defined as the presence of elevated TSH and decreased serum FT4 concentration during gestation, with both concentrations outside the (trimester-specific) reference ranges. It is important to exclude other causes of abnormal thyroid function, such as TSH-secreting pituitary tumors, thyroid hormone resistance, or central hypothyroidism with biologically inactive TSH.^[7],[40]

When iodine is adequate, the most frequent cause of hypothyroidism is autoimmune thyroid disease (Hashimoto's thyroiditis). Therefore, not surprisingly, thyroid autoantibodies can be detected in approximately 30%–60% of pregnant women with an elevated TSH concentration.^[11]

When available, population- and trimester-specific reference ranges for serum TSH during pregnancy should be established. If pregnancy-specific TSH reference ranges are not available, an upper reference limit of 4.0 mIU/L may be used.^[41]

Overt maternal hypothyroidism has consistently been shown to be associated with an increased risk of adverse pregnancy complications as well as negative effects on fetal neurocognitive development. Specific adverse outcomes associated with overt maternal hypothyroidism include increased risks of premature birth, low birth weight, pregnancy loss, lower offspring IQ, and gestational hypertension.^[6],[10]

Pregnant women with TSH concentrations >2.5 mIU/L should be evaluated for TPOAb status.^[8] SCH in pregnancy should be approached as follows [Table 2]:^{[8],[42],[43]}

Table 2: Recommendation of levothyroxine 4 therapy in women with subclinical hypothyroidism

Click here to view

The oral LT4 is the recommended treatment of maternal hypothyroidism. In parallel to the treatment of hypothyroidism in a general population, it is reasonable to target TSH in the lower half of the trimester-specific reference range. When this is not available, it is reasonable to target maternal TSH concentrations below 2.5 mIU/L.^[44]

Women with overt and SCH (treated or untreated) or those at risk for hypothyroidism (e. g., patients who are euthyroid but TPOAb-or TgAb-positive, post-hemithyroidectomy, or treated with radioactive iodine) should be monitored with a serum TSH measurement approximately every 4 weeks until mid-gestation and at least once near 30 weeks of gestation.^[45]

In hypothyroid women treated with LT4 who are planning pregnancy, serum TSH should be evaluated preconception, and the LT4 dose should be adjusted to achieve a TSH value between the lower reference limit and 2.5 mIU/L. Hypothyroid patients receiving LT4 treatment with a suspected or confirmed pregnancy (e.g., positive home pregnancy test) should urgently notify their caregivers for prompt testing and usually need to increase the dose of LT4 by 20%–30%. Following delivery, thyroid function testing should be performed at approximately 6 weeks postpartum with adjustment of dose if needed.^[46]

Recommendations

All pregnant women should be screened for thyroid disorders by testing serum FT4 and TSH
Maternal hypothyroidism should be treated with oral LT4, and the dose should initially be titrated monthly and thereafter in the 2^nd or 3^rd trimester 2 months later
In Bangladesh, it is reasonable to target maternal TSH concentrations below 2.5 mIU/L as a trimester-specific reference range of TSH is not available here
When the LT4 dose is changed, thyroid function tests (TSH, free T4) should be measured over 30−40 days to evaluate its effects
Once a stable thyroid function level is established, thyroid function tests should be monitored in each trimester.
SCH (TSH is elevated but the free T4 level is within the normal rang e poses an unclear risk for fetal intellectual development. Replacement therapy is recommended in SCH
The LT4 dose may return to the prepregnancy dose after the birth of the baby.

Section-5.0: Hyperthyroidism in pregnancy

The most common cause of hyperthyroidism in women of childbearing age is autoimmune Graves' disease (GD), occurring before pregnancy in 0.4%–1.0% of women and in approximately 0.2% during pregnancy.^[47] It is evident that poorly controlled thyrotoxicosis is associated with adverse maternal and fetal outcomes mostly due to transplancental transfer of thyroid-stimulating antibody, TSH receptor antibodies (TRAb). As placental hCG has a great influence on maternal thyroid hormone synthesis, the assessment and interpretation of thyroid function tests need caution, especially during pregnancy.

