1. Thyroid Disease in Pregnancy 2011 Update
Endocrinology Rounds
February 16, 2011
Selina Liu
PGY5 Endocrinology 1

2. Objectives
To briefly review thyroid anatomy and physiology in pregnancy and fetal thyroid physiology
To review causes of thyroid disease in pregnancy
To review the maternal and fetal outcomes of thyroid disease in pregnancy
To discuss the controversy surrounding screening for thyroid disease in pregnancy

3. Objectives
To review special considerations in management of thyroid disease in pregnancy
To highlight recent articles published on thyroid disease in pregnancy

4. Thyroid in Pregnancy non-pregnant: 10-30 g (North America)
increased vascularity
thyroid gland hyperplasia
if enlargement noted incidentally on exam, may lead to lab evaluation of thyroid function
normal pregnancy - significant but reversible changes in maternal thyroid physiology

5. Total T4: 150 % above normal non-pregnant reference interval
Casey BM & Leveno KJ. Obstet Gynecol 2006;

6. Clinical Importance of Physiological Changes
Increased TBG
Placental de-iodination of T4
Increased iodine clearance (renal clearance and fetal transfer)
Need for  T4 production
 total T4, T3
interference with fT4 assay
Need for  T4 production
 T4 and T3 metabolism
Need increased T4 to maintain fT4 levels
 need for iodine supplementation
risk of maternal & fetal hypothyroidism and goitre
Keely E & Casey BM (2010). Thyroid disease in pregnancy. In RO Powrie, MF Greene, W Camann (Eds) deSwiet’s Medical Disorders in Obstetric Practice (5th Edition pp322-34). West Sussex, Wiley-Blackwell

7. Clinical Importance of Physiological Changes
 bhCG (1st trimester)
 TSH-R Abs (TSI/TBII)
 thyroid antibodies (post-partum)
 fT4 and  TSH
may have mild transient thyrotoxicosis
Graves’ disease may improve during pregnancy
exacerbation of Graves’ disease
precipitation of postpartum thyroiditis
?need for trimester-specific ranges
Keely E & Casey BM (2010). Thyroid disease in pregnancy. In RO Powrie, MF Greene, W Camann (Eds) deSwiet’s Medical Disorders in Obstetric Practice (5th Edition pp322-34). West Sussex, Wiley-Blackwell

8. Fetal Thyroid Physiology
12 weeks gestational age:
embryogenesis of fetal thyroid gland is complete
synthesis of thyroid hormone
fetal TSH also detectable
Mid-gestation:
negative feedback control of thyroid hormone synthesis develops
Throughout gestation:
pituitary-thyroid axis continues to develop

9. Fetal Thyroid Physiology
What crosses the placenta?
iodine
T3, T4 (poorly) – but large maternal–fetal gradient
maternal TRH – but negligible amount in maternal circulation
TSH-R antibodies (TSI/TBII)
anti-thyroid medication – methimazole, PTU
Maternal TSH does NOT cross the placenta

10. Fetal Thyroid Physiology
Prior to 12 weeks gestation,
fetus dependent on maternal thyroid hormone production
critical time for fetal neural development (as well as later in gestation)
Throughout pregnancy,
T4 and iodine supplied by mother to fetus
maternal iodine supply very important throughout
unclear role of maternal T4 after fetal T4 production begins

11. Thyroid Disease in Pregnancy
Hyperthyroidism
Hypothyroidism
Post-partum Thyroiditis
Thyroid Nodules

12. Hyperthyroidism in Pregnancy
~ 0.2% of pregnancies complicated by hyperthyroidism
Causes:
Graves’ Disease
toxic nodule/MNG
thyroiditis
exogenous iodine
TSHoma
struma ovarii
non hCG-mediated
gestational transient thyrotoxicosis
hyperemesis gravidarum
gestational trophoblastic disease
familial gestational thyrotoxicosis
hCG-mediated

