Thyroid Disease & Pregnancy Updates and Ongoing Questions

Transcription

1 Thyroid Disease & Pregnancy Updates and Ongoing Questions Erik K. Alexander, MD Chief, Thyroid Section, Division of Endocrinology Brigham & Women s Hospital Professor of Medicine, Harvard Medical School

2 DISCLOSURES No Relevant Disclosures.

3 Outline: I. The last 5-10 years tremendous data, new ATA guidelines; many uncertainties II. Active cases and discussion: i. Hypothyroidism ii. TPO Ab status iii. Hyperthyroidism III. Screening for thyroid disease during pregnancy?

4 A lot of new Data # Publications

5 ATA 2017 Guidelines: Members: Erik K. Alexander, MD Elizabeth Pearce, MD (co-chair) (co-chair) Greg Brent UCLA, VA Healthcare System Christy Dosiou Stanford Medical Center Susan Mandel U Penn Medical Center Peter Laurberg Arhaus Medical Center, Denmark Robin Peeters Erasmus Medical Center, Netherlands John Lazarus Cardiff University, England Rosalind Brown Childrens Hospital, Boston Herb Chan Univ Wisconsin Medical Center Bill Grobman Northwestern Univ Medical Center Scott Sullivan S. Carolina Medical Center Expertise & Active Research International Representation Pediatric & Surgical Input Obstetrical Expertise

6 Similar to the 2011 Guidelines: Chapters on: I. Hypothyroidism II. Hyperthyroidism III. Iodine Metabolism & Supplementation IV. Thyroid Nodules & Thyroid Cancer V. Thyroid Function Tests VI. Thyroid Autoimmunity (TPO Ab) VII. Screening for Disease VIII.Post Partum Disease

7 New to the 2017 Guidelines: Based upon feedback, surveys & expert input: Chapters on: I. Lactation & Thyroid Disease II. Infertility & Assisted Reproduction III. Prenatal, Neonatal, & Postnatal Considerations Broader Discussion: IV. Surgical Considerations

8 Complex Clinical Discussions:

9 2017 Thyroid & Pregnancy Guidelines: Complex Area of Discussion: I. How to define Hypothyroidism, & When to Recommend Treatment?

10 Case #1a - Hypothyroidism 32yo healthy Caucasian female presents for care and is found to be newly pregnant (estimated 14 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 22.6 miu/l (normal mIU/L). Would you recommend treatment?

11 Case #1b 29yo healthy African American female presents for care and is found to be newly pregnant (estimated 12 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 7.6 miu/l (normal mIU/L). Would you recommend treatment?

12 Case #1c 29yo healthy Turkish female presents for care and is found to be newly pregnant (estimated 9 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 3.5 miu/l (normal mIU/L). Would you recommend treatment?

13 Spectrum of Maternal Thyroid Status Myxedema Coma (severe) Mild (subclinical) Hypothyroidism Moderate Hypothyroidism Mild (subclinical) Hyperthyroidism Moderate Hyperthyroidism Thyroid Storm (severe) Euthyroid

14 Spectrum of Maternal Thyroid Status Myxedema Coma (severe) Mild (subclinical) Hypothyroidism Moderate Hypothyroidism Mild (subclinical) Hyperthyroidism Moderate Hyperthyroidism Thyroid Storm (severe) Euthyroid UNSAF E SAF Risk Eto Fetus & Pregnancy:

15 Uncertainties: Euthyroid I. Where do we draw these lines? II. How do we define each category? III. How do we balance the risks and benefits of any i t ti?

16 Dangers of overt maternal hypothyroidism: ~13yo Untreated Cretin Courtesy: P. Reed Larsen

17 4 Family Members from Congo (Zaire). All age yo 1 euthyroid male and 3 females with severe longstanding hypothyroidism. Courtesy: F. Delange

18 But most patients: Young, generally healthy Iodine sufficient (at least moderately) Hashimoto s Disease Have easy access to healthcare Importantly: TSH elevation will be (very) mild

19 Background: Available data creates a paradox? Data: I. Treatment of overt maternal hypothyroidism (TSH >10mIU/L or TSH freet4) widely accepted. Note no randomized interventional trial data II. Increasingly, subclinical hypothyroidism (TSH <10mIU/L) treated on basis of pregnancy/miscarriage risk. III. How is an elevated TSH defined? One prospective trial (Negro, et al) may demonstrate benefit when >3.0mIU/L IV. Other healthy populations / ethnicities appear to have different TSH ranges ( mIU/L) in pregnancy