Causes of thyrotoxicosis in pregnancy

Gestational transient thyrotoxicosis: More frequent than GD^[8]
GD: Common autoimmune cause
Toxic multinodular goiter (TMG): Nonautoimmune cause, less common than GD
Toxic adenoma: Nonautoimmune cause, less common than TMG
Subacute painful or painless thyroiditis: Less common causes
Overtreatment with or factitious intake of thyroid hormone: A special cause of thyrotoxicosis
Other rare causes:

TSH-secreting pituitary adenoma^[48]
Struma ovarii^[49]
hCG-induced thyrotoxicosis includes multiple gestation
hydatidiform mole and choriocarcinoma^[50],[51]
Functional thyroid cancer metastases or germline TSH receptor mutations^[52]
A TSH receptor mutation leading to functional hypersensitivity to hCG.^[53]

Maternal and fetal outcomes

Maternal outcome

Poorly controlled thyrotoxicosis may result in pregnancy-induced hypertension, thyroid storms, maternal congestive heart failure, arrhythmias, and others.^[54]

Fetal outcome

Regarding thyroid health, fetal risks in women with previous or current Graves' hyperthyroidism include (a) fetal hyperthyroidism, (b) neonatal hyperthyroidism, (c) fetal hypothyroidism, (d) neonatal hypothyroidism, and (e) central hypothyroidism. The above potential complications depend on several factors: (a) poor control of hyperthyroidism throughout pregnancy may induce transient central hypothyroidism,^[55],[56] (b) excessive amounts of ATDs may be responsible for fetal and neonatal hypothyroidism,^[57] and (c) high levels of thyroid-stimulating antibodies in the second half of pregnancy may induce fetal and neonatal hyperthyroidism.^{[58],[59],[60],[61]} However, if not properly addressed, hyperthroidism and/or thyrotoxicosis may lead to intrauterine growth retardation, low birth weight, prematurity, stillbirth, and pregnancy loss. Even it influences the later life of a neonate and may cause seizure disorders and neurobehavioral disorders^[61]

Evaluation of Thyroid Function in Pregnancy for Hyperthyroidism

The TSH value should be evaluated in conjunction with either TT4 and/or TT3. The TT4 and TT3 reference values should be adjusted to 1.5 times the nonpregnant range or FT4 trimester-specific normal reference ranges (if available)^[8],[62]
When a suppressed serum TSH is detected in the first trimester (less than the reference range), a medical history, physical examination, and assay of maternal serum FT4 or TT4 should be performed. If available, measurement of TRAb and maternal TT3 may be helpful in clarifying the etiology of thyrotoxicosis
Radionuclide scintigraphy or radioiodine uptake determination should not be performed in pregnancy unless it outweighed the benefits
Overt hyperthyroidism is confirmed in the presence of a suppressed or undetectable serum TSH and elevated serum TT4/FT4 or TT3.

Management of different hyperthyroid conditions

Gestational transient thyrotoxicosis (GTT)

In early pregnancy, the differential diagnosis in the majority of cases is between Graves' hyperthyroidism and GTT.^[63],[64] GTT is characterized by elevated FT4 and suppressed serum TSH and is found in approximately 1%–3% of pregnancies.^[8] The frequency of GTT depends on the geographic area and is secondary to elevated hCG levels in the 1^st half of pregnancy.^[63],[64] It is often associated with hyperemesis gravidarum, which manifests as severe nausea and vomiting that results in weight loss, dehydration, and ketonuria in early pregnancy. Findings with no prior history of thyroid disease, no stigmata of GD (goiter and orbitopathy), self-limited mild disorder, and symptoms of emesis favor the diagnosis of GTT. Serum hCG is higher on average in GTT than in patients with GD, but overlap is considerable.^[65] No study has demonstrated the usefulness of thyroid ultrasonography for differentiating between GTT and GD. The management depends on the severity of symptoms. ATDs are not indicated. Serum T4 returns to normal by 14–18 weeks gestation, whereas the hCG level decreases. Supportive treatment, such as control of vomiting by antiemetics and treatment of dehydration with intravenous fluids and monitoring of electrolyte abnormalities, is the mainstay. In some cases, hospitalization is needed. Beta-blockers can be considered over a limited time period (propranolol or metoprolol). Follow-up should be performed with repeat investigation.^[8]

Management of Graves' hyperthyroidism during pregnancy

Thionamide ATDs (MMI, carbimazole [CM], and PTU) are the mainstays of treatment for hyperthyroidism during pregnancy. The initial dose of ATD depends on the severity of the symptoms and the degree of hyperthyroxinemia.^[8]

Initial doses of antithyroid drugs used during pregnancy in Graves' disease

CM, 10–40 mg/d^[8],[62]
MMI, 5–30 mg/d (typical dose in average patient 10–20 mg)^[8],[62]
PTU, 100–600 mg/d (typical PTU dose in average patient 200–400 mg/d)^{[8],[62],[66]}
The equivalent potency of CM to PTU is approximately 1:12.^[67],[68] The half-life of PTU is shorter than that of CM, so PTU dosing should generally be split into two or three daily doses. CM/MMI can generally be given in a once daily dose. In cases of severe hyperthyroidism, twice or three times daily dosing may be of benefit^[69],[70]

Adverse side effects of antithyroid drugs

Minor allergic reactions such as skin rash (3%–5%)^[71]
Rare but severe effects are agranulocytosis (0.15%)^[72],[73] and liver failure.
Most side effects develop within the 1^st months following initiation^[71] or reinitiation of therapy^[74]
Hepatotoxicity develops in patients exposed to PTU,^[75],[76] souse of PTU to the first trimester of pregnancy^[77]
Monitoring hepatic enzymes during the administration of PTU may be considered.