13. Hypothyroidism in Pregnancy
overt hypothyroidism ~ % of pregnancies
subclinical hypothyroidism ~ 3-5% of pregnancies
Causes:
Hashimoto’s Thyroiditis
iodine deficiency
prior RAI ablation/thyroidectomy
medications (lithium, amiodarone)
central hypothyroidism (rare)
(developed world)
(worldwide)
Either pre-existing or newly diagnosed in pregnancy
? genetic susceptibility

14. Subclinical Hypothyroidism
TSH variable
~ 40-60% of TSH variability under genetic control?
Genome Wide Association Scanning:
SNP in PDE 8B gene associated with circulating TSH levels
PDE 8 B – catalyzes hydrolysis of cAMP
responsible for 2.3% of variance in TSH
each copy of allele present – associated with an increase in
TSH concentration of 0.13 mIU/L
Found on GWAS – PDE 8B SNP (also TSH-R, THR, deiodinases, thyroid hormone transporters)
In thyroid – decreased cAMP  decreased responsiveness to TSH, therefore decreased thyroid hormone production
Arnaud-Lopez L et al Am J Hum Genet 82:

15. Subclinical Hypothyroidism – PDE8B
Arnaud-Lopez L et al Am J Hum Genet 82:

16. 1014 healthy pregnant women at 28 wks
TFTs, anti-TPO, PDE8B genotype (AA, AG, GG)
developed reference range (based on anti-TPO – subjects)
TSH mIU/L
AA group had highest, GG group had lowest TSH
AA group - greater proportion with TSH >4.21 mIU/L (ULN)
In thyroid – decreased cAMP  decreased responsiveness to TSH, therefore decreased thyroid hormone production

17. SNP in PDE8B associated with  TSH - AA highest, GG lowest
no difference in fT3, fT4 or prevalence of anti-TPO + Abs
In thyroid – decreased cAMP  decreased responsiveness to TSH, therefore decreased thyroid hormone production

18. Post-partum Thyroiditis (PPT)
due to rebound autoimmunity post-partum
lymphocytic infiltration, transient changes in thyroid function
+ anti-TPO in >90% women with PPT
those with high titres in early pregnancy more likely to be affected (50-60%)
high incidence in T1DM (18-25%)
(high prevalence anti-TPO)

19. Post-partum Thyroiditis (PPT)
Pearce EN et al N Engl J Med 348:

20. Thyroid Nodules in Pregnancy
nodule > 1cm – FNAB
if 1st or early 2nd trimester and malignant OR rapid growth, offer surgery in 2nd trimester
if follicular or papillary, no advanced disease – can defer surgery until post-partum
can suppress TSH if: previously treated thyroid cancer, FNAB suspicious or positive for malignancy, or if delaying surgery until post-partum
to detectable levels (keep fT4 in normal range)
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

21. Thyroid Nodules in Pregnancy
RAI with I131 should NOT be given to pregnant women or those breastfeeding
women with thyroid cancer treated with therapeutic doses of RAI should avoid pregnancy for 6-12 months post-ablation
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

22. Maternal Outcomes - Hyperthyroidism
increased risk of:
spontaneous pregnancy loss
CHF
thyroid storm
preterm birth
preeclampsia
perinatal morbidity & mortality

23. Fetal Outcomes – Maternal Hyperthyroidism
depends on degree of thyrotoxicosis, cause, and treatment of mother
in most cases, fetus is euthyroid
but, transplacental transfer of TSH-R Abs (TSI/TBII) can cause fetal Graves’ disease
1-10% of neonates of affected women
risk directly related to maternal Ab titre in 3rd trimester
manifestations:
fetal tachycardia
high output heart failure
hydrops fetalis
Chronic exposure to hyperthyroidism from inadequately treated maternal hyperthyroidism – may impair maturation of fetal HPT axis, leading to central congenital hypothyroidism in infant
craniosynostosis
IUGR
fetal goitre

