Chang Hoon Yim 

Dankook University Cheil General Hospital

Thyroid disease in Pregnancy

Maternal hypothyroidismMaternal FetalGestational hypertension Spontaneous abortion Preeclamsia Small for gestational age PIH Fetal stress during laborAnemia Fetal deathPostpartum hemorrhage Transient congenital hypothyroidismPlacental abruption Possible impairment in cognitive function

Best Pract Res Clin Endocrinol Metab. 2004

Maternal FetalMiscarriage LBW PIHPreterm delivery Goiter

CHF HypothyroidismThyroid storm StillbirthPlacenta abruptio Hyperthyroidism

Maternal hyperthyroidism

Screening for thyroid disease during pregnancy depends on

Is disease common during pregnancy? Does disease have adverse maternal /fetal effects? Is there a safe, inexpensive, & universally available test?Does therapeutic interventions exist? Is screening and intervention cost-effective?

Prevalence of thyroid dysfunction in pregnant women

0.3 – 0.5% Overt hypothyroidism 2 – 2.5% Subclinical hypothyroidism (SCH) Subclinical hyperthyroidism 0.1 – 0.4% Overt Hyperthyroidism

산모 과거력상 갑상선질환의 빈도 비교

2009 년 6353 명에서 314 명 (4.9%)2010 년 7010 명에서 326 명 (4.7%) ( 제일병원산모인덱스 2009, 2010)

2009 년 2010 년

치료중

기능저하증 69 1.1% 123 1.8% 기능항진증 28 0.4% 37 0.5% 갑상선암 15 0.2% 20 0.3%과거치료

기능저하증 44 0.7% 11 0.2% 기능항진증 39 0.6% 29 0.4% 갑상선결절 26 0.4% 36 0.5%갑상선질환 ( 진단 모름 ) 93 1.5% 70 1.0%

314 명 4.9% 326 명 4.7%

Serum TSH testing is inexpensive, is widely avail-able, and is a reliable test.

Trimester-specific reference ranges for TSH should be applied. (B)

Recommended reference range for TSH (I) 1st trimester : 0.1–2.5 mIU/L 2nd : 0.2–3.0 3rd : 0.3–3.5 (3.0)

Sample Trimester-Specific Reference Intervals for Serum TSH

　 Trimester

Reference First Second Third

Haddow † 0.94 (0.08-2.73) 1.29 (0.39-2.70)

Stricker ‡ 1.04 (0.09-2.83) 1.02 (0.20-2.79) 1.14 (0.31-2.90)

Panesar † 0.8 (0.03-2.30) 1.1 (0.03-3.10) 1.3 (0.13-3.50)

Soldin ‡ 0.98 (0.24-2.99) 1.09 (0.46-2.95) 1.2 (0.43-2.78)

Bocos-Terraz ‡ 0.92 (0.03-2.65) 1.12 (0.12-2.64) 1.29 (0.23-3.56)

Marwaha † 2.10 (0.60-5.00) 2.40 (0.43-5.78) 2.10 (0.74-5.70)

(Thyroid 2011)†: 5th and 95th pefcentile, ‡: 2.5 th and 97.5th percentile

제일병원 TSH 정상치 0.30 - 4.5 mU/L

임신 초기산모

TSH 정상 상한치를 4.5 에서 2.5 mU/L 로 변경

임신 초기산모 1,826 명중 ,

TSH > 2.5 인 경우가 387 명 (21.0 %)

weeks number %percentile

5 median 955 55 6.3 0.76 2.20 4.616 155 17.6 0.30 2.10 5.407 265 30.1 0.20 1.60 4.178 168 19.1 0.11 1.28 3.649 125 14.2 0.10 1.10 3.57

10 65 7.4 0.03 0.95 3.8511 22 2.5 0.01 0.85 2.9212 24 2.7 0.01 1.10 4.38

total 879 100 0.10 　 1.50 　 4.20 　

Gestational week-specific TSH values

( 제일병원 2012)

Gestational weeksGestational weeks

TSH

Num

bers

( 제일병원 산모인덱스 2010)

6 7 8 9 10 11 12 13 140

50

100

150

5 6 7 8 9 10 11 12 130.0

1.0

2.0

3.0

4.0

Gestational age (weeks)

