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What is new?

What is new?. In 2011, the American Thyroid Association (ATA) first published guidelines on the diagnosis and management of thyroid disease during pregnancy and postpartum. ATA 2011 Recommendations:76 ATA 2017 Recommendations:97.

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What is new?

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  1. What is new?

  2. In 2011, the American Thyroid Association (ATA) first published guidelines on the diagnosis and management of thyroid disease during pregnancy and postpartum. ATA 2011 Recommendations:76 ATA 2017 Recommendations:97

  3. In addition to evidence-based updates of traditional content areas, the task force also sought to expand the prior document to address topics such as thyroid disease during lactation, the treatment of thyroid illness in infertile women and those undergoing assisted reproductive techniques (ART), as well as the approach to thyroid disease in the newborn.

  4. III. Thyroid Function Testing and Pregnancy

  5. THYROID FUNCTION TESTS DURING PREGNANCY • The reference ranges for the most widely applied tests, TSH and FT4, may vary significantly in different populations. • TSH below the nonpregnant lower limit of 0.4 mU/L is observed in as many as 15% of healthy women during 1th trimester of pregnancy. • The fraction of women with a suppressed TSH falls to about 10% in the second trimester, and 5% in the third trimester

  6. Measurement of free T4 (FT4) concentration by automated immunoassays results in a significant and assay dependent reduction in the measured serum FT4 concentrations in 3th trimester. • FT4 automated immunoassays, are complicated in pregnant women by the increase in TBG and decrease in albumin concentrations. • Other methods of direct measurement, such as measurement by equilibrium dialysis, ultrafiltration, or liquid chromatography/tandem mass spectrometry (LC/MS/MS), are less influenced by the pregnancy-associated changes in serum proteins, but are significantly more expensive and less widely available.

  7. Recommendation 1 When possible, population-based trimester-specific reference ranges for serum TSH should be defined through assessment of local population data representative of a healthcare provider’s practice. Reference range determinations should only include pregnant women with no known thyroid disease, optimal iodine intake, and negative TPOAb status. (Strong recommendation, Moderate quality evidence)

  8. NL RANGE FOR TSH IN EACH TRIMESTER • Although the downward shift in TSH reference ranges is seen in essentially all populations, the extent of this reduction varies significantly between different racial and ethnic groups. • Serum TSH reference range determinations should take into account iodine intake, TPO positivity, and according to some studies, body mass index (BMI).

  9. J ClinEndocrinolMetab 2014 • Design: We screened 4800 pregnant women in the first trimester and 2000 women who planned to become pregnant and evaluated 535 pregnant women in follow-up visits during the second and third trimester. • Results: Median concentrations of serum TSH decreased significantly from the seventh week of gestation. The median of TSH from 4 to 6 weeks was significantly higher than from 7 to 12 weeks (2.15 [0.56 –5.31] mIU/L vs 1.47 [0.10–4.34] mIU/L, P .001). The median of free T4 was not significantly altered in the first trimester. The prevalence of subclinical hypothyroidism in the 4800 pregnant women was 27.8% on the diagnostic criteria of TSH 2.5 mIU/L and 4.0% using the reference interval derived by our laboratory (0.14–4.87 mIU/L).

  10. Journal of Thyroid Research 2013 • Methods. The serum of 215 cases was analyzed for measurement of thyroid function tests by immunoassay method of which 152 iodine-sufficient pregnant women without thyroid autoantibodies and history of thyroid disorder or goiter were selected for final analysis. Reference intervals were defined as 5th and 95th percentiles. • Results. Reference intervals in the first, second, and third trimesters were as follows: TSH (0.2–3.9, 0.5–4.1, and 0.6–4.1 mIU/l), TT4 (8.2–18.5, 10.1–20.6, and 9–19.4 𝜇g/dl), and TT3 (137.8–278.3, 154.8–327.6, and 137–323.6 ng/dl), respectively

  11. Table 4.

  12. Recommendation 2 The accuracy of serum Free T4 measurement by the indirect analog immunoassays is influenced by pregnancy and also varies significantly by manufacturer. If measured in pregnant women, assay method-specific and trimester-specific pregnancy reference ranges should be applied. (Strong recommendation, Moderate quality evidence)