24. J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47
Fetal Outcomes – Maternal Hyperthyroidism
Endocrine Society Clinical Practice Guidelines 2007
measure TSH-R Abs prior to pregnancy or before end of 2nd trimester in women with:
current Graves’ Disease
prior history of Graves’ Disease and I131 treatment or thyroidectomy
previous neonate with Graves’ Disease
if – TSH-R Abs and don’t require anti-thyroid Rx
low risk of fetal/neonatal thyroid dysfunction
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

25. Fetal Outcomes – Maternal Hyperthyroidism
if + TSH-R Abs, need close fetal monitoring:
fetal heart rate at each OB visit - ?tachycardia
fetal ultrasound – assess growth, ?goitre – especially if mother on anti-thyroid medication
consider serial U/S q2-4 wks in 3rd trimester – if very high TSH-R Abs titres
? fetal blood sampling for thyroid indices – not routine
if high maternal TSH-R Abs, evidence of IUGR, fetal CHF, or fetal goitre
Fetal blood sampling – if in doubt if due to TSH-R Abs or from hypothyroidism from overtreatment with ATDs
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47
ACOG Practice Bulletin Obstet Gynecol 2002, 100(2):

26. Maternal Outcomes - Hypothyroidism
increased risk of:
early pregnancy failure
preeclampsia
placental abruption
treatment of women with overt hypothyroidism associated with improved pregnancy outcomes

27. Fetal Outcomes – Maternal Hypothyroidism
increased risk of:
low birthweight
stillbirth
intellectual impairment
especially if overt maternal hypothyroidism in 1st trimester

28. Outcomes – Subclinical Thyroid Disease
less clear effect of:
subclinical hypo/hyperthyroidism
euthyroid thyroid autoimmunity (+ autoantibodies)
maternal hypothroxinemia
normal TSH but low fT4
on both maternal and fetal outcomes

29. population-based cohort - Netherlands
3659 children and their mothers (Apr/02-Jan/06)
examined association between early pregnancy thyroid function and cognitive function in early childhood
maternal TFTs (mean 13.3 wk GA)
verbal/nonverbal cognitive development – as per mailed parent-report measures (18 and 30 months)
specifically looked at maternal hypothyroxinemia
(normal TSH, but fT4)

30. Mild hypothyroxinemia Normal TSH fT4 <11.76 (10th %ile)
TSH range
fT (non-preg)
Hypothyroid
TSH>2.5, fT4 <11
Hyperthyroid
TSH <0.03, fT4>25
Mild hypothyroxinemia
Normal TSH
fT4 <11.76 (10th %ile)
Severe hypothyroxinemia
fT4 < (5th %ile)
Hypothyroxinemia = normal TSH but low fT4
mild fT4 <11.76 (<10th %ile), severe fT4 <10.96 (<5th%ile)

31. mild hypothyroxinemia significantly related to expressive language delay across ages
severe hypothyroxinemia predicted  likelihood of expressive language delay at 18m, 30m, and across ages

32. severe hypothyroxinemia predicted  likelihood of nonverbal cognitive delay at 30m

33. Conclusions:
maternal hypothyroxinemia predicted a higher risk of verbal and nonverbal cognitive delay in early childhood
maternal TSH did not predict cognitive outcomes
need more studies assessing potential benefit of iodine or T4 supplementation in early pregnancy before can justify implementation of fT4 screening in early pregnancy

34. Screening in Pregnancy ?
What is a normal TSH in pregnancy?
Gestational age-specific TSH reference range?
several studies, in variety of populations
reference ranges in non-pregnant populations are not applicable to pregnancy

35. Gestational Age-Specific TSH Range
Dashe JS et al Obstet Gynecol 106:753-7
pregnancies
singleton and twin pregnancies
measured TSH
assay reference 0.4 – 4
created nomogram based on gestational age
To allow for detection of overt undiagnosed thyroid disease, after first 2000 women, developed preliminary TSH percentile values without adjustment for GA for entire group, and fT4 level obtained if above 95%ile or below 5%ile.
TSH elevated or suppressed if above or below 2 SD from the mean

