Thyroid Disorders in Pregnancy

Transcription

1 Thyroid Disorders in Pregnancy Akane Ide, M.D., Ph.D., Nobuyuki Amino, M.D., Ph.D. Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan the Asia-Oceania Congress of Endocrinology (AOCE) October 8-11, 2014 at the Radisson Blu in Cebu City

2 Thyroid Disorders in Pregnancy 1. International guidelines on thyroid management in pregnancy 2.Activated thyroid function in pregnancy 3. Gestational thyrotoxicosis 4. Hyperthyroidism and pregnancy 5. Hypothyroidism and pregnancy 6. Anti-thyroid antibodies and miscarriage 7. Postpartum thyroid dysfunction 8. Thyroid problems and female infertility

3 Interna'onal Guidelines on thyroid and pregnancy 2007 GUIDELINES FOR MANAGEMENT OF THYROID DYSFUNCTION DURING PREGNANCY AND POSTPARTUM Abalovich M, Amino N, Barbour L, Cobin HR, Glinoer D, DeGroot LJ, Mandel S, Stagnaro-Green A J Clin Endocrinol Metab 92:S1-47, Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W; Thyroid 21: , GUIDELINES FOR MANAGEMENT OF THYROID DYSFUNCTION DURING PREGNANCY AND POSTPARTUM DeGroot L Abalovich M, Alexander EK, Amino N, Barbour L, Cobin R, Eastman C,Lazarus J, Luton D, Mandel S, Mestman J, Rovet J, Sullivan S J Clin Endocrinol Metab 97: ,2012

5 Thyroid Regulation during Pregnancy Food I - Pituitary Urine Hypothalamus TRH TSH TSH-R Thyroid I 2 MIT DIT T 4 T 3 FT 4 FT 3 T 4 T 3 TBG Thyroglobulin Peripheral Tissue Negative feedback Stool Stimulation Increase T 4 by 50% Glucuronide formation Placenta hcg Estrogen TRH Fetal Pituitary?

6 Serial Change of Thyroid Function in Normal Pregnancy TBG TBG TT4 TT4 FT4, FT3 TSH FT4, FT3 TSH Estrogen hcg hcg 1st 2nd Trimester 3rd

7 Comparison of serum FT4 or TSH levels of women in early pregnancy and controls 2.5 P< P< FT4(ng/dl) TSH(µIU/ml) Control (15 45yo) Pregnant women (7 14W) 0 Control Pregnant (15 45yo) women (7 14W)

9 Serial change of thyroid function in normal pregnancy FT4, FT3 Normal range in non-pregnancy TSH Gestational weeks Postpartum Delivery months TSH is reliable for evaluation of thyroid function in pregnancy.

10 A Case of Gestational Thyrotoxicosis hcg (10 4 IU/L) TSH (mu/l) Thyroid stimulating activity (%) FT4 (pmol/l) 600 TSA TSA MMI 80 FT mg hcg FT4 TSH hcg Gestational Weeks Postpartum Months ( Kimura M et al Clin Endocrinol 38: 345, 1993 )

11 Characteristics of Gestational Thyrotoxicosis 1. Thyrotoxic symptoms, such as palpitation, hyperhidrosis and weight loss in early pregnancy. 2. Increase in FT4 and FT3. 3. Complication with hyperemesis gravidarum. 4. Spontaneous recovery in the later half of pregnancy. 5. Negative for anti-thyroid antibodies. 6. Negative for anti-tsh receptor antibody. 7. No goiter. (Modified from Kimura M et al Clin Endocrinol 38: 345, 1993 )

12 Serum TSH and FT4 in early pregnancy (7-14 weeks) FT4 (ng/dl ) TSH (miu/l) No (%) < >1.66 > (1.6%) ~ (60.5%) ~ (28.9%) < (9.1%) Total 509 Gestational thyrotoxicosis: 17 out of 509(3.3%), one of 30 normal pregnancies. (Orito Y et al. J Clin Endocrinol Metab 94:1683, 2009)

13 American Endocrine Society Guideline 2012 Gestational hyperemesis and hyperthyroidism 3.1. Thyroid function tests and TRAb should be measured in patients with hyperemesis gravidarum and clinical features of hyperthyroidism Most women with hyperemesis gravidarum, clinical hyperthyroidism, suppressed TSH, and elevated free T4 do not require ATD treatment. Beta blockers may be helpful and may be used with obstetrical agreement.