Potential teratogenic effects of antithyroid drugs

CM/MMI has been associated with aplasia cutis,^[78] dysmorphic facies,^[79] choanal or esophageal atresia; various types of abdominal wall defects, including umbilicocele; and eye, urinary system, and ventricular septal defects.^{[80],[81],[82]} PTU-associated birth defects, such as face and neck cysts and urinary tract abnormalities, appear less severe than CM/MMI-associated birth defects but occur with similar incidence.^[8]

Antithyroid drugs options during different trimesters

Many patients receiving ATD therapy for GD become euthyroid and gradually enter the remission stage. When ATDs are withdrawn, patients may relapse. There is a varied risk of rapid relapse of hyperthyroidism after medication withdrawal in early pregnancy in different patients. An approach is that when pregnancy is diagnosed in a woman with GD receiving a low dose of ATD (CM/MMI (5 mg) or PTU (100–200 mg/d) and clinical and biochemical findings appear to be in remission, the approach is to consider the withdrawal of all ATD medications and to repeat thyroid function testing. Cessation of medication must be recommended early in gestation (6–10 weeks) when organogenesis occurs to prevent teratogenicity. After stopping the medications, maternal thyroid function testing (TSH and FT4 or TT4) and clinical examination should be performed every 1–2 weeks during the first trimester and every 2–4 weeks during the second and third trimesters. At each assessment, the decision to continue conservative management (withholding antithyroid medication) should be guided both by the clinical and the biochemical assessment of maternal thyroid status.^[8] The risk of rapid relapse after medication withdrawal in early pregnancy is higher in patients treated for a shorter duration (<6 months), those who had suppressed or low serum TSH at prepregnancy and those who were on >5–10 mg of MMI per day to stay euthyroid, those who had active orbitopathy or large goiter, and those who had high levels of TRAb^[83]
In high-risk cases, medication should not be withdrawn, and PTU should be administered as drug of choice and at 1^st trimester. From 16 weeks of pregnancy, PTU is recommended. Pregnant women receiving CM/MMI ideally should be switched to PTU as early as possible. CM/MMI may also be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU or has known hypersensitivity. Patients started on propylthiouracil during the first trimester be switched to CM/methimazole at the beginning of the second trimester. When needed, beta-adrenergic blockers should be used for a limited period (∼2–6 weeks)
A combination regimen of LT4 and an ATD should not be used in pregnancy, except in the rare situation of isolated fetal hyperthyroidism caused by maternal TRAb production who previously received ablative therapy for GD.^[84],[85] The ATD will pass the placenta and treat fetal hyperthyroidism, whereas TT4 is necessary to keep the mother euthyroid.^[8]

Principles of thyroid testing and monitoring antithyroid drugs therapy during pregnancy

Thyroid-stimulating antibodies, ATDs and most maternal thyroid hormones effectively cross the placenta and modulate fetal thyroid function. All the ATDs are more potent in the fetus than in the mother. Thus, when the mother is made euthyroid, the fetus is often overtreated.^[86] To avoid this, the aim is to maintain maternal TT4/FT4 and TT3 values at or just above the pregnancy-specific upper limit of normal with the smallest possible dose of ATDs.^[8] Maternal TT4/FT4 and TSH (in cases of severe hyperthyroidism, also serum TT3/FT3) should be measured every 2-4 weeks following initiation of therapy and every 4-6 weeks after achieving the target level.^{[87],[88],[89]}

If trimester-specific FT4 values are not available, use of the reference range for nonpregnant patients is recommended, or TT4 measurement with a reference value 1.5 times the nonpregnancy range may be used during the second and third trimesters.^[8],[62]

Discontinuation of ATD therapy is feasible in 20%–30% of patients in the last trimester of gestation. The disappearance of maternal TRAb in late pregnancy indicates a high likelihood of successful ATD withdrawal.^[13] Maternal serum TSH well within the reference range is a sign that the ATD dose has to be reduced to avoid fetal overtreatment.^[8] Sometimes, in GD, serum TT3 may remain elevated even if TT4/FT4 becomes normal or even low.^[40] An increase in ATD dose to normalize maternal serum TT3 will cause elevated serum TSH in infants at birth; therefore, a balance in ATD dosing with careful clinical evaluation of the fetus and the mother is needed.^[88]

