CROSS TOWN ENDOCRINE CLUB. Alex S. Stagnaro-Green, M.D. THURSDAY, OCTOBER 22, 2009

Transcription

1 CROSS TOWN ENDOCRINE CLUB Alex S. Stagnaro-Green, M.D. Professor of Medicine, Professor of Obstetrics & Gynecology Touro University College of Medicine Hackensack, New Jersey USC School of Medicine Visiting Professor of Endocrinology "AN OVERVIEW, THYROID DYSFUNCTION / AUTOIMMUNITY AND PREGNANCY LOSS" THURSDAY, OCTOBER 22, 2009 UCLA Faculty Center Los Angeles, CA The attached slides were prepared by Dr. Stagnaro-Green. Kindly acknowlege the source should you use them in a presentation. References for this material are listed on the last page. Alex Stagnaro-Green, MD, MHPE Senior Associate Dean for Academic Affairs Chair-Academy of Medical Educators 19 Main Street Hackensack, New Jersey alex.stagnaro-green@touro.edu phone Ext 2010 fax

2 Thyroid Dysfunction, Autoimmunity and Pregnancy Loss The Holy Family by Rubens, 1615 Alex Stagnaro-Green, MD, MHPE

3 Case Presentation A 37 year old woman is referred by her obstetrician. She is 6 weeks pregnant (first pregnancy). Her younger sister developed Hashimoto s disease 5 years ago and has a history of a preterm delivery. Knowing this history the obstetrician performed thyroid function tests on the patient with the following results: TSH 4.3 and positive thyroid peroxidase and thyroglobulin antibodies.

4 Case Presentation The patient is an avid reader of the internet and presents with the following questions: Is my TSH abnormal? Is there a risk for pregnancy loss or PTD? Will there be an impact on my child s IQ? Am I at risk for postpartum thyroiditis? What can I do to decrease these risks?

5 Reference Intervals for Thyroid Hormones in Pregnant Chinese Woman Recruited 343 pregnant women without pre-existing thyroid disease Prospective study Did not exclude women who were TAb+ 2001, Panesar & Rogers, Ann Clin Biochem

6 TSH Levels in Normal Pregnancies 2001, Panesar & Rogers, Ann Clin Biochem

7 Risk of Sub clinical Hypothyroidism in Pregnant Women with Asymptomatic Autoimmune Thyroid Disorders Evaluated TSH prospectively in the following two groups 1) 87 healthy pregnant women with normal TFTS and TAb+ 2) 550 healthy pregnant women with normal TFTS and TAb- 1994, Glinoer, JCEM

8 Risk of Subclinical Hypothyroidism in Pregnant Women with Asymptomatic Autoimmune Thyroid Disorders 1994, Glinoer, JCEM

9 Risk of Sub clinical Hypothyroidism in Pregnant Women with Asymptomatic Autoimmune Thyroid Disorders At delivery 40% of TAb+ women had a TSH > 3.0 At delivery 16% of TAb+ women had a TSH > 4.0 TRH tests revealed an exaggerated response in 50% of the TAb+ women Free T4 levels were in the hypothyroid range in 42% of TAb+ women 1994, Glinoer, JCEM

10 Overt and Sub clinical Hypothyroidism Complicating Pregnancy 51 Pregnancies 16 Overt Hypo 35 Subclinical hypo 60% abortion 0% abortion 71% abortion 0% abortion Rx inadequate Rx adequate Inadequate Rx Adequate Rx Adequate Rx TSH < 4 miu/l 2002, Abalovich, Thyroid

11 Maternal Thyroid Deficiency and Pregnancy Complications: Implications for Population Screening 9403 women had a TSH performed at weeks gestation Outcome data - fetal death - pregnancy induced hypertension - low Apgar scores 2000, Allan, J Med Screening

12 % Fetal Death Maternal Thyroid Deficiency and Pregnancy Complications: Implications for Population Screening 0.9 p < TSH < 6 TSH > , Allan, J Med Screening

13 HIGHER MATERNAL TSH LEVELS IN PREGNANCY ARE ASSOCIATED WITH INCREASED RISK FOR MISCARRIAGE, FETAL OR NEONATAL DEATHS Amsterdam Born Children and their Development (ABCD Study) (n=8266) Evaluates differences in pregnancy outcome by ethnicity, lifestyle, and psychosocial factors Nested cohort of 2,497 singleton pregnancies Completed questionnaire TSH, ft4, and TPO-Ab prior to week 28 Benhadi et al, Eur J Endo, 2009