36. 342 women (singleton) with TSH above 97.5%ile
95 (28%) would not have been identified with TSH elevation as per assay reference value
340 women (singleton) with TSH below 2.5%ile
1448 (11%) euthyroid women would have been incorrectly characterized as abnormal as per assay reference value
342 women with singleton pregnancies above 97.5%ile
None of the twin pregnancies had TSH values >4.0, and 15 (11%) had TSH <0.4
Dashe JS et al Obstet Gynecol 106:753-7

37. Gestational Age-Specific TSH Range
Gestational-age specific normal TSH range
converted TSH values to MoM “multiples of median” to facilitate use in other populations
97.5%ile values for TSH (i.e. upper limit) presented as MoM
Dashe JS et al Obstet Gynecol 106:753-7

38. Thyroid 2011 Jan 22 epub ahead of print
goal – to calculate gestational age-specific TSH, fT4 and fT3 reference intervals in an iodine sufficient, thyroid antibody-negative population
also – to establish association between BMI and fT4, fT3
prospective population-based cohort
Northern Finland Birth Cohort 1986 (9632 singleton births)
Thyroid 2011 Jan 22 epub ahead of print

39. Assay reference range TSH 0.35-4.94
Thyroid 2011 Jan 22 epub ahead of print

40. Thyroid 2011 Jan 22 epub ahead of print19
Assay reference range
fT4 9-19
Assay reference range fT
5.7
Thyroid 2011 Jan 22 epub ahead of print

41. Thyroid 2011 Jan 22 epub ahead of print
95%ile selected as upper limit
therefore, upper limit of mU/L in 1st trimester and mU/L in early 2nd trimester
Thyroid 2011 Jan 22 epub ahead of print

42. Thyroid 2011 Jan 22 epub ahead of print
TSH increases and fT4 decreases with increasing BMI
fT3 increases with increasing BMI
Thyroid 2011 Jan 22 epub ahead of print

43. Screening in Pregnancy?
YES - ? potential harm to fetus if undiagnosed thyroid disease
NO – ? unclear benefits of screening in preventing adverse events
screening of only high-risk women failed to detect 30% of hypothyroid and 69% of hyperthyroid women
Vaidya B et al J Clin Endocrinol Metab 92:203-7

44. J Clin Endocrinol Metab 2010 95(4):1699-707
4562 women, 2 centres in Italy
randomized to universal screening or case-finding
stratified as high risk or low risk
all women in universal screening group, and high risk women in case-finding group, had TSH, fT4, antiTPO
low risk women in case-finding group:
serum frozen, tested post-partum
Rx LT4 if TSH >2.5 if +anti-TPO, or Rx antithyroid medication if hyperthyroid
J Clin Endocrinol Metab (4):

45. J Clin Endocrinol Metab 2010 95(4):1699-707
Inferred NNT = 1.8 to prevent 1 women from adverse outcome
J Clin Endocrinol Metab (4):

46. J Clin Endocrinol Metab 2010 95(4):1699-707
No difference in total number of adverse outcomes in case finding vs screening
Majority of adverse outcomes in euthyroid groups
J Clin Endocrinol Metab (4):

47. Interaction between thyroid status and trial arm:
low risk women: adverse outcomes less likely in screening vs case finding
inferred NNT = 1.8
36/39 had at least 1 adverse outcome
19/51 had at least 1 adverse outcome
Mixed logistic model
Inferred NNT = 1.8 to prevent 1 women from adverse outcome
J Clin Endocrinol Metab (4):

48. J Clin Endocrinol Metab 2010 95(4):1699-707

49. J Clin Endocrinol Metab 2010 95(4):1699-707
universal screening vs case-finding did not result in less adverse outcomes
BUT - low risk women in universal screening group with abnormal thyroid function (who were treated) avoided adverse outcomes more often than low risk women in case finding group with abnormal thyroid function (not detected, so not treated)
Majority of adverse events (95%) were in euthyroid women
J Clin Endocrinol Metab (4):