20 Is TSH >3.0mIU/L really the cutoff? Li, et al : (prospective screening) >7,000 women: 4800 pregnant women seeking future pregnancy Excluded women if: 1) fam hx of thyroid dz, 2) TPO Ab+, 3) goiter. Reference range defined as >2SD from mean (95% of cohort). Chinese population reference range: TSH: (Pregnancy week 4-12) (miu/l) -2SD: mean: +2SD: If >2.5mIU/L used: If >4.9mIU/L used: 28% hypothyroid (5 mil births/year): 4% hypothyroid (<1mil births/year): Li, et al. JCEM 2014;99:73

21 Ethnicity Impacts TSH normalcy : Korevaar & Medici, et al : ~4,000 women: Generation R Study screened 13wks. Excluded women if: TPO Ab+, known thyroid dz, or Assist Reproduction Reference range defined as >2SD from mean (95% of cohort). -2SD: mean: +2SD: All patients: TSH Dutch: TSH Moroccan: TSH Turkish: TSH Surinamese: TSH Korevaar, et al. JCEM 2013;98:3678

22 Similar data from Spain Castillo Lara, et al : (prospective screening) >100 women: newly pregnant. 1 st trimester Excluded women if: 1) fam hx of thyroid dz, 2) TPO Ab+, 3) goiter. Reference range defined as >2SD from mean (95% of cohort). Spanish population reference range: TSH: (Pregnancy week 4-12) (miu/l) -2SD: mean: +2SD: Similar report from Catalonia: Similar report from Andalusia: >2SD TSH 5.7mIU/L >2SD TSH 4.2mIU/L Casillo Lara, et al. BMC Pregnancy Childbirth. 2017;17:438

23 Difficult Translation: Where to define abnormality? Questions: I. Does a reference range calculation mean that no harm is conveyed by maternal thyroid status in that range? II. Can a physician truly know the reference range for his/her population? How should one take ethnicity into account? Downstream Impact: Defining abnormal cut-off s also defines when LT4 should be started, and what the treatment targets should be.

24 Difficult Translation: Where to define abnormality? 2018 Standard: I. A more generous TSH threshold (up to ~4.0) seems to be highly appropriate for defining hypothyroidism II. Do your best to know your populations baseline thyroid function. Know and understand your ethnicities.

25 ATA 2017 Guidelines Alexander, et al. Thyroid 2017;27:315.

26 2017 Thyroid & Pregnancy Guidelines: Complex Area of Discussion: II. Does TPO Antibody status matter? If so, Why?

27 Background: Understanding the Influence of TPO Ab? Data: I. The harm attributable to maternal hypothyroidism has long been assumed to be caused directly by the low levels of maternal hormone itself II. Increasingly, TPO Ab status is independently shown to amplify the harmful effects of maternal hypothyroidism III. Even euthyroid (nl TSH) mothers who are TPO Ab positive appear to have an increased risk of miscarriage IV. Until now, testing for TPO Ab status has not routinely been recommended.

28 Case #2a 37yo female is newly pregnant (9 weeks). She is euthyroid and not receiving LT4. However, workup of a goiter 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 3.6 miu/l, and TPO Ab 520 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about miscarriage, and asks if TPO Ab will influence this. She asks if anything can be done? How would you respond?

29 Case #2b 37yo female is newly pregnant (9 weeks). She is euthyroid and not receiving LT4. However, workup of a goiter 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 4.4 miu/l, and TPO Ab 18 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about miscarriage, and asks if TPO Ab will influence this. She asks if anything can be done? How would you respond?

30 TPO Ab status Modifies the Risk of Maternal Hypothyroidism Liu, et al : (prospective cohort study) Screened 3,315 women low-risk women at 4-8 weeks gestation Assessed TSH, FreeT4, and TPO Ab status Primary Endpoint - Miscarriage Miscarriage Risk: TSH , TPO neg 2.2% TSH , TPO positive 5.7% TSH , TPO neg TSH , TPO positive 3.5% 10.0% TSH , TPO neg TSH , TPO positive 7.1% 15.2% TPO Ab status augments the harm of elevated TSH levels Liu, et al. Thyroid 2014;24:1642