  13. Recommendation 3 In lieu of measuring freeT4, total T4 measurement (with a pregnancy-adjusted reference range), is a highly reliable means of estimating hormone concentration during the last part of pregnancy. Accurate estimation of the free T4 concentrations can also be done by calculating a free thyroxine index. (Strong recommendation, Moderate quality evidence)

  14. RECOMMENDATION 3 The optimal method to assess serum FT4 during pregnancy is measurement of T4 in the dialysate or ultrafiltrateof serum samples employing on-line extraction/liquid chromatography/tandem mass spectrometry (LC/MS/MS). Level A-USPSTF • RECOMMENDATION 4 If FT4 measurement by LC/MS/MS is not available, clinicians should use whichever measure or estimate of FT4 is available in their laboratory, being aware of the limitations of each method. Serum TSH is a more accurate indication of thyroid status in pregnancy than any of these alternative methods. Level A-USPSTF

  15. OPTIMAL METHOD TO ASSESS T4 CONCENTRATION • Serum total T4 concentrations are measured in the nanomolarrange,whileFT4 concentrations are measured in the picomolarrange. • Indirect analog immunoassays is prone to inaccuracy in the setting of pregnancy because of disruption of the original equilibrium – a process dependent upon dilution, temperature, buffer composition, affinity, and the concentration of the T4 antibody reagent and the T4-binding capacity within the serum sample.

  16. TT4 measurements may be superior to immunoassay measurement of FT4 measurements in pregnant women. • Reference values should take the 50% increase in TBG witnessed during pregnancy by calculating the FT4 index using a serum thyroid hormone uptake test into account. • An increase in total T4 concentration from weeks 7-16 of gestation is seen, ultimately reaching ~50% above the prepregnancy level and then sustained through pregnancy.

  17. If a T4 measurement is required before weeks 7-16 of pregnancy,acalculation can be made for the upper reference range based on increasing the non-pregnant upper reference limit by 5% per week, beginning with week 7.(For example, at 11 weeks of gestation (4 weeks beyond week 7), the upper reference range for T4 is increased by 20%)

  18. We have demonstrated that the measurement of free thyroxine by 2 different immunoassays did not reflect the expected physiological hCG mediated rise in the first trimester. In addition, the expected return to nonpregnant concentrations in the second and third trimesters was not seen. Instead, a continued decline in FT4 was identified, resulting in 57-68% of women falling into a range that would be classified as hypothyroxinemic by the manufacturer’s recommended ranges. • In contrast, the FT4I performed as expected, with a physiologic increase in the first trimester with normalization to nonpregnant levels in the second and third trimesters

  19. Methods: A total of 466 healthy pregnant women were evaluated. After exclusion of women with history, ultrasonographic, or laboratory evidence of any thyroid disorder or iodine deficiency and those who were positive for thyroid autoantibodies, 152 women entered the study. Serum thyrotropin (TSH), TT4, and triiodothyronine-resineuptake were measured by an immunoassay method. Reference intervals were defined as 5th and 95th percentiles, using the bootstrap-based procedure.

  20. IV. Iodine Status and Nutrition

  21. Recommendation 4 Median urinary iodine concentrations can be used to assess the iodine status of populations,butsingle spot or 24-hour urine iodine concentrations are not a valid marker for the iodine nutritional status of individual patients. (Strong recommendation, High quality evidence)

  22. Kozing et al (2011): In a prospective, longitudinal, 15-mo study, healthy Swiss women (n = 22) aged 52–77 y collected repeated 24-h urine samples (total n = 341) and corresponding fasting, second-void, morning spot urine samples (n = 177). From the UIC in spot samples, 24-h urinary iodine excretion (UIE) was extrapolated based on the age- and sex-adjusted iodine:creatinine ratio. The CV tended to be higher for the spot UIC (38%) than for the estimated 24-h UIE (33%) (P = 0.12). In this population, 10 spot urine samples or 24-h urine samples were needed to assess individual iodine status with 20% precision.

