1. Pregnancy & Endocrinology
William Harper
Hamilton General Hospital
McMaster University

2. Objectives Thyroid Disorders & Pregnancy Diabetes & Pregnancy
Normal thyroid phsyiology & pregnancy
Hypothyroidism & pregnancy
Thyrotoxicosis & pregnancy
Postpartum thyroid dysfunction
Diabetes & Pregnancy
Gestational DM
Type 1 & Type 2 DM & Pregnancy

3. Case 1 31 year old female Somalia  Canada 3 years ago
G2P1A0, 11 weeks pregnant
Well except fatigue
Hb 108, ferritin 7 (Fe and LT4 interaction?)
TSH 0.2 mU/L, FT4 7 pM
Started on LT  TSH < 0.01 mU/L
FT4 12 pM, FT3 2.1 pM

4. Case 1 How would you characterize her hypothyroidism?
What are the ramifications of pregnancy to thyroid function/dysfunction?

6. TSH Low High FT4 & FT3 FT4 Low High Low High Central Hypothyroid
1° Thyrotoxicosis
1° Hypothyroid If
equivocal
2° thyrotoxicosis
RAIU
TRH Stim.
Endo consult
FT3, rT3
MRI, α-SU
MRI, etc.

7. Case 1
GH, IGF-1 normal
LH, FSH, E2, progesterone, PRL normal for pregnancy
8 AM cortisol 345, short ACTH test normal
MRI: normal pituitary
TGAB, TPOAB negative
Normal pregnancy, delivery, baby, lactation

8. Thyroid & Pregnancy: Normal Physiology
Increased estrogen  increased TBG (peaks wk 15-20)
Higher total T4 & T3:
normal FT4 & FT3 if normal thyroid fn. and good assay
many automated FT4 assays underestimate true FT4 level (except Nichols equilibrium dialysis free T4 assay)
if suspect your local FT4 assay is underestimating FT4 can check total T4 & T3 instead (normal pregnant range ~ 1.5x nonpregnant)
hCG peak end of 1st trimester, hCG has weak TSH agonist effect so may cause:
slight goitre
mild TSH suppression ( mU/L) in 9% of preg
mild FT4 rise in 14% of preg

9. Thyroid & Pregnancy: Normal Physiology
Fetal thyroid starts working at wks
T4 & T3 cross placenta but do so minimally
Cross placenta well:
MTZ > PTU
TSH-R Ab (stim or block)
ATD (PTU & MTZ):
Fetal goitre (can compress trachea after birth)
MTZ  aplasia cutis scalp defects
Other MTZ reported embryopathy: choanal atresia, esophageal atresia, tracheo-esophageal fistula
Therefore do NOT use MTZ during pregnancy, use PTU instead

11. No TSH & FTI at end of 1st trimester as expected from hCG effect
Requirement to increase LT4 dose occurred between weeks 4 -20
Despite exponential rise in estradiol throughout pregnancy (note y-axis units) TBG levels plateau at 20 wks

12. LT4 dose requirement tied to rising TBG levels
(THBI inversely proportional to TBG level)
By 10 wks need average increase of 29% LT4 dose
By 20 wks need average increase of 48% LT4 dose
No increase of dose beyond 20 wks required

13. * Regardless of cause of hypothyroidism (Hashimoto’s, thyroidectomy) initial LT4 dose increase is usually required early (~ week 8), before 1st prenatal visit!

14. Thyroid & Pregnancy: Hypothyroidism
85% will need increase in LT4 dose during pregnancy due to increased TBG levels (ave dose increase 48%)
Risks:
increased spont abort, HTN/preeclampsia, abruption, anemia, postpartum hemorrhage, preterm labour, baby SGA
Fetal neuropsychological development (NEJM, 341(8): , Aug 31, 2001):
Cognitive testing of children age 7-9
Untreated hyothyroid mothers vs. normal mothers:
Average of 7 IQ points less in children
Increased risk of IQ < 85 (19% vs. 5%)
Retrospective study, data-dredging?

15. LT4 dose adjustment in Pregnancy: - Optimize TSH preconception (0
LT4 dose adjustment in Pregnancy: - Optimize TSH preconception (0.4 – 2.5 mU/L) - TSH at pregnancy diagnosis (~3-4 wk gestation), q1mos during 1st wks and after any LT4 dose change, q2mos 20 wks to term - Instruct women to take 2 extra thyroid pills/wk (q Mon, Thurs) for 29% dose increase once pregnancy suspected (+ commercial preg test) - If starting LT4 during preg: initial dose 2 ug/kg/d and recheck TSH q4wk until euthythyroid
TSH
Dose Adjustment
TSH increased but < 10
Increase dose by 50 ug/d
TSH 10-20
Increase dose by ug/d
TSH > 20
Increase dose by 100 ug/d