15 Pathophysiology of Graves disease B lymphocytes Suppress TSH TSH receptor Antibody (TRAb) Negative feedback Rising T4 T3

16 TRAb levels (IU/L) in Thyroid disorders and Controls ( 3rd-generation electrochemiluminescence immunoassay) 100 >100 (measured over 30 min) TRAb (IU/L) <0.3 untreated Graves disease Painless thyroidi's Subacute thyroidi's Controls

17 100 Change of An'- TSH Receptor An'bodies in Pregnancy TRAb TSAb TSBAb Ⅰ Ⅱ Ⅲ Post- Ⅰ Ⅱ Ⅲ Post- Ⅰ Ⅱ Ⅲ Post- partum partum partum Trimester Trimester Trimester ( Amino et al. J Clin Endocrinol Metab 88:5871, 2003 )

18 Treatment of Graves Disease During and After Pregnancy Substitute PTU for MMI during Week 4 to 7 gestational age PTU MMI 4 to 7 wk gestation PTU/MMI TSH receptor antibody (TRAb) Gestational weeks Delivery Postpartum months (N Amino Obstetrics and Gynecology Suppl.80 52,2013)

19 Prevention of Neonatal Hyperthyroidism TRAb 10 IU/L or 6 IU/L without ATD TRAb Neonatal Hyperthyroidism TSAb Placental barrier

20 Graves disease is aggravated in the first trimester by hcg stimulation but ameliorates in the later half of pregnancy due to a decrease of thyroid stimulating antibodies during pregnancy. However Graves disease is aggravated after delivery due to an increase of thyroid stimulating antibodies.

22 Transplacental transfer of thyroid hormone TSH TSH Thyroid hormone Fetal development is dependent on transfered maternal thyroid hormone Iodine Placental Barrier

23 Fetal Development and Thyroxine (maternal thyroxine is important for fetal development) (Morreale de Escobar et al. JCEM 85:3975, 2000)

24 Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child (7~9 years old) Children from Hypothyroid mothers (n=62) Control Children (n=124) p value IQ Score 103±15 107±12 p=0.06 Attention Continuous performance test score >8(%) (Untreated n=48) p= p=0.01 Language Word discrimination 10.5± ±2.4 p=0.04 TSH> 5 47cases, TPOAb 77% posi've (Haddow et al. N Engl J Med 341: 549, 1999)

25 Maternal hypothyroidism and neonates Year Author 1999 Haddow Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses. Screening for hypothyroidism during pregnancy was proposed. (USA) 1999 Pop Low maternal plasma free T4 concentrations during early pregnancy may be an important risk factor for impaired infant development.(netherland) 2000 Smit Maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean mental development index score in their infants during the first year of life. (Netherland) 2003 Blazer Birth weight and head circumference were lesser in neonate born to mothers with treated hypothyroidism. (Israel) 2005 Mirabella Decreased contrast sensitivity in infants with prenatal thyroid hormone insufficiencies. (Canada) 2006 Kooistra Low maternal plasma free T4 concentrations during early pregnancy constitutes a serious risk factor for impaired infant development.(netherland)

26 Effect of T4 treatment on miscarriage and premature birth in patients with hypothyroidism TSH>4.0mU/L (%) (%) TSH<4.0mU/L after Tx Overt Subclinical Overt n=10 Subclin n= Overt n=6 Subclin n=21 Overt Subclinical miscarriage Preterm Full term 0 miscarriage Preterm Full term (Abalovich M et al. Thyroid 12:63, 2002)

27 TSH in early pregnancy and pregnancy loss (Negative anti-thyroid antibodies) TSH in early pregnancy(μiu/ml) Group A <2.5 Group B No examined Median TSH (μiu/ml) * Median FT4(ng/dl) Pregnancy loss 3.6% 6.1%* *Significant at P<0.01 (Negro R et al. JCEM 95:E44, 2010)

28 30 30 Reference Value of TSH levels among healthy childbearing women between 15 and 45 y.o. Number N=131 Reference Value: 0.4~3.0 miu/l (95%C.I. 0.39~3.04 mu/l) < TSH (mu/l) 以上 (Amino and Ide Japan Thyroid Association magazine 5:66, 2014)

29 An Endocrine Society Guideline 2012 Hypothyroidism and pregnancy Overt maternal hypothyroidism is known to have serious adverse effects on the fetus. Therefore, maternal hypothyroidism should be avoided Subclinical hypothyroidism (SCH) may be associated with an adverse outcome for both the mother and offspring. In retrospective studies, T4 treatment improved obstetrical outcome, but it has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks, the panel recommends T4 replacement in women with SCH who aretpo-ab positive.