14 RELATIONSHIP BETWEEN TSH AND CHILD LOSS TSH was related to child loss with an odds ratio of 1.6 for every doubling of TSH (p=0.03) Child loss=miscarriage, fetal or neonatal death Absolute Risk TSH 0.54 mu/l (10 th percentile) estimated absolute risk was 0.8% TSH 3.13 mu/l (90 th percentile) estimated absolute risk of 2.2% Effect remained after correction for parity, smoking, TPO presence, and HTN Benhadi et al, Eur J Endo, 2009

15 THYROTOXICOSIS COMPLICATING PREGNANCY From , nearly 120,000 women delivered at Parkland Hospital, Texas 60 cases of overt thyrotoxicosis (1:2000) 28 women dx pre-pregnancy-earlier Rx 32 women dx during pregnancy had preponderance of morbidity Davis et al, Am J Obstet Gynecol, 1989

16 OUTCOME IN 32 WOMEN DELIVERED DURING PREGNANCY Complications more common in women who remained thyrotoxic despite treatment or women who were never treated Preterm delivery Perinatal mortality Maternal heart failure Davis et al, Am J Obstet Gynecol, 1989

17 FETAL LOSS ASSOCIATED WITH EXCESS THYROID HORMONE EXPOSURE Retrospective study of 167 members of a family with resistance to TH (RTH) RTH = increased ft4 and T3 with nonsuppressed TSH values All had presence of a single nucleotide substitution in 1 allele of TRβ gene Anselmo et al, JAMA, 2004

18 FETAL LOSS ASSOCIATED WITH EXCESS THYROID HORMONE EXPOSURE Miscarriage rates 24% affected mothers (may have involved predominately unaffected fetuses) 7% affected fathers 8% unaffected parents Birth weight Unaffected infants born to affected mothers were significantly smaller than affected infants of affected mothers Anselmo et al, JAMA, 2004

19 SUBCLINICAL HYPERTHYROIDISM (SH) AND PREGNANCY OUTCOME 25,765 women screened at Parkland Hospital, Texas (gestational week?) Included singleton pregnancies that delivered an infant at 500 grams or more TSH to mu/l 2.5 th percentile for weeks gestation ft4 < 1.75 ug/dl 433 women with SH 1.7% Casey et al, Obstetrics & Gynecology, 2006

20 SUBCLINICAL HYPERTHYROIDISM (SH) AND PREGNANCY OUTCOME Women with SH had less gestational HTN 6.0% vs 8.8% - p=0.04 There was no significant difference in neonatal outcomes No convincing evidence that SH should be treated in pregnancy Casey et al, Obstetrics & Gynecology, 2006

21 Thyroid Antibodies and Spontaneous Miscarriage

22 Thyroid Antibodies and Spontaneous Miscarriage Tab+ Tab P <.05 P <.005 P <.005 P <.05 P <.05 P <.0001 P <.05 P <0.01 P <0.05

23 Recurrent Abortion and Thyroid Antibodies P = NS P <.01 P <.01 P = NS P < 0.05 P <.05 TAb+ TAb-

24 Maternal Thyroid Function and IQ of Offspring

25 Maternal Thyroid Function and the Developing Fetus Maternal thyroid function in first trimester is critical to fetal brain development Fetal thyroid begins to produce T4 between weeks Overt maternal hypothyroidism is linked to severely impaired neurological development Subtle thyroid dysfunction is correlated with decreased IQ in the offspring

26 Maternal Thyroid Deficiency During Pregnancy and Subsequent Neuropsychological Development of the child 1999, Haddow, NEJM Screening program in Maine for Down s Measured TSH in 25,216 samples Identified 62 women with a TSH > 98 th percentile and 124 matched controls Performed the Wechsler Intelligent Scale for Children in the offspring at 7-9 years old

27 Maternal Thyroid Deficiency During Pregnancy and Subsequent Neuropsychological Development of the child

28 Maternal Thyroid Deficiency During Pregnancy and Subsequent Neuropsychological Development of the child Full scale IQ results in TSH group - Overall 4 points lower - 7 points lower in 48 untreated women - 19% had scores of 85 or less (5% in controls)

29 Neurodevelopmental Consequences of Maternal Hypothyroidism During Pregnancy 2004, Rovet, Abstract, ATA 66 children born to hypothyroid women from Treatment was suboptimal (TSH 5-10) Children (and controls) tested at 5 years of age Mild reduction in global intelligence, as well as specific memory defect No negative impact on language, visual-spatial ability or fine motor performance

30 The Madonna of the Pinks Raphael,

31 Maternal Thyroid Function, AITD and Preterm Delivery

32 Definitions Preterm delivery birth of a child prior to 37 weeks gestation. Very preterm delivery birth of a child prior to 32 weeks gestation.