31 TPO Ab status May Modify the Risk more than Hypothyroidism Seungdamrong, etal: (2 prospective cohort studies) Prospective, PRE-PREGNANCY serum from 1,468 infertile women Assessed TSH, FreeT4, and TPO Ab status Primary Endpoint Conception Rate, Miscarriage, Live Birth Rates TSH >2.5 vs. <2.5mIU/L Miscarriage Risk: P=NS TSH TPO neg TSH TPO positive Similar conception rates (33.3 vs. 36.3%, p=ns) Higher miscarriage rates (43.9% vs. 25.3%, p<0.01) Lower live birth rates (17.1% vs. 25.4%, p<0.01) Seungdamrong, et al. Fertil Steril 2017; Oct (epub)

32 Should you treat & What is the Evidence: Alexander, et al. Thyroid 2017;27:315.

33 Does the level of TPO Ab matter? Korevaar et al: data from 3 prospective birth cohorts (association study) n=11,212 pregnant women in total; Blood drawn before 20weeks Primary Endpoint Pre-Mature Delivery Dose-dependent positive association of TSH with Premature Delivery Dose-dependent positive association of TPO Ab with Premature Delivery Impact of TPO Ab was linear, and extended below the normal range cut-off. Perhaps the TPO Ab titer matters as well, even into the normal range Korevaar TIM, et al. JCEM 2017 (Dec); Epub

34 Case #2b 37yo female is seeking pregnancy. She is euthyroid and not receiving LT4. However, workup of a goiter 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 1.9 miu/l, and TPO Ab 758 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about infertility, and asks if TPO Ab will influence this. She asks if anything can be done? How would you respond?

35 Treating Euthyroid, TPO Ab+ Women 57 Treated L-T4 (~50ug/d) Endpoints: 1. Miscarriage 3.5% Rates: 2. Premature Delivery: Reduces Miscarriage Rate? 115 TPO Ab positive 984 Pregnant Women: 58 Not Treated 869 TPO Ab negative (Controls) 13.8% * 2.4% 7.0% 22.4% * 8.2% Negro, JCEM 2006; * p<0.05

36 Treating Euthyroid, TPO Ab+ Women Reduces Miscarriage Rate? Supporting Evidence: LaPoutre Retrospective Cohort Analysis 537 Consecutive women with singleton pregnancy all with TSH <3.5mIU/L In TPO Ab Positive Cohort, half treated when TSH >1mIU/L Initiated 50mcg daily. Other half not treated. Miscarriage Reduced from 16% to 0% with LT4 treatment LaPoutre, et al. Gynecol Obstet Invest 2012;74:265

37 LT4 Treatment in TPO+ women: Newly Pregnant Before Pregnancy normal conception Before Pregnancy IVF/ART Alexander, et al. Thyroid 2017;27:315.

38 LT4 treatment of euthyroid, TPO Ab+ women does not improve ART outcome Wang H, et al: (prospective, randomized trial) Prospective, randomized trial of 600 women in China ALL have normal thyroid function, but +TPO Ab Primary Endpoint Miscarriage & Pregnancy Rate Miscarriage Rate: Successful Pregnancy Received Levothyroxine: 10.3% No Levothyroxine: 10.6% NS 35.7% 37.7% NS Administration of LT4 to euthyroid, TPO Ab+ women did NOT improve results of IVF/ART Wang H, et al. JAMA 2017;318:2190

39 In TPO Ab+ women, should you measure anything else? Maternal serum hcg? High TSH, low hcg: High TSH, high hcg: Premature Delivery, or Preterm PROM Decreased (graded effect) Increased (graded effect) P<0.01 Intriguing initial data. Not separately validated. Korevaar TIM, JCEM 2017;102:3360

40 2017 Thyroid & Pregnancy Guidelines: Active Area of Discussion: III. Is low-normal freet4 harmful (in the setting of a normal TSH)?

41 Case #3 29yo healthy female presents for care and is found to be newly pregnant (estimated 9 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting testing. TSH 2.1mIU/L (nl: mIU/L). FreeT4 0.9ng/dL (nl: ng/dl) What would you recommend?