Thyroidectomy during pregnancy

Subtotal thyroidectomy may be indicated during pregnancy as therapy for maternal GD if (1) a patient has a severe adverse reaction or contraindication to ATD therapy; (2) persistently high doses of ATD are required (over 30 mg/d of MMI or 50 mg/d CM or 450 mg/d of PTU); or (3) a patient is nonadherent to ATD therapy and has uncontrolled hyperthyroidism.^[62] The optimal timing of surgery is in the second trimester.^[62] Preoperative preparation for thyroidectomy during the second trimester of pregnancy includes 10–14 days of iodine, along with ATD therapy and beta-blockers to control hyperthyroidism.^{[90],[91],[92]}

TRAb measurement of a pregnant woman with Graves' hyperthyroidism

TRAb is measurable in approximately 95% of patients with active Graves' hyperthyroidism, and levels may remain high following ablation therapy. High levels of thyroid-stimulating antibodies in the second half of pregnancy may induce fetal and neonatal hyperthyroidism. A value >5 mIU/L or 3 times the upper normal limit of normal in the mother is an indication for establishing close follow-up of the fetus.^[93]

Fetal monitoring in women with Graves' hyperthyroidism

Fetal well-being may be compromised in the presence of elevated TRAb, uncontrolled hyperthyroidism, and preeclampsia.^[94],[95] Ultrasonographic surveillance should be performed in women with uncontrolled hyperthyroidism in the second half of pregnancy or with high TRAb levels detected at any time during pregnancy (greater than 3 times the upper limit of normal).^[8] Ultrasonography can detect signs of potential fetal hyperthyroidism i.e., fetal tachycardia (heart rate >170 bpm, persistent for over 10 min), intrauterine growth restriction, presence of fetal goiter (the earliest sonographic sign), accelerated bone maturation, signs of congestive heart failure, and fetal hydrops.^[95] It is rational to evaluate all the newborns of mothers with GD (except those with negative TRAb and not requiring ATD) by medical care provider for thyroid dysfunction and treated if necessary.^[62]

Hyperthyroidism caused by autonomous thyroid nodule(s) in pregnancy

Autonomous nodules causing hyperthyroidism develop insidiously and are usually less severe than in GD. ATDs should be kept at a low dose with the goal of maternal FT4 or TT4 concentration at the upper limit or moderately above the reference range. Surgical removal of autonomous nodule (s) should be considered if signs of fetal hypothyroidism develop. In general, surgical removal should be considered before conception in women with hyperthyroidism seeking future pregnancy.^[62]

Subclinical hyperthyroidism

There is no evidence that the treatment of this condition improves pregnancy outcome. Rather, treatment can adversely affect fetal outcome.^[62],[96]

Antithyroid drugs during lactation

A small but detectable amount of both PTU and CM/MMI are transferred into breast milk. Due to potential for hepatic necrosis in either mother or child from maternal use (maximum 450 mg/day), carbimazole (CM) (up to 20 mg/day) is the preferred ATD in nursing mothers.^[97]

Recommendations

The TSH value should be evaluated in conjunction with TT4 and TT3. The TT4 and TT3 reference values should be adjusted at 1.5 times the nonpregnant range or FT4 trimester-specific normal reference ranges (if available)
Overt hyperthyroidism needs to be confirmed against the light of the presence of suppressed or undetectable serum TSH and inappropriately elevated serum TT4/FT4 or TT3 levels
The use of the antithyroid medications carbimazole/methimazole and propylthiouracil requires trimester-specific consideration, and before prescription, appropriate justification and counseling are required about potential teratogenic effects
ATDs should be avoided in the first trimester of pregnancy, but when necessary, PTU is generally favored, but it should be outweighed in light of benefits rather than harm
Subtotal thyroidectomy is recommended based upon best judgment, and it should be performed during the second trimester
All newborns of mothers with GD (except those with negative TRAb and not requiring ATD) should be evaluated for thyroid dysfunction and treated if necessary

Section-6.0 management of thyroid nodule in pregnancy

The prevalence of thyroid nodules in pregnancy is 3%–21% and increases with increasing parity.^{[98],[99],[100]} Throughout the pregnancy period, nodules tend to increase in volume and number, and there is a chance of developing increasing nodular seizures with increasing maternal age.^{[98],[99],[100],[101],[102],[103]}

Evaluation of a pregnant woman with thyroid nodules

History

Family history of thyroid disorder, including medullary thyroid carcinoma, multiple endocrine neoplasis - 2, etc.^{[104],[105],[106],[107],[108]}
History of childhood cancers
Childhood exposure to ionizing radiation involving the head and neck