  23. Recommendation 5 All pregnant women should ingest approximately 250 μg iodine daily. To achieve a total of 250 μg iodine ingestion daily, strategies may need to be varied based on country of origin. (Strong recommendation, High-quality evidence) Recommendation 6 In most regions, including the United States, women who are planning pregnancy or currently pregnant, should supplement their diet with a daily oral supplement that contains 150 μgof iodine in the form of potassium iodide. This is optimally started 3 months in advance of planned pregnancy. (Strong recommendation, Moderate-quality evidence)

  24. Recommendation 7 In low-resource countries and regions where neither salt iodization nor daily iodine supplements are feasible, a single annual dose of ~400 mg iodized oil for pregnant women and women of childbearing age can be used as a temporary measure to protect vulnerable populations. This should not be employed as a long-term strategy or in regions where other options are available. (Weak Recommendation, Moderate-quality evidence). • Recommendation 8 There is no need to initiate iodine supplementation in pregnant women who are being treated for hyperthyroidism or who are taking LT4. (Weak recommendation, Low quality evidence)

  25. Current Medical Research & Opinion 2015 Methods: a total of 460 pregnant women belonging to non-goiter areas (group 1; n=156) and endemic areas without (group 2; n=154) and with iodine supplementation (group 3; n=150), and their respective newborns,Women of group 3 with visible goiter were administered 2 capsules of iodized oil orally each containing 200mg of iodine, between 6-8 weeks of pregnancy. Blood samples were obtained from all groups during each trimester, at parturition (umbilical cord blood) and after delivery. T3,T4 and TSH levels were measured by specific enzyme immunoassays. Results: In group 2, serum T4 concentrations were low while T3 and TSH levels were high which showed hypothyroidism in the women of endemic areas. Goiter size decreased in most of the subjects who received a single dose of iodized oil and resulted in increase in serum concentrations of thyroid hormones; whereas, TSH levels decreased. Iodinesupplementation also resulted in raised T4 and low TSH levels in the cord-blood of neonates.

  26. Recommendation 10 Sustained iodine intake from diet and dietary supplements exceeding 500 μg daily should be avoided during pregnancy due to concerns about the potential for fetal thyroid dysfunction. (Strong recommendation, Moderate quality evidence) (RECOMMENDATION 40:Sustained iodine intake from diet and dietary supplements exceeding 500–1100 mcg daily should be avoided due to concerns about the potential for fetal hypothyroidism.Level C-USPSTF)

  27. J ClinEndocrinolMetab 2015 • Method: 7190 pregnant women at 4–8 weeks gestation were investigated and their UIC, serum thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroidperoxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and thyroglobulin (Tg) were measured. • Results: The prevalence of overt hypothyroidism was lowest in the group with UIC 150–249 mcg/L. Prevalences of subclinical hypothyroidism (2.4%) and isolated hypothyroxinemia (1.7%) were lower in the group with UIC 150–249 mcg/L. Multivariate logistic regression indicated thatexcessive iodine intake (UIC 500 mcg/L) was associated with a 2.17-fold increased risk of subclinical hypothyroidism. Meanwhile, excessive iodine intake was associated with a 2.85-fold increased risk of isolated hypothyroxinemia.

  28. METHODS: In this cohort study, we assessed a total of 203 pregnant women in the first trimester of pregnancy and followed them in the second and third trimesters. They were divided into two groups, group I with urinary iodine excretion (UIE)<150 mg/l, and group II with UIE >=150 mg/l. Serum samples from women were assayed for levels of total T4, T3, FT4I and thyroidstimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) only once in each trimester. Urinary iodine concentration was measured three times and the median was considered as UIE in the first trimester, but it was measured only once in the second and third trimesters.

  29. V. Thyroid Auto-Antibodies & Pregnancy Complications

  30. PREVALENCE OF THYROID AUTO-AB IN PREGNANCY? • Anti-thyroperoxidase or anti-thyroglobulin thyroid autoantibodies are present in 2 to 17% of unselected pregnant women. • In U.S.populations, thyroid antibodies are most frequent in Caucasian and Asian women and least frequent in African-Americans.

  31. A recent study from Belgium in women seeking fertility treatment showed that both TPOAband TgAb were present in 8% of women, while 5% demonstrated isolated Tgantibodies, and 4% demonstrated isolated TPOAbconcentrations. Those women with isolated TgAb positivity had a significantly higher serum TSH than women without thyroid autoimmunity. • While testing thyroid autoimmunity using only TPOAb would likely miss a small proportion of women with isolated Tgantibodies,the vast majority of studies investigating thyroid autoimmunity and clinical outcomes used only TPOAb measurements.