50. Screening in Pregnancy?
CATS study – Controlled Antenatal Thyroid Screening
multicentre, prospective randomized trial in UK from
~ women, blood drawn prior to 16 wks GA
before testing, randomized to “screening” or “control”
screening group – tested, and if TSH or  fT4 – Rx LT4
control group – tested post-partum, and if TSH or  fT4 – Rx LT4 post-partum
1o outcome: children’s IQ at months - no difference
97.5%ile TSH 4.2, 2.5%ile fT4 11.2

51. J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

52. Management – Special Considerations
Hyperthyroidism
goal – fT4 in upper limit normal range using lowest possible dose, monitor q4 weeks
PTU vs. methimazole ? – both equally effective
benefits of PTU:
crosses placenta less readily, less excreted in breastmilk
decreased conversion fT4 to fT3
methimazole – risk of aplasia cutis, esophageal/choanal atresia (or is it due to hyperthyroidism itself?)
If pt already on methimazole prior to pregnancy, switch to PTU
Aplasia cutis 0.03%, choanal atresia OR=18

53. Management – Special Considerations
Endocrine Society Clinical Practice Guidelines – 2007
PTU is first line, especially during 1st trimester (organogenesis)
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47
However – concern re: PTU and hepatotoxicity
2009 – meeting between American Thyroid Association and U.S. FDA reviewing role of PTU vs. methimazole in pregnancy
consider changing to methimazole in 2nd trimester?
Cooper DS & Rivkees SA J Clin Endocrinol Metab, 94(6):1881-2
MMZ can cause hepatotoxicity also, but less common – also more cholestatic, vs. PTU is more hepatocellular

54. Cochrane Database Syst Rev 2010 (9):CD008633
systematic review to assess the effects of interventions for preventing or treating hyperthyroidism in pregnant women
criteria – RCTs (or “quasi-randomized” trials), including abstracts, comparing antithyroid treatments in pregnant women
unable to identify any eligible studies….
Cochrane Database Syst Rev 2010 (9):CD008633

55. Cochrane Database Syst Rev 2010 (9):CD008633
Conclusions:
unable to comment on implications for practice
early identification of hyperthyroidism before pregnancy may allow a woman to choose RAI or surgery before planning to have a child
Cochrane Database Syst Rev 2010 (9):CD008633

56. Br J Clin Pharmacol 2009, 68(4):609-17
PTU in Pregnancy
Br J Clin Pharmacol 2009, 68(4):609-17
prospective observational controlled cohort study –
115 PTU-exposed pregnancies and 1141 controls
1o outcome – rate of major structural anomalies
PTU exposure between weeks 4-13 GA
2o outcomes – rate of fetal/neonatal thyroid dysfunction +/- goitre
PTU exposure beyond 13 weeks GA
other – pregnancy outcomes, pre-term delivery, birth weight

57. PTU in Pregnancy median daily dose of PTU 150 mg
PTU women – older (31 (28-35) vs 30 (27-33), more miscarriages 29.1% one or more vs 20%
55% on PTU prior to pregnancy, 46% started in 1st trimester
Median daily dose 150 mg
median daily dose of PTU 150 mg
Rosenfeld et al Br J Clin Pharmacol, 68(4):609-17

58. Rosenfeld et al. 2009 Br J Clin Pharmacol, 68(4):609-17
PTU in Pregnancy
data on neonatal thyroid function in 87 cases and fetal thyroid ultrasound in 89 cases
16/87 had thyroid dysfunction:
hypothyroidism - 7/74 (9.5%) pregnancies with PTU exposure after 13wks resulting in live birth
dose range mg/day – dose constant until goitre found
3 without goitre, 4 with goitre
hyperthyroidism – 9/87 (10.3%)
dose range mg/day – 50% dose constant, 50% dose had been decreased
7 without goitre, 2 with goitre
Rosenfeld et al Br J Clin Pharmacol, 68(4):609-17