Physical examination

Physical examination should be performed by a competent physician, especially focusing on the area of T in the thyroid and neck region. The physician will exclude all the possibilities that may cause nodules. The cervical lymph nodes and other lymphatics should be identified to rule out any cancer or differentials.^[109]

Ultrasound

Thyroid ultrasound should be performed in all patients with thyroid nodules to determine their sonographic features and pattern, monitor growth, and evaluate cervical lymph nodes.^[8]

Thyroid function tests

Thyroid function test (TFT) should be tested in all pregnant women with a thyroid nodule.^[110],[111]

Fine-needle aspiration cytology

FNAC from a suspicious nodule is safe in pregnancy and may be performed at any trimester^{[112],[113],[114],[115],[116],[117],[118],[119],[120]} and is usually recommended for newly detected nodules in pregnant women with a nonsuppressed TSH. Indications of FNAC are based upon the nodule's sonographic pattern, as outlined in [Table 3].^[8]

Table 3: Ultrasound patterns and recommendations for fine-needle aspiration cytology for a thyroid nodule^[8]

Click here to view

For women with suppressed serum TSH levels persisting after 16 weeks gestation, FNAC of a clinically relevant thyroid nodule may be deferred until after pregnancy.^[8]

Radionuclide scanning

Iodine 131 and technetium pertechnetate scanning are contraindicated in pregnancy because all maternal radionuclides are associated with fetal irradiation resulting from both placental transfer and external irradiation from maternal organs.^[121]

Management of thyroid nodules

Thyroid nodules are usually benign in nature unless proven otherwise. Esthetic problems could be a concern for women, and some are suggesting the use of LT4 as a suppressive agent. However, LT4 treatment is not effective in decreasing the size or arresting the growth of thyroid nodules in pregnancy. Therefore, suppressive therapy by LT4 for thyroid nodules is not recommended during pregnancy.^[8]

Benign nodules

Nodules that were benign on FNA but showed rapid growth or ultrasound changes suspicious for malignancy should be evaluated with a repeat FNA and considered for surgical intervention. In the absence of rapid growth, nodules with biopsies that are benign are advised to wait up to the completion of the pregnancy.^[122] Even no special surveillance strategies will be suggested in pregnancy when there is a lack of evidence of malignancy in FNA.^[8] Thus, in instances in which surgery during pregnancy is indicated or desired, it should be performed in the second trimester to minimize the complications to both the mother and fetus. Surgery in the first trimester may alter organogenesis and spontaneous abortion, while surgery in the third trimester may induce preterm labor. In almost all cases, it is recommended to consult with experienced thyroid surgeons for this kind of intervention.^[123] With all protective measures taken, the risk of postthyroidectomy maternal hypothyroidism and hypoparathyroidism still cannot be ruled out, and patients should be counselled appropriately.

Atypia of undetermined significance/follicular lesion of undetermined significance, suspicious for follicular neoplasm

The chances of malignancy associated with these cytological diagnoses are variable (6%–48% for atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS], 14%–34% for suspicious for follicular neoplasm [SFN], and 53-87% for SUSP).^[124] As the prognosis for differentiated thyroid cancer (DTC) diagnosed during pregnancy is not adversely affected by performing surgery postpartum, it is reasonable to defer surgery until subsequent delivery. LT4 suppressive therapy during pregnancy is not recommended, as the majority of these women will have benign nodules. If there is clinical suspicion of aggressive behavior in cytologically indeterminate nodules, surgery may be performed in the second trimester of pregnancy. Nonetheless, molecular testing is not recommended for this type of nodule in current pregnancy.^[8]

Thyroid carcinoma

Papillary thyroid carcinoma (PTC), if detected in early pregnancy should be monitored sonographically. If it grows substantially earlier than 24–26 weeks of gestation or if cytologically malignant cervical lymph nodes are present, surgery should be considered during pregnancy. However, if the disease remains stable by mid-gestation or if it is diagnosed in the second half of pregnancy, surgery may be deferred until after delivery.^[8]

The impact of pregnancy on women with newly diagnosed medullary carcinoma or anaplastic cancer is unknown. A delay in treatment is likely to adversely affect outcome; therefore, surgery should be strongly advised after confirmation of the diagnosis and assessment of all clinical factors.^[8]

Based on studies that have demonstrated a lack of maternal or neonatal complications from subclinical hyperthyroidism, it is reasonable to assume that the preconception degree of TSH suppression can be safely maintained throughout pregnancy. The appropriate level of TSH suppression depends upon the preconception risk of residual or recurrent disease. Hence, for a patient at an initial high risk for recurrence, TSH suppression at or below 0.1 mU/L is recommended. If the patient then demonstrates an excellent response to therapy at 1 year with undetectable suppressed serum Tg and negative imaging, the TSH target may rise to the lower half of the reference range.^[8]