42 Background: The Uncertain meaning of nl TSH, low ft4? Data: I. TSH is a surrogate measurement for total hormone levels. Its may be more logical to measure T4 or T3 II. Increasingly low (or low-normal) maternal free T4 is associated with adverse fetal/pregnancy outcomes III. There are NO interventional trials.treating low T4 would suppress TSH which has been associated with risk. IV. Measurement of FreeT4 hormone concentrations are fraught with analytic error & variability

43 The Generation R data: Generation R study: Population-based birth cohort in Rotterdam, the Netherlands Followup of Children from fetal life onward 7069 pregnant women enrolled early pregnancy; 5100 evaluable TFT s If Pregnant Mother has freet4 lowest 5 th % (normal TSH) Ghassabian, et al Korevaar, et al Roman, et al Child s IQ (age 6) decreased 4.3pts ~3x increased risk premature delivery 4x increased risk autistic symptoms Uncertainties for several parameters, no linear effect was identified (only a threshold ). All data from single cohort - reanalyzed. Ghassabian, et al. JCEM 2014;99:2383; Korevaar, JCEM 2013;98:4382; Roman, et al, Ann Neurol 2013;74:733

44 Does low FreeT4 during 1 st versus 3 rd trimester matter?: Zhang et al: Large cohort association study; no intervention 6,031 women in China; TSH, FreeT4 1 st & 3 rd timesters Primary Endpoint: Pregnancy outcomes Findings: Low FreeT4 1 st Trimester Increase risk GDM Low FreeT4 3 rd Trimester Increased Preeclampsia Uncertainties Data not reproduced. Difficulty with multifaceted / composite endpoint; No intervention Zhang Y, et al. PLOS One 2017;12(5). PMID

45 Is there any harm from raising FT4?: Johns et al Large cohort analysis of maternal tft s & fetal growth 439 pregnant women in Boston Measurement of fetal growth (ultrasound) & birth weight Findings: Higher maternal freet4 lower Birth Weight Higher maternal freet4 lower head & abd circumference, No associations with maternal TSH Association studies raise many questions. Raising maternal FreeT4 may not be without risk to the fetus Johns et al. JCEM 2018;103:1349

46 How to (can we?) integrate all these variable? What level of TSH matters? What level of freet4 matters? Is TPO Ab positivity important? What is your ethnicity? When during pregnancy are you testing? When during pregnancy are you treating?

47 2017 Thyroid & Pregnancy Guidelines: Active Area of Discussion: IV. How to Treat Maternal Graves Disease, Especially early in Gestation?

48 Case #3a 24yo female presents for care and is seeking pregnancy. She has Graves disease, currently treated with 5mg daily MMI. She feels well. TSH 0.2mIU/L (nl: mIU/L). FreeT4 1.5ng/dL (nl: ng/dl) What would you recommend now? What would you recommend once pregnant?

49 Case #3b 24yo female presents for care newly pregnant (5 wks). She has Graves disease, currently treated with 7.5mg daily MMI. She feels well. TSH 0.2mIU/L (nl: mIU/L). FreeT4 1.6ng/dL (nl: ng/dl) What would you recommend now?

50 Background: Treating severe maternal Hyperthyroidism Data: I. The data confirming when to initiate treatment, and what level to target on treatment, are imperfect. II. New data suggest both MMI and PTU are teratogenic, though profiles differ. III. Question is there any danger from maternal hyperthyroidism itself? Can MMI/PTU be stopped? III. Most important the greatest danger is overtreatment

51 Danish Registry Study: Andersen et al: Population-based cohort in Denmark (n=817,093) Prescription medication and birth defects assessed by national registry >2000 women exposed to ATD during pregnancy I. Medication During Pregnancy: PTU 8.0% Methimazole 9.1% PTU & Methimazole 10.1% II. ONLY Pre-Pregnancy ATD Use: Serious Birth Defects: 5.4% III. No history ATD Use at any time: 5.7% P=ns P<0.01 Andersen, et al. JCEM 2014;98:4373

52 Alexander, et al. Thyroid 2017;27:315.

53 Preconception counselling: Alexander, et al. Thyroid 2017;27:315.

54 2017 Thyroid & Pregnancy Guidelines: Active Area of Discussion: V. Should we universally assess the thyroid function in newly pregnant women?