59. Rosenfeld et al. 2009 Br J Clin Pharmacol, 68(4):609-17
PTU in Pregnancy
Conclusions:
no increased risk of major anomalies with PTU exposure from 4-13 weeks GA
PTU exposure after 13th week GA:
9.5% neonatal hypothyroidism
10.3% neonatal hyperthyroidism
<50% goitre in neonates with thyroid dysfunction
role of directed fetal thyroid ultrasound in prenatal diagnosis of thyroid dysfunction, and for modification of PTU dosing ?
Rosenfeld et al Br J Clin Pharmacol, 68(4):609-17

60. Obstet Gynecol 2010, 116 Suppl 2:485-7
PTU in Pregnancy
started PTU 1st trimester for Graves’ Disease
at 30 wks GA, fever, sore throat, malaise, cough, dyspnea
WBC 0.7 x109/L (3-10 x109/L), neutrophils 0.1x109/L (1.5-8 x109/L), lymphocytes 0.5 x109/L (1-3.5 x109/L)
PTU stopped, Rx antibiotics & bB, expectant management
required thyroidectomy at 35 wks GA
Only 1 prior case report in pregnancy (24 weeks) 2009
General population 0.4% risk agranulocytosis
Obstet Gynecol 2010, 116 Suppl 2:485-7

61. Management – Special Considerations
Hypothyroidism – LT4
if diagnosed pre-pregnancy, target TSH <2.5 prior to pregnancy
if diagnosed during pregnancy, normalize TFTs as rapidly as possible
goal – TSH < 2.5 mIU/L in 1st trimester < 3.0 mIU/L in 2nd and 3rd trimesters or to trimester-specific normal TSH range
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

62. Management – Special Considerations
Hypothyroidism – LT4
thyroid hormone requirements  by 20-40% in pregnancy
? best way to meet these increased requirements in women with pre-existing hypothyroidism already on replacement

63. Management – Special Considerations
Endocrine Society guidelines do not specify how
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47

64. prospective randomized trial
enrolled 60 pregnant women with 1o hypothyroidism on LT4, either seeking pregnancy or newly pregnant (<11wks GA)
on stable dose of LT4 for at least 6 wks prior, with normal baseline TSH within 6 months of conception
after pregnancy confirmed, randomized to either:
group A – increase by 2 tablets/week (extra tablet Sat, W)
29% dose increase
group B – increase by 3 tablets/week (extra tablet M, W, Fri)
43% dose increase
If prior thyroid cancer, pre-pregnancy TSH
If no thyroid cancer, pre-pregnancy TSH 0.5-5

65. LT4 dose adjusted q 4 wks as per protocol
repeat TSH, total T4, thyroid hormone binding ratio q 2 weeks until 20 wks GA, then at 30 wks
LT4 dose adjusted q 4 wks as per protocol
wks 4, 8, 12, 16, 20, 30
on other weeks, LT4 changed only if TSH >10 or <0.1
wks 6, 10, 14, 18

66. 1 stillbirth (20 wks – incompetent cervix) 1 molar pregnancy
12 women didn’t complete protocol – mean prepregnancy TSH 1.2 (not different), pre-pregnancy LT4 requirement 99ug/d (not different)
10 miscarriages (16.6%)
1 stillbirth (20 wks – incompetent cervix)
1 molar pregnancy

67. If prior thyroid cancer, pre-pregnancy TSH 0.1-2.5
If no thyroid cancer, pre-pregnancy TSH 0.5-5

70. initial LT4 dose increase normalized TSH <5 in all patients for the remainder of the 1st trimester
initial LT4 increase caused TSH suppression <0.5 (or <0.1 in thyroid cancer patients) in:
8/25 = 32% in Group A
15/23 = 65% in Group B
Elevation: Group A – 2 women at wk 14 and 16 required dose increase (both athyreotic), Group B – 1 woman 2x (at wk 14, 16) required dose increase.
Suppression: 78% occurred before 14 wks GA (though avg TSH only mildly below non-pregnant ref range)
P <0.01

71. 18/29
20/32
P=0.02
13/20

72. also investigated optimal frequency of TSH evaluation
in 25 patients in Group A:
if tested every 4 wks, 24/26 (92%) of abnormal TSH values would have been detected
if tested every 6 wks, 19/26 (73%) of abnormal TSH values would have been detected