TS

H (m

U/L

)

95th

50th

5th

Gestational age (weeks)

Num

bers

Gestational age-specific reference ranges for TSH

Importance of Gestational Age–Specific Reference Ranges Singleton pregnancies (solid lines) and twin (dashed lines)

(Dashe JS, Obstet Gynecol 2005)

(Zornitzki T, IMAJ 2014)

What is the Upper Limit of Serum TSH During the First Trimester in Chinese Pregnant Women? (Chenyan Li, J Clin Endocrinol Metab , 2014)

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 upper limit of serum TSH in the first trimester was much higher than 2.5 mIU/L in Chinese pregnant women.

Thyroid Function in Pregnancy: What Is Normal? (Marco Medici, Clinical Chemistry, 2015)

Institutions do not rely on fixed universal cutoff concentrations, but calculate their own pregnancy-specific reference intervals.

Adverse maternal and fetal effects

Associated with Overt hypothyroidism Overt hyperthyroidism

Not associated with Subclinical hyperthyroidism

? Subclinical hypothyroidism (SCH)

Subclinical hypothyroidism (SCH)

Many studies association between SCH and adverse preg-nancy outcome (increased risk of placental abruption, preterm delivery, miscarriage & fetal death)

Some studies no association

Children of treated women

with hypothyroidism(N=14)

Children of untreated women with hypothy-

roidism(N=48)

Control

(N=124)IQ score 111 100 107

p=0.20 p=0.005

IQ =< 85 0 19 5p=0.90 p=0.007

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

(Haddow JE, N Engl J Med 1999)

62/25,000 children

Universal Screening vs Case Finding for Detection and Treatment of Thyroid Hormonal Dysfunction During pregnancy (Negro R, JCEM 2010)

Women assessed 4657 95 excluded for known

thyroid disease

Randomized4562

Case finding2282

Universal screening

2280Analyzed

High risk454

Euthyroid432

Hypothy-roid20Hyperthy-roid2

Low risk1828

Euthyroid1789

Hypothy-roid34Hyperthy-roid5

Analyzed & check TSH

High risk481

Euthyroid451

Hypothy-roid19Hyperthy-roid2

Low risk1789

Euthyroid1747

Hypothy-roid44Hyperthy-

roid7

check TSH

Number of women experiencing at least one adverse outcome

Case finding (n=2257) Universal screening (n=2259)

High risk Low risk Total High risk Low risk Total

Euthyroid without Ab

166 (41.3%) 659 (39.5%) 824 (39.9%) 179 (41.7%) 637 (39.1%) 816 (39.7%)

Euthyroid with Ab

10 (40%) 49 (47.1%) 59 (45.7%) 13 (48.1%) 45 (42.9%) 58 (43.9%)

Hypothyroid 9 (45%) 31 (91.2%) 40 (74.1%) 6 (31.6%) 15 (34.9%) 21 (33.9%)

Hyperthyroid 2 (100%) 5 (100%) 7 (100%) 1 (50%) 4 (57.1%) 5 (55.5%)

Total 187 (41.7%) 742 (41.1%) 930 (41.2%) 199 (41.7%) 701 (40.5%) 900 (39.8%)

(Negro R, JCEM 2010)

Complications in patients with thyroid dysfunction, divided by study group (case finding or universal screening) and risk classification (high risk or low risk)

(Negro R, JCEM 2010)

Antenatal Thyroid Screening and ChildhoodCognitive Function (Lazarus JH, N Engl J Med 2012)

21,846 women

10,924 Screening(Assay within 1

wk)

10,922 Control(Assay after deliv-

ery)499 (4.6%) tested posi-tive

242 low fT4232 high TSH

25 low fT4 & high TSH499 LT4 at 13 gwk

390 childrenpsychological

test

404 childrenpsychological

test

After delivery551 (5.0%) tested posi-

tive257 low fT4

264 high TSH30 low fT4 & high TSH

(Lazarus JH, N Engl J Med 2012)

Screening Gr(N=390)

Control Gr(N=404)

G wks median 12.3 12.3 NS interquartile range 11.6 – 13.6 11.6 – 13.5 NS

TSH (median) median 3.8 3.2 NS interquartile range 1.5 – 4.7 1.2 – 4.2 NSIQ mean 99.2 ± 13.3 100.0 ± 13.3 0.40 <85 (% of children) 12.1 14.1 0.39

Cost-effective

Universal screening is cost-effective, not only compared with no screening but also compared with screening of high-risk women.

