HYPERTHYROIDISM IN PREGNANCY Anita Kuruvilla, MD Washington University School of Medicine

39 y o AA lady, with 9 living children, 3 miscarriages,

PMH: Hyperthyroidism, noncompliant on PTU Tobacco(1PPD), alcohol, cocaine and marijuana abuse Bipolar Disorder Syphilis in the past, treated twice with Benz. PCN HIV exposure (father of the baby). Pt tested HIV neg. Asthma

Pt adm. on 4/29/05, at 21 wks GA with vaginal bleeding partial placental abruption due to cocaine abuse.

4/29- FT4 3.8 5/3 - FT4 2.1 5/8- FT4 3.0

TSH <0.02 TSH <0.02 TSH <0.02

PTU 150 mg tid started PTU to 100mg bid Left AMA Noncompliant on PTU PTU 100 mg bid FWB reassured by Doppler tones. Pt Tx to psych.

FWB reassured by Doppler tones 6/21- FT4 2.3 TSH <0.02 PTU 100 mg tid 6/23- Adm. with PROM- GA 29 wks, 4 days.
C. Section, male infant-30 wks, Apgar 9,9; HR 160/min,sats>96% Peds suspected- baby appeared older than GA (35 wks)

5/11- FT4 2.3 5/17- FT4 2.4

TSH <0.02

PHYSIOLOGICAL ADAPTATION IN PREGNANCY

Iodine requirement in pregnant & lactating women 200 mcg/day

HCG and thyroid function

FETAL THYROID MATURATION

10-12 wks of gestation : Fetal thyroid concentrates iodine, synthesize T3 and T4. The fetal pituitary differentiates. Prior to 12 weeks the mother is the sole source of thyroid hormone to the fetus. Fetal thyroid function is at low basal level till 18-20 wks At birth TSH 70uU/ml. Day 2 max.TSH 12uU/ml

EASE OF TRANSPLACENTAL PASSAGE

HIGH
Immunoglobulins

MEDIUM
L-Thyroxine L-Triiodothyronine

ABSENT
TSH

(TSI and TBII) Iodides (127 I and 131 I) Antithyroid Drugs (Tapazole and PTU) Beta Blockers TRH

HYPERTHYROIDISM IN PREGNANCY Etiologies: Intrinsic thyroid disease:

Graves Disease Toxic Adenoma Iatrogenic hyperthyroidism: Excessive Levothyroxine intake Gestational thyrotoxicosis

GESTATIONAL THYROTOXICOSIS

Transient hyperthyroidism, with none or few symptoms, limited to the first half of pregnancy GTT can occur in up to 15-18% of nl pregnancies, mild TSH suppression & nl FT4 in single pregnancies. More profound TSH blunting, TSH <0.2 mU/L with transient rise in FT4 can be seen in twin pregnancies
(Glinoer. Thyroid; vol 8,no.9,1998)

Almost always related to inappropriate HCG secretion No evidence of thyroid autoimmunity

HCG mediated hyperthyroidism

Hyper emesis Gravid arum: Nausea and vomiting with weight loss >5% during early pregnancy, thought to be secondary to high serum HCG and estradiol conc. or secretion of HCG with biological activity. Transient, and resolves with hyper emesis. Hydatiform mole Choriocarcinoma

HYPERTHYROIDISM IN PREGNANCYCLINICAL CLUES

GESTATIONAL GRAVES

Symptoms pre-pregnancy Symptoms during pregnancy Nausea & vomiting Goiter/opthalmopathy Anti TPO Ab

+/++ -

++ +/+++ -/+ + +

ACTIVITY IN GRAVES DISEASE DURING PREGNANCY

(Kung et al JCEM 1998,vol 83, no.2,514-518)

Indicators for TSI determination in the mother

Fetal or neonatal hyperthyroidism in previous pregnancy Active hyperthyroidism on antidrug treatment Thyroidectomy during pregnancy Euthyroid, post ablation In the presence of - fetal tachycardia - fetal goiter on ultrasound

TSH Receptor Antibodies in pregnancy

MATERNAL SERUM TSI & FETAL OUTCOMES

29 women (35 pregnancies)
Serum TSI( 14-26 weeks) Normal <1.3 Index units
Peleg et al Obst. & Gynecology 2002:99:1040-1043

19 women <5 Index Units

10 women > 5 Index Units

Normal Infants

6 women Normal Infants

4 women 6 Hyperthyroid Infants

MATERNAL SERUM TSI & FETAL OUTCOMES

Peleg et al Obstretics & Gynecology 2002:99:1040-1043

Maternal TSI>5 Index Units

Sensitivity 100% Specificity 74% Predictive Value of a positive test was 40% Predictive value of a negative test was 100% Serum TSI decreases during pregnancy, hence the best time to obtain a TSI would be at 26 weeks(24 -28) of gestation. (Mestman) The effect of TSI on the fetus may be noted only after 20 wks of gestation

