Should every pregnant woman be screened for thyroid disease?

Should every pregnant woman be screened for thyroid disease? Tal Biron-Shental Rinat Gabbay-Benziv

Is there a debate?

Thyroid screening Guidelines

Targeted case finding criteria Age > 30 years Personal history of thyroid dysfunction Prior head or neck irradiation Prior thyroid surgery Family history Symptoms Presence of Goiter TPO Ab positivity Autoimmunity Infertility Miscarriage or preterm delivery Iodine deficient population Medications and iodinated contrast media Morbid obesity (BMI > 40 kg/m2) Only for American Thyroid Association 2011 guidelines.

Definitions Overt hypothyroidism )OH) TSH >2.5 miu/l + decreased FT4 TSH 10.0 miu/l irrespective of FT4 levels. Isolated hypothyroxinemia (IH) Normal TSH with FT4 at 5th -10th percentile. Subclinical hypothyroidism (SCH) TSH 2.5-10 miu/l with normal FT4 levels. Positive antibodies Anti TPO Ab, anti TG Ab

TEAMBATE Tal Rinat

Screening criteria I. Prevalent diagnosis, important enough to warrant population screening II. Clear evidence of bad outcomes III. Improvement in outcome following intervention IV. Cost-effective AHRQ Publication No. 08-05118-EF July 2008 Wilson, JMG; Jungner, G (1968). "Principles and practice of screening for disease". WHO Chronicle (Geneva: World Health Organization) 22 (11): 473Public Health Papers, #34.

Subclinical Hypothyroidism Elevated TSH level Normal ft4 Symptoms, if present, might be attributed to pregnancy, their absence fails to exclude it Prevalence: 0.25 2.5% Upper limit of thyrotropin in the first trimester of 2.5mIU/L Increased the prevalence of subclinical hypothyroidism from 2%to 3% even up to 15% With iodine deficiency even higher prevalence Inaccurate numbers

Subclinical Hypothyroidism Adverse outcome pre-eclampsia placental abnormalities miscarriages preterm labor low birth weights Low cost blood tests TSH ft4 Thyroid Ab s

Comparison of universal screening with targeted high-risk case finding for diagnosis of thyroid disorders Nazarpour et al, European Journal of Endocrinology, 2016 Universal screening / Targeted high-risk case findings Prospective study, 1600 pregnant women in their first trimester 44.3% had at least one risk factor - high-risk group 55.7% had no risk factors - low-risk group

Comparison of universal screening with targeted high-risk case finding for diagnosis of thyroid disorders Nazarpour et al, European Journal of Endocrinology, 2016 974 (65.8%) - normal thyroid status 506 (34.2%) - thyroid disturbances: Overt hypothyroidism - 1.1% Subclinical hypothyroidism - 30.1% Of women with thyroid dysfunction: 64.4% were in the high-risk group 35.6% were in the low-risk group (P=0.0001) The targeted high-risk case finding approach overlooks about one-third of pregnant women with thyroid dysfunction!

Screening 30% 55% 55% of women with thyroid abnormalities would have been missed using a case-finding approach rather than a universal screening approach. 80%

Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review Boogaard E, Hum Reprod Update 2016 According to the results of Negro et al: 40 women would need to be screened to prevent a single adverse event NNS 1:40

IQ & Brain development

I. 48 TSH>98 % (without treatment) II. 124 euthyroid controls Intelligence tests at 7-9 years IQ tests: lower in study group P=0.005 Haddow et al. N Engl J Med. 1999 Aug 19;341(8):549-55

220 uncomplicated pregnancies TSH, FT4, TPO AB at 12, 32w Bayley scores at 10 month FT4 < 10 th % at 12w correlated with low Bayley scores Pop VG et al. Clinical Endocrinology (1999) 149-155, 50

Lancet 2016 Prospective cohort study TSH, Thyroid Abx, ft4 - prior to 18 GW Assessment of child IQ at the age of 6 yo (n=3839) + brain MRI (646) at 8 yo Both high and low maternal thyroxine concentrations were associated with lower IQ and lower grey matter and cortex volume. The associations remained after adjustments and exclusion of overt thyroid diseases. Overtreatment could also have a potential damage!