73. Conclusions:
a 29% LT4 dose increase (2 tablets extra/week) significantly decreased risk of maternal hypothyroidism throughout 1st trimester
q4 week TSH required to detect further changes in dose requirements
predictors of suppression: pre-pregnancy LT4 dose, pre-pregnancy TSH and etiology of hypothyroidism

74. stable LT4 dose pre-conception as at first visit divided into:
retrospective study
53 pregnant women on LT4, with pre-conception (within 6 months) TSH <2.5, but within normal range
stable LT4 dose pre-conception as at first visit
divided into:
Group 1 – women who required LT4 dose increase
Group 2 – women who did not require dose increase
2010 Thyroid 20(10):1175-8

75. pre-conception TSH higher in Group 1 vs. Group 2
mU/L vs mU/L (p<0.005)
when pre-conception TSH – 50% needed 
when pre-conception TSH – 17.2% needed 
(p<0.02)
As per Endo guidelines, with TSH <2.5 = 32.1% would still require dose increase!
2010 Thyroid 20(10):1175-8

76. Management – Special Considerations
Subclinical Hypothyroidism
recall: ~3-5% of pregnancies
does this require treatment?
is there any evidence showing benefit in treating?
what about euthyroid women with + antibodies?

77. Cochrane Database Syst Rev 2010 (7):CD007752
to identify interventions used in management of clinical and subclinical hypothyroidism in pregnancy
to ascertain the impact of these interventions on important maternal, fetal, neonatal and childhood outcomes
Cochrane Database Syst Rev 2010 (7):CD007752

78. Cochrane Database Syst Rev 2010 (7):CD007752
1o outcomes:
Maternal – pre-eclampsia (variously defined)
Infant – pre-term delivery (<37 weeks GA)
Infant as child – neurodevelopmental delay (variously defined)
Cochrane Database Syst Rev 2010 (7):CD007752

79. Cochrane Database Syst Rev 2010 (7):CD007752
2o outcomes:
Maternal
miscarriage
anemia
gestational HTN
excessive weight gain
placental abruption
preterm labour
symptomatic hypothyroidism
Infant
SGA
cretinism
goitre
admission to special care nursery
jaundice requiring Rx
poor feeding
hoarse cry
constipation
Fetal
IUFD
PP hemorrhage
PP depression
maternal death
QOL
infertility
lethargy
macroglossia
hypotonia
Cochrane Database Syst Rev 2010 (7):CD007752

80. Cochrane Database Syst Rev 2010 (7):CD007752
3 trials involving 314 women, all in Italy
moderate iodine-deficient area
compared:
levothyroxine vs. no treatment
selenomethionine (selenium) vs. placebo
levothyroxine adjusted dose vs. no adjusted dose
all at moderate risk of bias
Selenium – modifies expression of selenoproteins, (antioxidant)  decrease thyroid inflammation in autoimmune thyroiditis
Cochrane Database Syst Rev 2010 (7):CD007752

81. Cochrane Database Syst Rev 2010 (7):CD007752
Results - LT4 vs. none:
euthyroid women with +anti-TPO
 risk of pre-term birth
non-significant trend towards fewer miscarriages (1st trimester)

82. Cochrane Database Syst Rev 2010 (7):CD007752
Results - selenium:
 risk of PP thyroid dysfunction w/in 12 months post delivery
non-significant trend towards less overt hypothyroidism 12 months post delivery

83. Cochrane Database Syst Rev 2010 (7):CD007752
Conclusions:
LT4 in overt hypothyroidism – standard practice
“Whether levothyroxine should be utilised in autoimmune and subclinical hypothyroidism remains to be seen, but it may prove worthwhile, given a possible reduction in preterm birth and miscarriage.”
selenium – promising, but needs further study
Cochrane Database Syst Rev 2010 (7):CD007752

