Pregnancy & Endocrinology

William Harper Hamilton General Hospital McMaster University

www.drharper.ca

Objectives

Thyroid Disorders & Pregnancy

Normal thyroid phsyiology & pregnancy Hypothyroidism & pregnancy Thyrotoxicosis & pregnancy Postpartum thyroid dysfunction

Diabetes & Pregnancy

Gestational DM Type 1 & Type 2 DM & Pregnancy

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 LT4 0.05 TSH < 0.01 mU/L FT4 12 pM, FT3 2.1 pM

Case 1
1.
2.

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

TSH High Low

FT4
High Low 1 Hypothyroid 2 thyrotoxicosis
Endo consult FT3, rT3 MRI, -SU
If equivocal

FT4 & FT3 Low

High

Central 1 Thyrotoxicosis Hypothyroid

TRH Stim. MRI, etc.

RAIU

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

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 (0.1-0.4 mU/L) in 9% of preg mild FT4 rise in 14% of preg

Thyroid & Pregnancy: Normal Physiology

Fetal thyroid starts working at 12-14 wks T4 & T3 cross placenta but do so minimally Cross placenta well:

MTZ > PTU TSH-R Ab (stim or block) Fetal goitre (can compress trachea after birth) Other MTZ reported embryopathy: choanal atresia, esophageal atresia, tracheo-esophageal fistula Therefore do NOT use MTZ during pregnancy, use PTU instead

ATD (PTU & MTZ):

MTZ aplasia cutis scalp defects

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

 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

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

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):549-555, 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?

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 20 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 TSH > 20

Increase dose by 50-75 ug/d Increase dose by 100 ug/d

Pregnancy: screen for thyroid dysfn ?

Universal screening not currently recommended:

ACOG, AACE, Endo Society, ATA Controversial! Goitre, FHx thyroid dysfn., prior postpartum thyroiditis, T1DM 2.5-5.0 mU/L: recheck TSH during 1st trimester 0.4-2.5 mU/L: do not need to recheck during preg

Definitely screen:

Ideally, check TSH preconception:

If TSH not done preconception do at earliest prenatal visit:

0.1-0.4 mU/L: hCG effect (9% preg), recheck in 5wk < 0.1 mU/L: recheck immediately with FT4, FT3, T4, T3

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

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

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 TSH, FT4, FT3, T4, T3, thyroid antibodies? Examine: goitre? orbitopathy? pretibial myxedema?

Measure:

Pregnant & Suppressed TSH

TSH < 0.1 TSH 0.1 0.4 Recheck in 5 wks FT4, FT3, T4, T3 Thyroid Abs Examine Still suppressed Normalizes

Hyperemesis Gravidarum

Very High TFTs: TSH undetectable very high free/total T4/T3 hyperthyroid symptoms no hyperemesis TSH-R ab + orbitopathy goitre, nodule/TMNG pretibial myxedema

Dont treat with PTU

Abnormal TFTs past 20 wk

Treat Hyperthyroidism (PTU)

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

T4 150-230 nM, T3 3.8-4.6 nM, FT4 26-32 pM

3rd trimester: titrate PTU down & d/c prior to delivery if TFTs permit to minimize risk of fetal goitre Consider fetal U/S wk 28-30 to R/O fetal goitre

If allergy/neutropenia on PTU: 2nd trimester thyroidectomy

Thyrotoxicosis & Lactation

ATD generally dont get into breast milk unless at higher doses:

PTU > 450-600 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

Neonatal Graves
Rare, 1% infants born to Graves moms 2 types: Transplacental trnsfr of TSH-R ab (IgG)

Present at birth, self-limited Rx PTU, Lugols, 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 wont cross placenta)

Child develops own TSH-R ab

Strong family hx of Graves Present @ 3-6 mos 20% mortality, persistant brain dysfunction

Postpartum & Thyroid

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

Postpartum & Thyroid

Distinguish Thyrotoxic phase from Graves:

No Eye disease, pretibial myxedema Less severe thyrotoxic, transient (repeat thyroid fn 2-3 mos) RAI (if not breast-feeding)

Rx:

Hyperthyroid symptoms: atenolol 25-50 mg od Hypothyroid symptoms: LT4 50-100 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)

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

Objectives

Thyroid Disorders & Pregnancy

Normal thyroid phsyiology & pregnancy Hypothyroidism & pregnancy Thyrotoxicosis & pregnancy Postpartum thyroid dysfunction

Diabetes & Pregnancy

Gestational DM Type 1 & Type 2 DM & Pregnancy

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:

3.5 - 3.8% non-Aboriginal (but multi-ethnic) population 8.0 - 18.0% Aboriginal

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

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

GDM: Morbidity
Maternal
Macrosomia (birth trauma,cesarian) Preeclampsia Polyhydramnios Perinatal mortality (fetus) Postpartum IFG, IGT, DM 3-6 mos: 16-20 % Lifetime: 30-50 %

Fetal/Neonatal
Macrosomia (shoulder dystocia) RDS Neonatal hypoglycemia Neonatal hypocalcemia Neonatal jaundice Obesity later in life?

IGT, IFG, or DM later in life?

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)

GDM Treatment
No OHAs, not standard of care yet. Glyburide

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

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 D/C all insulin (IV and SC) CBG in recovery:
> 10 mM CBG qid, may need Rx for T2DM < 10 mM stop CBG monitoring

Postpartum:

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)

T1DM, T2DM & Pregnancy

Congenital anomalies: 2-3x increased risk

Cardiac malformations Neural Tube Defects 1 % risk

Folate 1-4 mg/d (Prenatal vitamin 0.4-1.0 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

T1DM, T2DM & Pregnancy

< 8.0 ?

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!

END