  32. Recommendation 11 Euthyroid, but TPO or Tg antibody positive pregnant women should have measurement of serum TSH concentration performed at time of pregnancy confirmation, and every 4 weeks through mid-pregnancy. (Strong recommendation, High quality evidence) (RECOMMENDATION 20 Euthyroidwomen (not receiving LT4) who are TAb+ require monitoring for hypothyroidism during pregnancy. Serum TSH should be evaluated every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation. Level B-USPSTF)

  33. A clear association between thyroid autoimmunity and miscarriage was observed with a pooled odds ratio of 2.55 (95% CI 1.42–4.57, P = 0.002) in eight case–control studies and a pooled relative risk of 2.31 (95% CI 1.90–2.82, P < 0.000 01) in 14 cohort studies. Women with TAI were found to have slightly higher age [age difference, 1.29 years] (95% CI 0.43–2.16, P = 0.003) and TSH levels [TSH difference, 0.61 mIU/l] (95% CI 0.51–0.71, P < 0.000 01) compared with those without TAI.

  34. Although a clear association has been demonstrated between thyroid antibodies and spontaneous pregnancy loss, this does not prove causality and the underlying mechanisms for such an association remain unclear. • Several mechanistic hypotheses have been proposed, including increased fetal resorption in active immunization murine modelsantibody_mediated mild thyroid hypofunction, cross-reactivity of anti-thyroid antibodies with hCG receptors on the zona pellucida, the presence of concurrent non-organ specific autoimmunity, and increased levels of endometrial cytokines in women with thyroid autoimmunity.

  35. ASSOCIATION BETWEEN THYROID ANTIBODIES AND RECURRENT SPONTANEOUS PREGNANCY LOSS IN EUTHYROID WOMEN • The data for an association between thyroid antibodies and recurrent pregnancy loss are less robust than for sporadic loss. This may be because recurrent pregnancy loss has many potential causes, and endocrine dysfunction may only account for 15-20 % of all such cases. • One study reported an apparent interaction of anti-phospholipid antibodies (APAS) and anti-thyroid antibodies in the risk for recurrent pregnancy loss. In support of this, Kim and colleagues reported that women with recurrent pregnancy loss who were antithyroid antibody positive also demonstrated higher levels of anticardiolipin Ab and other nonorgan-specific antibodies.

  36. Recommendation 13 Intravenous immunoglobulin treatment of euthyroid women with a history of recurrent pregnancy loss is not recommended. (Weak recommendation, Low quality evidence)  Recommendation 14 There is insufficient evidence to conclusively determine whether levothyroxine therapy decreases pregnancy loss risk in TPOAb positive, euthyroid women who are newly pregnant. However, administration of levothyroxine to TPOAb positive, euthyroid pregnant women with a prior history of loss may be considered given its potential benefits in comparison to its minimal risk. In such cases, 25-50 mcg of levothyroxine is a typical starting dose. (Weak recommendation, Low quality evidence) (RECOMMENDATION 42 There is insufficient evidence to recommend for or against screening for thyroid antibodies, or treating in the first trimester of pregnancy with LT4 or IVIG, in euthyroid women with sporadic or recurrent abortion or in women undergoing in vitro fertilization (IVF). Level I-USPSTF)

  37. DOES TREATMENT WITH LT4 OR IVIG DECREASE THE RISK FOR PREGNANCY LOSS IN EUTHYROID WOMEN WITH THYROID AUTOIMMUNITY? • Lepoutre et al(GynecolObstet Invest 2012);In a non-randomized, retrospective study,analyzed data from 65 TPOAb positive pregnant women with serum TSH values of 1-3.5 mU/L at the first mantenatalvisit,Thirty-four of these women were treated with 50 μg LT4 daily starting at a mean 10 weeks gestation, while the others were not treated. None of the levothyroxine treated women miscarried, but 5 of 31 untreated women (16%) experienced pregnancy loss.

  38. Methods: In a prospective study, A total of 984 pregnant women were enrolled;11.7% were thyroid peroxidase antibody positive (TPOAb).TPOAbpatients were divided into two groups: group A (n=57) was treated with LT4, and group B (n=58) was not treated. The 869 TPOAb patients (group C) served as a normal population control group.

  39. VI. The Impact of Thyroid illness upon Infertility & Assisted Reproduction

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