84. Management – Special Considerations
Endocrine Society Clinical Practice Guidelines – 2007
LT4 treatment recommended in all pregnant women with subclinical hypothyroidism
not proven to modify long-term neurological development in offspring, but improvement in obstetrical outcomes
potential benefits outweigh potential risks
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47
For autoimmunity – monitor for elevated TSH

85. Objectives
To briefly review thyroid anatomy and physiology in pregnancy and fetal thyroid physiology
To review causes of thyroid disease in pregnancy
To review the maternal and fetal outcomes of thyroid disease in pregnancy
To discuss the controversy surrounding screening for thyroid disease in pregnancy

86. Objectives
To review special considerations in management of thyroid disease in pregnancy
To highlight recent articles published on thyroid disease in pregnancy

87. References Casey BM & Leveno KJ. Obstet Gynecol 2006;1081283-9
Keely E & Casey BM (2010). Thyroid disease in pregnancy. In RO Powrie, MF Greene, W Camann (Eds) de Swiet’s Medical Disorders in Obstetric Practice (5th Edition pp322-34). West Sussex, Wiley-Blackwell
Arnaud-Lopez L et al Am J Hum Genet 82:
Shields BM et al J Clin Endocrinol Metab 94(11):
Pearce EN et al N Engl J Med 348:
J Clin Endocrinol Metab 2007, 92(8):Suppl:S1-47
Cooper DS & Rivkees SA J Clin Endocrinol Metab, 94(6):1881-2
Earl R et al Cochrane Database Syst Rev, (9):CD008633
Rosenfeld H et al Br J Clin Pharmacol, 68(4):609-17
Murji A et al Obstet Gynecol, 116 Suppl 2:485-7
ACOG Practice Bulletin Obstet Gynecol 2002, 100(2):
Yassa L et al J Clin Endocrinol Metab, 95:
Abalovich M et al Thyroid 20(10):1175-8
Reid SM et al Cochrane Database Syst Rev, (7):CD007752

88. References Negro R et al. 2006 J Clin Endocrinol Metab 91(7):2587-91
Rotondi M et al Eur J Endocrinol 151:
Dashe JS et al Obstet Gynecol 106:753-7
Männistö T et al Thyroid Jan 22 epub ahead of print
Vaidya B et al J Clin Endocrinol Metab 92:203-7
Negro R et al J Clin Endocrinol Metab 95(4):
Henrichs J et al J Clin Endocrinol Metab 95(9):

90. Cochrane Database Syst Rev 2010 (7):CD007752
Negro R. et al J Clin Endocrinol Metab 91(7):
115 euthyroid anti-TPO+ women randomized to LT4 vs. no treatment
0.5 ug/kg/d if TSH <1 mIU/L, 1.0 ug/kg/d if TSH 1-2 mIU/L, ug/kg/d if TSH >2 mIU/L or anti-TPO > 1500 kIU/L
euthyroid anti-TPO- women were controls
gestational HTN, severe pre-eclampsia, pre-term birth, TSH, fT4, miscarriage, abruption, neonatal characteristics
Cochrane Database Syst Rev 2010 (7):CD007752

91. Cochrane Database Syst Rev 2010 (7):CD007752
Negro R. et al J Clin Endocrinol Metab 92(4):1263-8
169 euthyroid anti-TPO+ women randomized to selenium 200 ug/d) at or after 12 wks GA vs. placebo
anti-TPO- women were controls
permanent hypothyroidism, PP thyroid dysfunction, TSH, fT4, anti-TPO Ab levels
Cochrane Database Syst Rev 2010 (7):CD007752

92. Cochrane Database Syst Rev 2010 (7):CD007752
Rotondi M. et al Eur J Endocrinol 151:
25 women with 1o hypothyroidism (Hashimotos or thyroidectomy) on LT4 who were anticipating pregnancy within next 1 yr, randomized to “modified” (target low-normal TSH) vs. “non-modified” (same dose), then seen at <12 wks GA
TFTs pre-conception and post-conception
Didn’t evaluate any of the primary outcomes (only TFTs)
Cochrane Database Syst Rev 2010 (7):CD007752