33 Impact Preterm delivery leading cause of perinatal mortality and congenital neurological disability in the U.S. Majority of neonatal mortality and morbidity in the United States occurs in very preterm infants perinatal deaths annually are due to PTD

34 Incidence of PTD Lancet 2008

35 % PTD AITD and PTD p< % 8% Glinoer 1994 (Belgium) p=ns 4% 3% Iijima 1997 (Japan) 26.8% Ghafoor 2006 (Pakistan) p<0.01 8% 22.4% Negro 2006 (Italy) p< % TAb+ TAb-

36 Postpartum Thyroiditis

37 Madonna Enthroned Duccio, Wood Panel. 1310

38 Postpartum Thyroiditis The occurrence of transient hyperthyroidism and/or transient hypothyroidism in the postpartum period in women who were euthyroid during pregnancy.

39 PPT-Hyperthyroid Phase Does not occur in all women Frequently asymptomatic Occurs between 1 to 6 months postpartum Precedes hypothyroid phase Rarely requires treatment Low uptake on radionucleide scanning

40 PPT Hypothyroid Phase Occurs between 3 to 12 months postpartum May require treatment in some women Most women return to the euthyroid state by one year postpartum

41 Prevalence of PPT Canada 6.0% 8.8% USA 16.7% UK 7.8% Spain 13.3% Brazil 6.5% Sweden 3.9% Denmark 5.2% Netherlands 11.4% 8.7% Iran Italy 7% India 1.1% Thailand 5.5% Japan Prevalence rate of postpartum thyroiditis is 7.5%

42 Biochemical Presentation of Postpartum Thyroiditis Hypothyroidism Alone 45% 34% Hyperthyroidism Alone 21% Hyperthyroidism Followed by Hypothyroidism Stagnaro-Green, 2002

43 Thyroid Disease Peripartum and Systemic Lupus Erythematosus 63 women 8 women on L-T elevated TSH in first trimester 49 6 women with no postpartum sera (86%) 2 (4.7%) 4 (9.3%) Euthyroid Hyperthyroid Hypothyroid Postpartum PPT PPT Stagnaro-Green et al (submitted)

44 % PPT PPT in Autoimmune Diseases DM Denmark DM Canada 1993 DM USA DM Netherlands GD Japan CVH Greece SLE USA 7.5 General Population Stagnaro-Green et al (submitted)

45 Data In Support of PPT As An Autoimmune Disease The association of PPT and thyroid autoantibodies The association of PPT and HLA serotypes T-cell changes identified in women who develop PPT Biopsy of patients with PPT reveals lymphocytic thyroiditis.

46 Outcome of Pregnancy Based On Initial Thyroid Antibody Status Antibody Miscar. Miscarr.+PPT Antibody Miscarr. PPT Miscarr.+PPT Stagnaro-Green, Roman, Cobin et al, JCEM. 1992

47 PPT and Postpartum Depression Is There a Relationship? DEPRESSION Two Studies + Two Studies - Mother and Child, Pablo Picasso

48 Permanent Primary Hypothyroidism in Women with PPT Tachi, 1998 Ot hmar, 2000 Sarughad, 2005 Control PPT Lucas, 2000 Prem Permanent Hypothyroidism

49 An Algorithm For Treating and Monitoring PPT Hyperthyroid Phase Asymptomatic No Treatment Symptomatic (Palpitations, fatigue, etc) Treat, Propranolol mg. qid Repeat TSH in 4-6 weeks or if becomes symptomatic Euthyroid Repeat TSH every two months until approximately 9 months postpartum 2002, Stagnaro-Green, JCEM

50 An Algorithm For Treating and Monitoring PPT Hypothyroid Phase TSH 4-10 uu/ml Asymptomatic No Treatment Repeat TSH in 4-8 weeks TSH 4-10 uu/ml Symptomatic (decreased energy, poor memory, dry skin, carelessness) or planning pregnancy. Treat with Levothyroxine mcg/qd TSH > 10uU/ml Treat with Levothyroxine mcg/day Continue treatment until 1 year after completing family. Attempt weaning trial by halfing the dose and repeating TSH in 6-8 weeks.