Universal screening remained cost-effective even when only overt hypothyroidism, rather than

subclinical hypothyroidism, was detected and treated.(Dosiou C, J Clin Endocrinol Metab, 2012)

TSH screening in pregnant women ?

Endo Society (2012), committee did not reach consensus on the screening.

“Some members recommended screening”

“Some members recommended neither for nor against uni-versal screening. These members strongly support ag-gressive case finding”

TSH screening in pregnant women

The current recommendations for targeted screening for women at high risk for thyroid dysfunction

Endocrine Society (2012) American Thyroid Association (2011)Aged > 30 years Aged > 30 FHx of autoimmune thyroid disease orHypothyroidism

FHx of thyroid disease

Hx of thyroid surgery Hx of thyroid dysfunction and/or thyroid opGoiter GoiterThyroid antibodies Thyroid antibodiesSx or signs of thyroid hypofunction Sx or signs suggestive of hypothyroidismT1DM or other autoimmune disorders T1DM or other autoimmune disordersHx of miscarriage or preterm delivery Hx of miscarriage or preterm deliveryInfertility InfertilityPrior head or neck irradiation Prior head or neck irradiationCurrent levothyroxine replacement  Living in a region with iodine deficiency    Morbid obesity  Treated with amiodarone or lithium   Recent exposure to contrast agents

Screened thyroid function in 1560 pregnant women,

413 women (26.5%), as a high-risk group (PHx or FHx of thyroid disorder or PHx of other autoimmune disease)

12 of 40 women with raised TSH (30%) were in the low-risk group.

(Vaidya B, J Clin Endocrinol Metab, 2005)

55% of women with thyroid abnormalities would have been missed using a case-finding rather than a universal screening approach. (Horacek J, Eur J Endocrinol, 2010)

Consensus guideline risk factor Occurrence (%)Personal history of a thyroid disorder 4 (8%)Family history of a thyroid disorder 15 (31%)

Goitre 1 (2%)History of positive thyroid antibodies 0 (0%)Symptoms/signs of thyroid hypo/hyperfunction 0 (0%)History of type 1 diabetes mellitus 0 (0%)

History of other autoimmune disorders 1 (2%)Infertility 0 (0%)History of head/neck irradiation 0 (0%)

History of miscarriage or preterm delivery 7 (14%)None of them 27 (55%)

(in Cheil Hospital)

in 511 first trimester women,

TPO-Ab (+) 65 / 511 (12.7%)

TPO-Ab (+) with subclinical hypothyroidism 15 / 511 (2.9%)

Hx of thyroid dysfunction or Tx (+) 7 / 15

(-) 8 / 15

(in Cheil Hospital)

523 1st trimester women(mean age 33.6 ± 3.7 yrs, IUP 6.8 ± 2.0 wks)

Age > 30 yrs 425PHx of thyroid disease 46FHx of thyroid disease 51Age > 30 yrs or PHx or FHx 436

Low risk87 women(16.6%)

High risk436 women

(83.4%)

2010 년에 분만한 6072 명에서 산모의 연령분포 ( 제일병원산모인덱스 2010)

평균연령 33.4 ± 3.6 세

연령 >30 세4782 명 (78.6%)

Universal screening is superior in detecting thyroid dysfunction than selective screening.

In Korea 1st visit : IUP 6.8 주 delivery age : 33.6 세

To screen or not to screen, that is the question.

- European Thyroid Association, 2010 42% responders screened all pregnant women

for thyroid dysfunction.

- American Thyroid Association, 2013Universal screening was recommended by 74%

of the survey respondents.

Screening Pregnant Women for Overt Thyroid Disease(Alex Stagnaro-Green, JAMA, 2015)

Sufficient evidence exists for the routine screening to de-tect and treat overt thyroid disease during pregnancy.

The lack of data regarding the treatment of subclinical hy-pothyroidism should not affect the decision to screen for overt thyroid disease.