Lancet 2016

*Neurodevelopment

*Motor skills

Pregnancy Outcome

18 studies, 3995 pregnant women with SCH Thyroid, 2016

2014 % APO Prospective cohort, 8012 pregnancies. SCH n=371 (4.6%) Euthyroid P aor (95% CI) G-HTN 1.81 3.5 0.02 2.24 (1.25-4.024) PROM 4.97 8.62 0.002 6.01 (3.97-9.099) IUGR 1 2.96 <0.001 3.33 (1.74-6.37) LBW 1.88 4.58 <0.001 2.91 (1.65-5.16)

AJOG 2009

Screening for overt thyroid disease during pregnancy Screening for overt thyroid disease during pregnancy meets the criteria required for the institution of universal screening: Relatively common (0.5-1% of pregnant women) Has serious adverse maternal and fetal outcomes that can be prevented with levothyroxine therapy Cost-effective In addition, it appears that at no additional cost, universal screening will detect pregnant women with overt hyperthyroidism that will allow for treatment and decrease maternal and fetal adverse outcomes.

In Israel we perform so many tests, is TSH screening will decrease pregnancy expenses?

I m confused!!!?

Pubmed 392 manuscripts??? 217 last 5 years???

American Thyroid Association (ATA) Satellite Symposium: The 2016 Release of Two ATA Clinical Guidelines: Management of Hyperthyroidism and Thyroid Illness During Pregnancy Thyroid in pregnancy task force Presented 31.3.2016 Boston USA Planned publication by the end of 2016 Thyroid function test Iodine nutrition Thyroid autoimmunity Infertility Thyrotoxicosis Hypothyroidism Cancer and nodules Fetal and neonatal consideration Lactation Postpartum thyroiditis Screening Future research

Thyroid function tests - 1 Trimester specific references ranges should be defined for every population Should only include pregnant women with: no known thyroid disease optimal iodine intake negative TPO Ab status Free T4 varies with population and manufacture and requires trimester and manufacturer specific values

Diagnosis of subclinical hypothyroidism during pregnancy - 2 If internal or transferable reference ranges are not available, the upper limit of the TSH reference range as applied to non-pregnant patients (usually ~4mU/L) should be used.

Levothyroxine Rx - 3 Levothyroxine recommended Levothyroxine may be considered Levothyroxine not recommended TSH TPO Antibodies

-4 Screening for SCH Insufficient evidence to recommend for/against screening in pregnancy Insufficient evidence to recommend for/against preconception screening with exception of ART Universal screening to detect low FT4 not recommended All women should be verbally screened at initial visit. High risk TSH with reflex TPO Ab for TSH 2.5-10.

What changed everything?

PREVALENCE is determined by DEFINITION TSH varies with ethnicity: Obstet Gynecol. 2005 Dec;106(6):1365-71.

Assessment of thyroid function during firsttrimester pregnancy: what is the rational upper limit of serum TSH during the first trimester in Chinese pregnant women? First trimester TSH in 4800 iodine sufficient pregnant women Reference range: 0.14 4.87 miu/l Only 30% from TSH> 2.5 had SCH at 2 nd /3 rd trimester Reflex point Li et al. J Clin Endocrinol Metab. 2014 Jan;99(1):73-9.

Diagnosis and management of subclinical hypothyroidism in pregnancy Negro et al. BMJ. 2014 Oct 6;349:g4929.

Adverse outcome Adverse pregnancy outcome Child IQ

Prospective study Parkland hospital 11.2000-04.2003 Screening TSH, FT4 at <20 weeks 17,298 screened 404 (2.3%) SCH BUT Rx? Hypothesis? X3 abruption X 1.8 PTD<34 weeks Obstet Gynecol. 2005 Feb;105(2):239-45.

Prospective study FASTER trial 1999-2002 TSH, FT4, TAb at 1 st, 2 nd Tri 10,990 screened 443(2.2%) SCH SCH - No difference! IH PTL, macrosomia, GDM TG/TPO Ab - PPROM Obstet Gynecol. 2008 Jul;112(1):85-92

Prospective study 17,298 women at 1 st trimester Isolated hypothyroxinemia/ab IH 2.3% SCH - No difference! IH No difference! Obstet Gynecol. 2007 May;109(5):1129-35

Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study Group TSH 2.5-5.22 TSH 5.22-10 TPO positive TSH 2.5-5.22 + TPO Ab TSH 5.22-10 + TPO Ab OR for miscarriage 1.62 3.4 2.71 4.96 9.56 Liu et al. Thyroid. 2014 Nov;24(11):1642-9.