51 Madonna Enthroned Cosme Tura, 1474

52 To Screen or Not to Screen Is thyroid disease and pregnancy common Are there important associated morbidities Availability of an inexpensive, available, and accurate screening test Can the morbidities be prevented

53 Levothyroxine in AITD During Objective Pregnancy - To determine if women with AITD have a higher rate of obstetrical complications. - First randomized perspective study - Performed in Italy Negro et al, JCEM, 2006

54 Methods Woman - TSH, and TPO Ab at first prenatal visit women were TPO Ab+ (11.7%) were TPO Ab- ( control group) Negro, et al, JCEM, 2006

55 Methods 115 (TPO Ab+) 57 L-T4 Rx 58 No RX -TSH dose varied based on initial TSH and TPO Ab titer-begun 3-7 days after initial visit Negro, et al, JCEM, 2006

56 Results - First endocrine visit occurred at gestational age of 10.4 weeks - Average age of control was less than TPO-Ab+ women (28 vs 30, p<0.05) Negro, et al, JCEM, 2006

57 Results P <.05 Miscarriage P <.05 Preterm Delivery TPO+/T4- TPO+/T4+ Control Negro et al, JCEM, 2006

58 Management of Thyroid Dysfunction During Pregnancy and the Postpartum Although the benefits of universal screening for thyroid dysfunction may not be justified by the current evidence, we recommend case finding among the following group of women at high risk for thyroid disease by measurement of TSH An Endocrine Society Guideline, 2007

59 The Problem with Sitting on the Fence You cannot sit on the fence forever. It is very uncomfortable for the backside Davies, 2007

60 Detection of Thyroid Dysfunction in Early Pregnancy: Universal Screening or Targeted High-Risk Case Finding 1,560 women first prenatal visit (9 weeks) TFT s and TPO-Ab performed 413 classified 1,147 no risk high risk High risk = personal or FH of thyroid or autoimmune disease 2007, Vaidya, Journal of Clinical Endocrinology & Metabolism

61 Prevalence of Raised or Fully Suppressed TSH TSH > 4.2 miu/liter TSH < 0.03 m IU/liter High Risk No Risk High Risk Low Risk 28 (70%) 12 (30%) 9 (31%) 20 (69%) Conclusion Targeted case finding misses 30% of hypothyroid women and 69% of women with fully suppressed TSH 2007, Vaidya, Journal of Clinical Endocrinology & Metabolism

62 Young Woman with Bound Hair Albrecht Durer, 1497

63 REFERENCES Alex Stagnaro-Green, M.D. talk for Cross Town Endo Club Oct Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA. 1990;264(11): Glinoer D, Fernandez Soto M, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endo. 1991;73(2): Prummel MF, Wiersinga WM. Thyroid autioimmunity and miscarriage. Eur J Endo. 2004;150: Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12(1): Allan, WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen. 2000;7: Haddow JE, Palomaki, GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8): Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet & Gynecol. 2005;105(2): Stagnaro-Green A, Chen X, Bodgen JD, et al. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid. 2005;15(4): Stagnaro-Green A, Roman SH, Cobin RH, et al. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endo Metab. 1992;74(3): Alvarez-Marfany M, Roman SH, Drexler AJ, et al. Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin Endo Metab. 1994;79(1): Nicholson WK, Robinson KA, Smallridge, RC, Ladenson PW, Powe NR. Prevalence of postpartum thyroid dysfunction: A quantitative review. Thyroid. 2006: 16(6): Casey BM. Subclinical hypothyroidism and pregnancy. Obstet Gynecol Surv. 2006;61(6): Negro R, Formoso G, Manigieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endoc Metab. 2006;91(7): Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endo Metab. 2007;92(8) (Supplement):S1-S Vaidya B, Anthony S, Bilous AS, et al. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? J Clin Endo Metab. 2007;92(1): Benhadi N, Wiersinga WM, Reitsma JB, et al Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. European J of Endo Mar (9), Epub ahead of print. 17. Davies T. Editorial: time for the American Thyroid Association to lead on thyroid screening in pregnancy. Thyroid. 2007:17(8):