55 Recent Data: All Associate Maternal TSH with harm: Taylor et al, JCEM 2014 Zhang, PLOS One 2017 Mannisto, JCEM 2013 Anderson, JCEM 2017 Pakkila F, JCEM 2014 Liu H et al. Thyroid 2014 Chen LM, PLoS One, 2014 Increased Miscarriage Risk when TSH>2.5, and climbing impressively if >4.5mIU/L Metaanalysis high qual studies. If non-treated SCH, higher rate miscarriage >223,000 deliveries. Maternal hypot4 increased obstetrical complications 1153 Children born to mothers. HypoT4 in early pregnancy a/w lower 5yrs Finnish Cohort (>9300 pregnancies) increase TSH increased girls ADHD risk Prospective, >3315 pregnancies. Subclinical hypot4 increase miscarriage risk in China >8000 pregnancies in China. Subclinical hypot4 increases HTN, PROM, IUGR, LBW

56 Prospective, Randomized Intervention 17wks Treatment of Maternal Hypothyroidism Does Not Improve Fetal Cognition 97,226 pregnancies screened <20 wks Hypothyroxinemia (TSH , ft4 <0.86) Subclinical Hypothyroidism (TSH 4.0, nl ft4) 526 randomized to LT4 vs. placebo 677 randomized to LT4 vs. placebo Mean 17 wks at randomization; IQ testing (WPPSI) in children at age 5 B Casey et al. NEJM. 2017;276:815

57 Prospective, Randomized Intervention 12wks Treatment of Maternal Hypothyroidism Does Not Improve Fetal Cognition Lazarus et al :(prospective, randomized) 22,000 women: ½ Screened (TSH, ft4) at 12 wks; ½ Not Screened Intervention Arm TSH >2.5 triggered 150mcg LT4 daily. IQ testing of offspring at 3 & 9 years. Primary Endpoint: IQ High TSH Detected & Treated at ~12wks: Control Group: vs. Lazarus et al. NEJM. 2012

58 Prospective, Randomized Intervention 12wks Treatment of Maternal Hypothyroidism Does Not Improve Fetal Cognition Lazarus et al :(prospective, randomized) 22,000 women: ½ Screened (TSH, ft4) at 12 wks; ½ Not Screened Intervention Arm TSH >2.5 triggered 150mcg LT4 daily. IQ testing of offspring at 3 & 9 years. Follow up IQ testing at 9.5yo Mothers Treated for Thyroid Dysfunction (TSH 1.1) Mothers Not Treated for Dysfunction (TSH 4.1) Mothers with NO Dysfunction (TSH 3.6) No Difference Lazarus et al. JCEM 2018 (epub)

59 Prospective, Randomized Intervention 9 wks Treatment of Maternal Hypothyroidism May(?not) Reduce Pregnancy Complications: Negro et al:(prospective, randomized) 4,562 prospective Intervention at 9wks when TSH>3mIU/L. Composite Endpt. Only low-risk TPO+ population studied w/ randomized intervention Rx: LT4 or not Conclusion misleading: No benefit to Universal Screening P< NS Complications / Treated Treated Treated Not -Treated High-risk Low-risk 0 Universal Screening Case Finding Negro et al. JCEM 95: , 2010

60 Prospective, Randomized Intervention 9 wks Treatment of Maternal Hypothyroidism May(?Not) Reduce Pregnancy Complications: Negro et al:(prospective, randomized) 4,562 prospective Intervention at 9wks when TSH>3mIU/L. Composite Endpt. Only low-risk TPO+ population studied w/ randomized intervention Rx: LT4 or not Conclusion misleading: No benefit to Universal Screening Complications / Treated Treated P<0.05 Treated Not -Treated High-risk Low-risk 0 Universal Screening Case Finding Negro et al. JCEM 95: , 2010

61 Uncertainties regarding Screening Can we intervene early enough in pregnancy to make a difference? What endpoint are we seeking to improve? If miscarriage, benefit in screening >12-14 weeks substantially lessens. What TSH (or FreeT4) would trigger an intervention? ETA guidelines Spanish Society of Endocrinology and Nutrition Indian Thyroid Society Indian National Guidelines China majority support universal screening universal screening universal screening selective testing of high-risk women universal screening

62 Summary: Evaluating & treating thyroid illness during pregnancy is complex. Awaiting future data, maternal hypothyroidism (mild or severe) is generally considered dangerous during pregnancy, and avoided when possible. But what is the upper-limit of TSH? Importance of TPO Ab positivity. Check hcg? Data now clearly associate teratogenic effects with both MMI and PTU. Increasingly, no treatment early in gestation is the most favorable option - unless severely ill? New factors, new molecules, & new investigations will continue to move the field forward 2018 & beyond! Thank you! Alexander, NEJM 2004; Kaplan, Thyroid 1992; Mandel, NEJM 1990

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