MANAGEMENT OF HYPERTHYROIDISM
Ant thyroid Rx PTU preferred Beta blockers for hyper metabolic symptoms for few weeks Avoid excess physical activity

Obstetric Team: Follow fetal growth and fetal heart tones in order to detect fetal hyperthyroidism Early detection of pregnancy induced hypertension

MANAGEMENT

PTU thought to have less trans placental passage than MMI. (Marchant B et al; JCEM 77, 45; 1187-93) Reports of congenital anomalies with MMI

- Aplasia Cutis- a scalp defect - MMI embryopathy: Choanal atresia, 1:10,000 births Esophageal atresia, 1:2500 births
Switch to PTU preconception or before organogenesis if on MMI



Treatment indicated if FT4>2.0ng/dl PTU 50-100mg q12 hours in pt. with minimal symptoms (doses>200 mg of PTU can result in fetal goiter & hypothyroidism Pt with large goiters & long disease duration may require larger initial doses 100-150mg tid Clinical improvement (weight gain & in HR) is noted in the first 2-6 wks, with FT4 improvement in the first 2 wks Once clinical improvement occurs the dose of PTU is by half. Goal to keep FT4 at the upper limit of normal, with least amt of medication In 30% of pt PTU may be D/Ced in the last 4 - 8wks of pregnancy (Mestman. Best Practice & Research clin endoMetb.,200,vol 18,no. 2,27-88)

NEONATAL HYPOTHYROIDISM DUE TO MATERNAL ATD Momotani et al, NEJM 86, vol 315,no. 1, 24-28) Group1- mothers continued on ATD till delivery Group 2- ATD was discontinued > 2 wks before delivery.

Babies in grp 1: Had T4 below normal range more often than mother and 54% were hypothyroid, in mothers who were euthyroid. In the mothers where the T4 values were near the upper normal limit or mildly hyperthyroid most of the fetuses had normal T4 levels mothers.(The maternal mean T4 in both the grps were not statistically significant)

Group 2: The T4 of the babies were virtually equivalent to that of the

ATD appears to suppress fetal thyroid function more than that of the mother. Dose sufficient to maintain mothers in euthyroid state may be somewhat excessive for the baby.

MANAGEMENT OF GRAVES HYPERTHYROIDISM

Mestman. BestPractice&Research, vol 18,no.2,p267-88

INDICATIONS FOR SURGERY- 2nd trimester

Allergy to both anti thyroid medications Large goiter Poor compliance to medicines

COMPLICATIONS OF HYPERTHYROIDISM IN PREGNANCY

MATERNAL
MISCARRIAGE PIH PRETERM DELIVERY CHF PLACENTA ABRUPTION

FETAL
LOW BIRTH WEIGHT PREMATURITY SMALL FOR GEST. AGE STILL BIRTH GOITER HYPOTHYROIDISM HYPERTHYROIDISM CENTRAL HYPOTHYROIDISM

Relative Risk of maternal and perinatal complications according to metabolic control

(Millar et al, Obstetrics& Gyne, 1994 ,84: 946-49)

INFANTS THYROID PROFILE 2 days of age:

Total T4 TSH 5.9mcg/dl 0 uIU/ml (4-17 mcg/dl) (<25uIU/ml)

20 days of age:
Free T4 TSH 0.7 ng/dl ( 1-2.8 ng/dl) 0.72 mcIU/ml (0.35- 5.50mcIU/ml)

CENTRAL CONGENITAL HYPOTHYROIDISM Uncontrolled maternal hyperthyroidism High levels of serum T4 in maternal circulation cross placental barrier Feed back to the fetal pituitary with suppression of fetal pituitary TSH Diagnosis : Neonatal serum FT4 is low & serum TSH is low normal or inappropriate for the level of FT4. In majority of infants there is a return to euthyroidism in a few weeks to months. Rx with LT4 and long term follow up is recommended
Mestman. BestPractice&Research, vol 18,no.2,p267-88

ATD AND LACTATION

Both MMI & PTU can be safely given during lactation

Max doses: - PTU 200mg/day - MMI 20mg/day No adverse effects on physical growth, TFT & IQ scores compared to controls between age 2-3 yrs.

( Azizi et al, JCEM 2000, 85, no 9,3233)

THYROID HORMONE SYNTHESIS

Thyroid Hormone Synthesis

Undiagnosed hypothyroidism in pregnant women may adversely affect the intellectual development in the offspring. Haddow et al, NEJM Aug 19,1999

% of miscarriages in unselected pregnancies in women with thyroid autoimmunity (Stagnaro-Green et al, Best Pract&Research, vol 18,#2,pg167-181)

Normal FT4 (2-3 wks of GA) is 0.9-2.3ng/dl TSH (0-3 months) was 1-10mu/liter