Thyroid function should be evaluated as soon as pregnancy is confirmed. The adequacy of LT4 treatment should be checked 4 weeks after any LT4 dose change. Assays from the same laboratory should be used to monitor TSH and Tg levels before, during, and after pregnancy. Pregnant women with thyroid cancer should be managed at the same TSH goal as determined in the preconception periods. TSH should be monitored every 4 weeks until 16 − 20 weeks of gestation and at least once between 26 and 32 weeks of gestation.^[8]

Papillary thyroid microcarcinoma

Ultrasound monitoring of the maternal thyroid should be performed each trimester during pregnancy in women diagnosed with papillary thyroid microcarcinoma who are under active surveillance.^[8]

Pregnant women with previously treated differentiated

thyroid cancer (DTC)

Ultrasound and Tg monitoring during pregnancy is not required in women with a history of previously treated differentiated thyroid cancer (DTC) with undetectable serum Tg levels (in the absence of Tg autoantibodies) classified as having no biochemical or structural evidence of disease prior to pregnancy. Ultrasound and Tg monitoring should be performed during pregnancy in women diagnosed with well-differentiated thyroid cancer and a biochemically or structurally incomplete response to therapy or in patients known to have active recurrent or residual disease.^[8]

Recommendations

Diagnostic work should be performed immediately in women who present with thyroid nodules irrespective of the clinical symptoms
In pregnant women with thyroid nodules and suppressed TSH levels beyond 16 weeks gestation, FNAC can be deferred until after pregnancy
Newly detected thyroid nodules with nonsuppressed TSH levels required FNAC to confirm the diagnosis
Radionuclide scanning or radioiodine uptake determination are contraindicated during pregnancy
Routine surgery is not recommended for women presenting cytologically indeterminate (AUS/FLUS, SFN, or SUSP) over the period of pregnancy. Surgery could be advised if the nodule was found to be clinically aggressive
PTC detected in early pregnancy should be monitored by ultrasound. No surgery is recommended up to the completion of the pregnancy. Immediate surgery should be advised if the tumor grows substantially earlier the second trimester or in the presence of malignant cervical lymph nodes
The TSH goal for pregnant women with thyroid cancer is the same as the preconception DTC goals.

Section-7.0: Thyroid emergencies during pregnancy

Treatment of overt maternal hyperthyroidism and OH clearly improves obstetric and fetal outcomes. These endocrine conditions can turn into an emergency if left ignored or untreated. This includes thyroid storm and myxedema coma. Management of these emergencies is crucial and requires prompt action to save both the mother and fetus. Myxedema coma and thyroid storm are multifaceted and should be managed by the interdisciplinary team approach in an intensive care unit (ICU) setup with special care.

Thyrotoxic crisis (thyroid storm)

Thyroid storms are a rare but serious complication in hyperthyroidism patients and account for 1%–2% of cases of hyperthyroidism.^[126] In pregnancy, it also risks both the mother and fetus and almost always causes adverse outcomes.^[133],[134] Very often, it results from patients with inadequately treated or undiagnosed hyperthyroidism. Labor and delivery stress, surgical intervention, infection or trauma also act as precipitating factors for these life-threatening conditions. During pregnancy, it is an endocrine emergency characterized by an extreme hypermetabolic state and is associated with a high risk of maternal heart failure and a cause of nonobstetric maternal death. As many as, 20%–30% of cases can result in maternal and fetal mortality.^[127]

Diagnosis is based on a combination of signs and symptoms: fever, tachycardia (out of proportion to the fever), altered mental status (nervousness, restlessness, confusion, and seizures), vomiting, and diarrhea. Life-threatening cardiac arrhythmia often identified may cause death.^[128] An inciting event (e.g., surgery, infection, labor, and delivery) may be identified. Untreated thyroid storms can result in shock, stupor, and coma. Serum-free triiodothyronine (FT₃), FT₄, and TSH levels help confirm the diagnosis, but the universal recommendation is that treatment should not be delayed for test results even in pregnancy.

Mainstays of thyroid storm management in pregnancy are (i) reducing the synthesis and secretion of thyroid hormones by using propylthiouracil or methimazole or carbimazole and/or a saturated solution of potassium iodide or sodium iodide, (ii) decreasing the peripheral effects of thyroid hormone by inhibiting the conversion of T4 to T3 using dexamethasone and phenobarbital, and (iii) general supportive measures, such as oxygen, antipyretics, and appropriate monitoring. The underlying cause or precipitating factors of thyroid storms need to be evaluated carefully, and treatment should be commenced immediately. Other management includes therapy directed to prevent systemic decompensation, trigger disease therapy, pregnancy management, and supportive therapy.^[129] In addition, depending on gestational age, fetal status should be evaluated with ultrasound examination, nonstress testing, or a biophysical profile. Unless at term or at necessity, delivery or any intervention during thyroid storm should be avoided.