16. Pregnancy: screen for thyroid dysfn ?
Universal screening not currently recommended:
ACOG, AACE, Endo Society, ATA
Controversial!
Definitely screen:
Goitre, FHx thyroid dysfn., prior postpartum thyroiditis, T1DM
Ideally, check TSH preconception:
mU/L: recheck TSH during 1st trimester
mU/L: do not need to recheck during preg
If TSH not done preconception do at earliest prenatal visit:
mU/L: hCG effect (9% preg), recheck in 5wk
< 0.1 mU/L: recheck immediately with FT4, FT3, T4, T3

17. Thyrotoxicosis & Pregnancy
Causes:
Graves’ disease
TMNG, toxic adenoma
Thyroiditis
Hydatiform mole
Gestational hCG-asscociated Thyrotoxicosis
Hyperemesis gravidarum   hCG
60%  TSH, 50%  FT4
Resolves by 20 wks gestation
Only Rx with ATD if persists > 20 wk

18. Thyrotoxicosis & Pregnancy
Risks:
Maternal: stillbirth, preterm labor, preeclampsia, CHF, thyroid storm during labor
Fetal: SGA, possibly congenital malformation (if 1st trimester thyrotoxicosis), fetal tachycardia, hydrops fetalis, neonatal thyrotoxicosis

19. Thyrotoxicosis & Pregnancy
Diagnosis difficult:
hCG effect:
Suppressed TSH (9%) +/-  FT4 (14%) until 12 wks
Enhanced if hyperemesis gravidarum: 50-60% with abnormal TSH & FT4, duration to 20 wks
FT4 assays reading falsely low
T4 elevated due to TBG (1.5x normal)
NO RADIOIODINE
Measure:
TSH, FT4, FT3, T4, T3, thyroid antibodies?
Examine: goitre? orbitopathy? pretibial myxedema?

20. Pregnant & Suppressed TSH
Recheck in 5 wks
FT4, FT3, T4, T3
Thyroid Ab’s
Examine
Still suppressed
Normalizes
Hyperemesis Gravidarum
Very High TFT’s:
TSH undetectable
very high free/total T4/T3
hyperthyroid symptoms
no hyperemesis
TSH-R ab +
orbitopathy
goitre, nodule/TMNG
pretibial myxedema
Don’t treat with PTU
Abnormal TFT’s past 20 wk
Treat Hyperthyroidism (PTU)

21. Thyrotoxicosis & Pregnancy: Rx
No RAI ever (destroy fetal thyroid)
PTU
Start 100 mg tid, titrate to lowest possible dose
Monitor qmos on Rx: T4, T3, FT4, FT3
TSH less useful (lags, hCG suppression)
Aim for high-normal to slightly elevated hormone levels
T nM, T nM, FT pM
3rd trimester: titrate PTU down & d/c prior to delivery if TFT’s permit to minimize risk of fetal goitre
Consider fetal U/S wk to R/O fetal goitre
If allergy/neutropenia on PTU: 2nd trimester thyroidectomy

22. Thyrotoxicosis & Lactation
ATD generally don’t get into breast milk unless at higher doses:
PTU > mg/d
MTZ > 20 mg/d
Generally safe
I prefer PTU > MTZ for preg  lactating
Take ATD dose just after breast-feeding
Should provide 3-4h interval before lactates again

23. Neonatal Grave’s Rare, 1% infants born to Graves’ moms 2 types:
Transplacental trnsfr of TSH-R ab (IgG)
Present at birth, self-limited
Rx PTU, Lugol’s, propanolol, prednisone
Prevention: TSI in mom 2nd trimester, if 5X normal then Rx mom with PTU (crosses placenta to protect fetus) even if mom is euthyroid (can give mom LT4 which won’t cross placenta)
Child develops own TSH-R ab
Strong family hx of Grave’s
3-6 mos
20% mortality, persistant brain dysfunction

24. Postpartum & Thyroid 5% (3-16%) postpartum women (25% T1DM)
Up to 1 year postpartum (most 1-4 months)
Lymphocytic infiltration (Hashimoto’s)
Postpartum  Exacerbation of all autoimmune dx
25-50% persistant hypothyroidism
Small, diffuse, nontender goitre
Transiently thyrotoxic  Hypothyroid

26. Postpartum & Thyroid Distinguish Thyrotoxic phase from Grave’s: Rx:
No Eye disease, pretibial myxedema
Less severe thyrotoxic, transient (repeat thyroid fn 2-3 mos)
RAI (if not breast-feeding)
Rx:
Hyperthyroid symptoms: atenolol mg od
Hypothyroid symptoms: LT ug/d to start
Adjust LT4 dose for symtoms and normalization TSH
Consider withdrawal at 6-9 months
(25-50% persistent hypothyroid, hi-risk recur future preg)