30 If hypothyroidism has been diagnosed before pregnancy, we recommend adjustment of the preconception T4 dose to reach before pregnancy a TSH level not higher than 2.5 miu/liter The T4 dose usually needs to be incremented by 4 to 6 wk gestation and may require a 30% or more increase in dosage If overt hypothyroidism is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. T4 dosage should be titrated to rapidly reach and thereafter maintain serum TSH concentration of less than 2.5 miu/liter in the first trimester ranges.

32 An'- thyroid An'bodies and Abor'on p<0.001 Abortion rate (%) n = 951 p<0.05 n = 125 n = 32 n = 81 Healthy controls (antibody negative) Anti-thyroid microsomal antibody (+) Anti-thyroglobulin antibody (+) Anti-nuclear antibody(+) (Iijima et al. Obstet Gynec 90: 364, 1997)

33 Anti-thyroid antibodies and miscarriage % Positive Negative P<.0001 Miscarriage rate (%) P<.05 P<.005 P<.005 P<.05 0 Stagnero- Green(1990) Glinoer (1991) Lejeune (1993) Iijima (1997) Bagis (2001)

34 Assisted reproductive technique and miscarriage % 60 Positive Negative P= Miscarriage rate (%) P=0.002 P=N.S. P=N.S Singh (1995) Muller (1999) Kutteh (1999) Poppe (2003)

35 Prevalence of anti-thyroid antibodies in habitual abortion Prevalence of antibody % P=N.S. P<.01 Abortion P<.01 P<.01 Control P=N.S. P<.05 P< Pratt (1993) Bussen (1995) Roberts (1996) Bussen (1997) Esplin (1998) Kutteh (1999) Dendrinos (2000)

36 Effect of T4 treatment in women with TPO antibody but normal thyroid function % 15 Miscarriage Group B 13.8% 25 % 20 Preterm delivery Group B 22.4% % Group A 3.5% % Group A 7% 0 Control TPO Ab TPO Ab Control TPO Ab TPO Ab + + LT4 LT4 T4 dose (µg/kg /day):tsh <1.0 miu/l:0.5; 1-2 miu/l :0.75; 2< miu/l:1.0µg/kg d (Effective to treat before 12 weeks) 0 ( modified Negro R et al. J Clin Endocrinol Metab 91:2587,2006 )

37 Effect of T4 treatment in women with anti-tpo antibody in pregnancy FT4(ng/L) Weeks of gestation TSH(mIU/L) Weeks of gestation TPOAb (+) LT4: Group A TPOAb (+) no LT4: Group B TPOAb (-): Group C (3 rd -generation electrochemiluminescence immunoassay, Roche) ( Negro R et al. J Clin Endocrinol Metab 91:2587,2006 )

38 American Endocrine Society Guideline A positive association exists between the presence of thyroid antibodies and pregnancy loss. Only one randomized interventional trial has suggested a decrease in the first trimester miscarriage rate in euthyroid antibody-positive women. Because women with elevated anti-tpo antibodies are at increased risk of progression of hypothyroidism, if identified such women should be screened for serum TSH abnormalities before pregnancy, as well as during the first and second trimesters of pregnancy. Thyroid antibodies are an influencing factor independent from thyroid dysfunction.

40 Immune Rebound After Delivery Activation Hashimoto s thyroiditis Graves disease Immune activity Not pregnant Pregnant Cellular immunity (Th1) Humoral immunity (Th2) Postpartum (months) Delivery Supression ( Amino et al. Thyroid 9:705,1999 )

41 Decrease Various types of postpartum thyroid dysfunction Postpartum thyroiditis (I)Persistent thyrotoxicosis (4.5%) Serum thyroid hormone Increase Delivery months (II)Transient thyrotoxicosis 8 elevated RAIU (6.8%) low RAIU (16.0%) (III)Destructive thyrotoxicosis (52.1%) (IV)Transient hypothyroidism (20.5%) (V)Persistent hypothyroidism (0.1%) Postpartum Graves disease 11.3% Postpartum exacerbation of autoimmune thyroiditis 72.7% ( Modified from Amino et al. Thyroid 9: 705,1999 )