The immediate treatment of heart failure and the correction of precipitating pregnancy factors usually result in good outcomes. Data regarding long-term follow-up suggest that thyrotoxic cardiac dysfunction is usually reversible with successful antithyroid therapy.^[130]

Myxedema coma

Myxedema coma is an extreme complication of uncontrolled hypothyroidism. It is usually seen in elderly women with undiagnosed hypothyroidism and is rare among young women. It is very rare among pregnant women, with <40 cases having been reported yet.^[131] It is a potentially fatal complication of uncontrolled hypothyroidism characterized by progressive mental deterioration, such as lethargy, stupor, delirium, or coma, along with multiple organ abnormalities. The diagnosis was delayed due to its insidious nature of onset. Several precipitating factors for example, infection, illness, drugs, labor, and delivery may incite the disease process and weaken compensatory responses. The prognosis of patients with myxedema coma is difficult to determine. However, poor predictors of outcome, as reported in the literature, were bradycardia, persistent hypothermia, altered level of consciousness, a high APACHE II score at presentation, hypotension and requirement of mechanical ventilation. Despite appropriate treatment, mortality ranges between 30% and 50%, more so in pregnancy.

Aggressive replacement of thyroid hormone in hypothyroid pregnant women is recommended regardless of the degree of thyroid function to minimize the time the fetus is exposed to a hypothyroid environment.^[132] Pregnancy itself and poor compliance with treatment are the most frequent causes of a lack of response to oral thyroid supplementation.^[133] Concurrent use of other chelating drugs, such as antacids, sucralfate, antiepiletics, calcium carbonate, and dietary interference, may cause a lack of availability of the required dose of thyroxine in the blood.^[134]

Thyroid hormone therapy is the cornerstone of management of patients with myxedema coma in pregnancy.^[135] Both oral and intravenous T4 and T3 could be used based in availability. If an injectable preparation is not available, oral administration of thyroxine through Ryle's tube may be an alternative. The major criticism against nasogastric administration is gastric atony that may prevent absorption and increase the chance of aspiration. The treatment of myxedema coma depends upon not only replacement of thyroid hormone but also supportive care and identification of coexistent illness and their treatment.

Recommendations

Thyroid emergencies in the form of thyrotoxic crisis and myxedema coma should be assessed immediately and should be managed promptly without any delay
Thyroid emergencies in pregnancy should be managed in the ICU with the greatest care and caution
A multidisciplinary team approach is required to manage the patients and to save the lives for both the mother and fetus

Section 8.0: Postpartum issues

The endocrinology of puerperium includes physiological and anatomical adjustments to expulsion of the feto-placental unit and onset of lactation.^[136] The common thyroid disorders in the postpartum period are GD and postpartum thyroiditis.^[137] There is also the issue of the impact of thyroid dysfunction, its diagnosis and treatment during lactation. All of the topics are discussed here briefly.

Postpartum thyroiditis

Postpartum thyroiditis occurs within 1 year after delivery in women who were previously euthyroid.^[138] The prevalence of postpartum thyroiditis is approximately 5% and is higher in women with autoimmune disorders.^[139] It can be followed after spontaneous or induced abortion. The classical course is transient hyperthyroidism, which usually begins 2−6 months after delivery and lasts 2–8 weeks, followed by hypothyroidism, which typically begins 3−12 months after delivery and then recovers (within 1 year postpartum). Only 20%–30% of women present with the classical course, 25% present with only thyrotoxicosis, and 50% present with hypothyroidism. Complete recovery is usual; however, 10%–20% becomes permanently hypothyroid.^[140]