27. Postpartum & Thyroid Postpartum depression
When studied, no association between postpartum depression/thyroiditis
Overlapping symtoms, R/O thyroid before start antidepressents
Screening for Postpartum Thyroiditis
HOW: TSH q3mos from 1 mos to 1 year postpartum?
WHO:
Symptoms of thyroid dysfn.
Goitre
T1DM
Postpartum thyroiditis with prior pregnancy

28. Objectives Thyroid Disorders & Pregnancy Diabetes & Pregnancy
Normal thyroid phsyiology & pregnancy
Hypothyroidism & pregnancy
Thyrotoxicosis & pregnancy
Postpartum thyroid dysfunction
Diabetes & Pregnancy
Gestational DM
Type 1 & Type 2 DM & Pregnancy

29. Gestational Diabetes Mellitus (GDM)
“Glucose intolerance with onset/discovery during pregnancy”
Some T2DM picked up during pregnancy
Rarely some T1DM may present during pregnancy
Prevalence higher than previously thought in Canada:
% non-Aboriginal (but multi-ethnic) population
% Aboriginal

30. Gestational Diabetes Mellitus (GDM)
Prior “selective screening” resulted in missed cases:
Caucassians < 25 y.o.
No personal or FHx of DM
No prior infant with birth weight > 4 kg
Treatment of GDM reduces perinatal morbidity
Diagnosis GDM   maternal anxiety ?
Evidence controversial for this
Therefore all women should be screened

32. * Presence of multiple risk factors warrants earlier screening (preconception, 1st & 2nd trimester)

33. GDM: Morbidity Maternal Fetal/Neonatal Macrosomia
(birth trauma,cesarian)
(shoulder dystocia)
Preeclampsia
RDS
Polyhydramnios
Neonatal hypoglycemia
Perinatal mortality (fetus)
Neonatal hypocalcemia
Postpartum IFG, IGT, DM
3-6 mos: %
Lifetime: %
Neonatal jaundice
Obesity later in life?
IGT, IFG, or DM later in life?

35. GDM Treatment CBG qid: FBS, 1-2h pc
Dietary: 3 small meals, 3 small snacks
If glycemic targets not met: Insulin
Multiple Daily Injection (MDI) best
Insulins: regular, lispro, aspart ? (still new)
No glargine (stimulates IGF-I receptors)

36. GDM Treatment No OHA’s, not standard of care yet. Glyburide Metformin
Minimal crossing of placenta, 3rd trimester most organogenesis complete
1 RCT: 404 women, mild GDM, glyburide vs. insulin, no difference in outcomes
Further study before safety established
Metformin
Retrospective cohort:
 preeclampsia & stillbirth
Bias: DM women older, more obese

37. GDM: Labour & Postpartum
NPO during Labour:
Monitor CBG q1h, target BS 4 – 6.5 mM
Hypoglycemia (BS < 4 mM): IV D5W
Hyperglycemia (BS > 6.5 mM): IV D5W & IV insulin gtt
Postpartum:
D/C all insulin (IV and SC)
CBG in recovery:
> 10 mM  CBG qid, may need Rx for T2DM
< 10 mM  stop CBG monitoring
FBS or 2hPG in 75g OGTT within 6 mos postpartum and prior to any future planned pregnancies
Encourage: breast feeding, healthy diet, exercise to prevent future Type 2 DM, GDM
Screen for future T2DM (GDM is a risk factor)

40. T1DM, T2DM & Pregnancy Congenital anomalies: 2-3x increased risk
Cardiac malformations
Neural Tube Defects 1 % risk
Folate 1-4 mg/d (Prenatal vitamin mg)
d/c ACE-I and ARBs  methyldopa, etc.
Dilated eye exam: preconception & 1st trimester
T2DM: d/c OHA  insulin
Good glycemic control prior to conception:
Prevent unplanned pregnancies: OCP or 2x barrier
Initiate MDI and qid (FBS, 2hPC) prior to preg
CSII also another option

41. T1DM, T2DM & Pregnancy
< 8.0 ?

42. T1DM & T2DM: Labour & Postpartum
NPO during Labor:
Monitor CBG q1h, target BS 4.0 – 6.5 mM
IV D5W & IV insulin gtt (Hamilton Health Sciences Protocol)
Postpartum:
D/C all IV insulin
Insulin resistance/requirements rapidly fall during & after labor
T2DM: monitor CBG qid
Restart insulin if CBG > 10 mM
T1DM: postpartum honeymoon
CBG q1h x 4h, then q2h x 4h, then q4h
Restart MDI insulin S.C. when CBG > 10 mM
No OHA, ACE-I or ARB during breast feeding!

45. END