42 Differentiation between postpartum destructive thyrotoxicosis (PPT) and postpartum Graves thyrotoxicosis (PPGr) Onset of postpartum thyrotoxicosis 4 A. PPGr TRAb Thyroid blood flow No. of cases No. of cases B. PPT TRAb(IU/L) PPGr PPT Thyroid blood flow (%) PPGr PPT Months postpartum (Ide, Amino et al. Thyroid 24: 1027, 2014)

43 Postpartum transient hypothyroidism 28 years old, housewife 3 months postpartum TSH 110 mu/l 6 months postpartum TSH 4.0 mu/l

44 Modified from An Endocrine Society Guideline 2012 l Postpartum thyroid dysfunction is typically transient in nature, with the majority of women returning to euthyroidism by the end of the first postpartum year. However, even after recovery from hypothyroidism, abnormalities in ultrasonography and/or iodide perchlorate discharge tests persist, reflecting underlying chronic autoimmune thyroiditis. It is therefore not surprising that a small percentage of women never recover from the initial hypothyroid phase, and 20 64% of women develop permanent hypothyroidism in the 5-to 10-yr period following the episode of postpartum thyroiditis. Therefore, an annual TSH level should be examined in these women.

45 Four different types of pregnancy associated thyrotoxicosis GTT PrGr PPT PPGr No. of cases Gestational weeks Months postpartum Delivery

47 Subclinical hypothyroidism in infertile women year author % case/ total control % diagnosis 1981 Bohnet 11 20/185 NT* TSH>3,TRH-TSH> Gerhard 43 80/185 NT TRH-TSH> Shalev 0.7 3/444 NT TSH> Arojoki /299 2~3 TSH> Grassi 4.6 6/129 NT TSH> Poppe 0.9 4/438 <1 TSH> Raber 34 96/283 NT TSH>4,TRH-TSH> Abalovich / Total /2207 One of 10 infertile women has subclinical hypothyroidism. TSH>4.2,TRH- TSH>26.6 *NT:Not Tested (modified Poppe et al. Clin Endocrinol 66:309, 2007)

48 Effect of T4 treatment on IVF and pregnancy in infer'le women with subclinical hypothyroidism No treatment T4 Cases a TSH 6.8± ±1.0 ** Embryo implanta'on rate Clinical pregnancy rate 14.9%(14/94) 26.9%(25/93) * 37.5%(12/32) 53.1%(17/32) Miscarriage rate 33.3%(4/12) 0.0%(0/17) * Live birth rate 25.0%(8/32) 53.1%(17/32) * a T4:50μg/day * Significant difference at p<0.05(*)and p<0.01(**) ( Kim CH et al. Fertility Sterility 95:1650, 2011 )

49 Clinical and laboratory data in inferble pabents with subclinical hypothyroidism: Comparison between successful and unsuccessful pregnancy aèr thyroxine treatment Median TSH ml) value (miu/l) FT4 (ng/dl) No. of positive antibodies Pregnancy No. examined Age (years) Before T4 Aèr T4 Before T4 Aèr T4 TgAb TPOAb Successful Successful (Group A) (Group A) ± * 0.98± ±0.22* (84.1%) Unsuccessful (Group ( B) ± * 1.00± ±0.20* 5 3 (15.9%) *Significantly different from value of before T4 at p<0.001 (Yoshioka W, Amino N, Ide A et al, Endocrine J in press)

50 Thyroxine treatment in infer'le woman with subclinical hypothyroidism 36 (59.0%) of 61 inferble women get pregnancy a`er T4 treatment 30(47.5%) of 61 had posibve anb- thyroid anbbodies T4 dose before pregnancy: mean 52 μg (25~100)/day T4 dose during pregnancy : mean 73 μg (50~125)/day A Years (miu/l) Durabon before T4 therapy Durabon of T4 therapy unbl pregnancy Before T4 therapy A`er T4 therapy (Yoshioka W, Amino N, Ide A et al, Endocrine J in press)

51 Guidelines have not represented recommendations clearly It is recommended to measure serum TSH and anti-tpo antibody or anti-thyroglobulin antibody to clarify the existence of subclinical hypothyroidism and/or thyroid autoimmunity abnormality, since infertile women are often associated with these conditions. The importance of levothyroxine replacement therapy in infertile women with subclinical hypothyroidism is demonstrated by subsequent successful pregnancy.

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