The thyrotoxic phase may be asymptomatic or present with features of mild toxicosis. Investigations showed increased FT4>FT3, low TSH, and low radioiodine uptake.^{[140],[141],[142],[143]} It is important to differentiate this phase from GD [Table 4]. The hypothyroid phase presents with typical features of hypothyroidism and diffuse and painless goiter. It is often confused with postpartum depression. A thyroid hormone assay revealed low FT4 and elevated TSH. Anti-thyroid peroxidase antibody is usually present with high titers.^[142],[143] Treatment of thyrotoxicosis is not required for asymptomatic women. Monitoring of thyroid function is recommended every 4 − 8 weeks. Symptomatic women should be prescribed propranolol 40 − 120 mg daily in three divided doses until FT3 and FT4 are normal. Propranolol has the lowest concentration in breast milk. A total of 25–50 mg daily atenolol or metoprolol can also be given. The lowest possible dose to alleviate symptoms should be used based on dose titration. ATDs are not recommended.^[144] In the case of hypothyroidism, treatment is unnecessary for asymptomatic women with TSH below 10 mU/L unless they are planning another pregnancy soon. Thyroid function should be monitored until it normalizes. Thyroxine supplementation is recommended for asymptomatic women with TSH above 10 mU/L and for symptomatic women. Thyroxine supplementation should be given at a dose of 1.7 mcg/kg/day to normalize TSH levels for 6–12 months. After 6–12 months, the dose should be reduced to half and reassessed after 6 weeks. If there is no abnormality of thyroid function, then thyroxin can be stopped and reassessed in another 6 weeks. Thyroxin should be continued if test results are beyond the normal range. In women with very elevated initial TSH values (>50 or 100 mU/L) and high antibody titers, thyroid hormone should be continued indefinitely. Thyroxine should not be stopped if the woman is pregnant, attempting pregnancy, or breastfeeding. For women who have fully recovered from postpartum thyroiditis, TSH should be measured annually, particularly within 5−10 years after the initial diagnosis.^[8]

Table 4: Indications for surgery of a thyroid nodule in the second trimester of pregnancy^[125]

Click here to view

Graves' disease in the postpartum period

GD is another common thyroid disorder in pregnancy. It can be a disease of new onset, relapse, or continuation of an ongoing disease. Patients may present with features of toxicosis. There may be diffuse goiter with bruit and other pathognomic signs of GD, such as ophthalmopathy. Elevated FT3>FT4, TSH low, and TSH receptor antibodies are usually present, and radioactive iodine uptake is high in scintigraphy.^[144]

Treatment consists of antithyroid medications. Low to moderate doses of either carbimazole (up to 30 mg/d) or propylthiouracil (up to 450 mg/d) can be given, as both are safe in breastfeeding.^[71] The drugs should be taken in divided doses following a feed. Since small amounts of both drugs are secreted in breast milk, the lowest possible dose should be given. When the maternal dose of carbimazole is >30 mg daily, infants should undergo thyroid function assays at 1 and 3 months.^[8] Although carbimazole is secreted at higher levels in breast milk than propylthiouracil,^[145] the former is preferred, as propylthiouracil is associated with a higher incidence of hepatotoxicity.^[25] In addition, there was no difference in the thyroid function of breastfed infants.^[145] Propranolol can also be given with carbimazole, if necessary.^[8]

Women with ongoing GD have an increased likelihood of worsening symptoms in the postpartum period. Therefore, FT4 and TSH should be measured 6 weeks from the date of delivery. If thyroid function tests are abnormal, the dose of carbimazole should be adjusted, and thyroid function should be reviewed after 6 weeks.^[146] Based on a normal level of thyroid hormone, the test can be repeated every 4 months. Women with GD who are in remission have an increased risk of relapse during this period, especially 4 − 8 months after delivery. Therefore, thyroid function (FT3, FT4, and TSH) should be monitored [Table 5].^[147]

Table 5: Features differentiating the thyrotoxic phase of postpartum thyroiditis from Grave's disease^[25],[144]

Click here to view

Lactation and thyroid dysfunction

Hypothyroidism can impair lactation,^[148] and treating this condition has been shown to improve lactation.^[149] Therefore, both subclinical and OH should be treated in lactating women.^[8] Moreover, women with poor lactation and no other cause should be screened for hypothyroidism.^[8] The effect of hyperthyroidism on lactation is not clear. Therefore, there is no recommendation suggesting treating hyperthyroidism for the sole purpose of improving lactation.^[8]

Lactation and radiopharmaceuticals

Diagnostic tests as well as therapy with ¹³¹I are contraindicated during lactation, as it has a long half-life and may result in fetal hypothyroidism. If absolutely necessary, ¹²³I and Tc-99 m pertechnetate can be used for the diagnosis. However, breastfeeding should be avoided, and breast milk should be pumped and discarded for 3 − 4 days after testing with ¹²³I and 1 day after Tc-99 m pertechnetate.^[150]

Recommendations

It is important to differentiate between postpartum thyroiditis and GD in the puerperium
Thyroiditis should not be treated with ATDs. Patients should be managed by symptomatic treatment only
The lowest possible dose of ATDs should be used in the treatment of GD in a lactating mother
Radioactive iodine is contraindicated for therapeutic purposes during lactation. Its use should be limited only to diagnosis if benefits can be revealed more than foreseen danger.

Availability of data and materials

Patient-level data will be available on request from the corresponding author.

Acknowledgments

The authors would like to express their sincere gratitude to Pi Research Consultancy Center, Dhaka, Bangladesh (www.pircc.org) for their help in manuscript revision and editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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