And maybe it s better to screen for TPO Ab??? 11.7% TPO Ab+ with normal TSH High obstetrical complications LT4 decreased complications TPO+ LT4 TPO+ TPO- TPO+ LT4 TPO+ TPO- Miscarriage % Preterm deliveries % J Clin Endocrinol Metab. 2006 Jul;91(7):2587-91.

Adverse outcome Adverse pregnancy outcome Child IQ

Will not repeat

Screening criteria I. Prevalent diagnosis, important enough to warrant population screening II. Clear evidence of adverse outcomes III. Improvement in outcome following intervention IV. Cost-effective? AHRQ Publication No. 08-05118-EF July 2008 Wilson, JMG; Jungner, G (1968). "Principles and practice of screening for disease". WHO Chronicle (Geneva: World Health Organization) 22 (11): 473Public Health Papers, #34.

Treatment? RCT I: Lazarus et al. N Engl J Med. 2012 Feb 9;366(6):493-501

10,425 negative 21,846 women <16 weeks 10,924 screening 10,922 control 10,364 negative 109 excluded 499 positive 232 high TSH at median 12w LT4 started 13w 551 positive 264 high TSH at median 12w 147 excluded 390 children at 3y 404 children at 3y Lazarus et al. N Engl J Med. 2012 Feb 9;366(6):493-501

Post hoc analyses: TSH only, FT4 only, RX<14w or >14w, TSH normalization No difference! Lazarus et al. N Engl J Med. 2012 Feb 9;366(6):493-501

RCT II Prospective, randomized, double masked I. SCH II. IH

Eligibility: SCH: TSH 4 mu/l and normal FT4 IH: normal TSH and low FT4 Singleton GA 8-20 weeks LT4 or Placebo Outcome: IQ scores at 3, 5 years Timetable: Enrollment 10.2006-11.2009 Data collection 10.2006-07.2015 Final analysis 07.2015-02.2016

97,226 screened 3,058 SCH (3.1%) 2,805 IH (2.9%) 677 included for randomization 526 included for randomization

Screening criteria I. Prevalent diagnosis, important enough to warrant population screening II. Clear evidence of adverse outcomes III. Improvement in outcome following intervention IV. Cost-effective?? AHRQ Publication No. 08-05118-EF July 2008 Wilson, JMG; Jungner, G (1968). "Principles and practice of screening for disease". WHO Chronicle (Geneva: World Health Organization) 22 (11): 473Public Health Papers, #34.

Cost effective Cost Over - treatment TSH T4, T3 Antibodies 38 ש"ח 80 ש"ח 300 ש"ח

Conclusions Proved APO. Risk based testing tests >40% of the patients and misses 30% of SCH. Clinical symptoms of SCH & OH may be missed as they mimic pregnancy related complains. Screening reveals OH which clearly has APO and improves by treatment cost effective. In Israel we perform so many tests, is TSH screening will decrease pregnancy expenses? No definition no prevalence Conflicting evidence for APO Maybe it s just the Ab? Timing of screening decrease time to treat limited evidence that LT4 can improve outcomes. Over diagnosis over treatment With Ab not necessarily cheap.

ATA guidelines 2016 Verbal screen at initial visit If high risk TSH + reflex TPO Ab if 2.5<TSH <10 TSH <2.5 2.5<TSH <4 4<TSH <10 TSH >10 TPO negative TPO positive TPO negative TPO positive No treatment No treatment Consider treatment Consider treatment Treat LT4 Treat LT4

Conclusion AACE Endocrine society 2007 ATA 2011 Endocrine society 2012 ETA guidelines Spanish society of endocrinology Indian thyroid society Indian national guidelines china Universal screening Selective testing high risk Selective testing high risk Universal screening Vs. aggressive case finding Majority support universal screening Universal screening Universal screening Selective testing high risk Universal screening