1. Hormonal Disease in Pregnancy

2. Thyroid gland Thyroid hormones—made from IODINE
Thyroxine (T4)
Triiodothyronine (T3) MOSTLY made in liver
Many targets in the human body
Synthetic T4 (LEVOTHYROXINE) readily available

3. 2011 Guidelines: Endocrine Society American Thyroid Association
Pre conception education of hypothyroid women and optimization of LT4 dosage
Check thyroid function tests as soon as pregnancy confirmed and consider empirically increasing LT4 dose by taking 2 additional LT4 tablets per week

4. Thyroid health in pregnant women without thyroid disease
Daily iodine requirements increase in pregnancy
WHO 250mcg/day
Institute of Medicine 220mcg/day
NOT all prenatal vitamins contain iodine!
In the USA, as of 2009, only 51% of prenatal vitamins labeled to contain iodine
Measured iodine content was only 75% of labeled content!
Leung A et al N Engl J Med :9

5. 2011 Guidelines: Endocrine Society American Thyroid Association
All women attempting to conceive and pregnant women take a prenatal vitamin containing 150mcg of potassium iodine

6. Physiologic Changes in Thyroid Function During Pregnancy
Thyroid binding globulin (TBG) increases due to reduced hepatic clearance and estrogenic stimulation of TBG synthesis
The test results that change in pregnancy are influenced by changes in TBG concentration
Plasma iodide levels decrease due to fetal iodide use and increased maternal clearance -> leads to notable increase in gland size in 15% of women (without abnormal TFTs)

7. Physiologic Changes in Thyroid Function During Pregnancy
Maternal Status
TSH
**initial screening test**
Free T4
Free Thyroxine Index (FTI)
Total T4
Total T3
Resin Triiodo-thyronine Uptake (RT3U)
Pregnancy
No change
Increase
Decrease
Hyperthyroidism
Increase or no change
Hypothyroidism
Decrease or no change

8. The Fetal Thyroid Begins concentrating iodine at 10-12 weeks
Controlled by pituitary TSH by approximately 20 weeks

9. Hyperthyroidism
Occurs in 0.2% of pregnancies; Graves’ disease accounts for 95% of cases
Look for:
-Nervousness
-Tremor
-Tachycardia
-Frequent stools
-Sweating
-Heat intolerance
-Weight loss
-Goiter
-Insomnia
-Palpitations
-Hypertension
-Lid lag/lid retraction
-Pretibial myxedema

10. Fetal & Neonatal Effects of Hyperthyroidism
Associated with preterm delivery, low birth weight, fetal loss
Fetal thyrotoxicosis (related to disease itself or treatment)
Risk of immune-mediated hypo/hyperthyroidism (due to antibodies crossing the placenta, esp. in Graves or chronic autoimmune thyroiditis)
Antibodies in Graves’ disease can be either stimulatory or inhibitory
Neonates of women with Graves’ who have been surgically/radioactively treated are at higher risk, b/c not taking suppression

11. Causes & Diagnosis of Hyperthyroidism
Most common cause of hyperthyroidism is Graves’ disease
Document elevated FT4 or elevated FTI with suppressed TSH, in absence of goiter/mass
Most patients have antibodies to TSH receptor, antimicrosomal, or antithyroid peroxidase antibodies, but measurement of these is not required (though some endocrinologists recommend measuring TSI, which are stimulatory antibodies to TSH receptor)
Other causes:
Excess TSH production, gestational trophoplastic disease, hyperfunctioning thyroid adenoma, toxic goiter, subacute thyroiditis, extrathyroid source of TH

12. Treatment of Hyperthyroidism
Goal is to maintain FT4/FTI in high normal range using lowest possible dose (minimize fetal exposure)
Measure FT4/FTI q2-4 weeks and titrate
Thioamides (PTU/methimazole) -> decrease thyroid hormone synthesis by blocking organification of iodide
PTU also reduces T4->T3 and may work more quickly
PTU traditionally preferred (older studies found that methimazole crossed placenta more readily and was associated with fetal aplasia cutis; newer studies refute this)

13. Treatment of Hyperthyroidism
Effect of treatment on fetal thyroid function:
Possible transient suppression of thyroid function
Fetal goiter associated with Graves’ (usually drug-induced fetal hypothyroidism)
Fetal thyrotoxicosis due to maternal antibodies is rare -> screen for growth and normal FHR
Neonate at risk for thyroid dysfunction; notify pediatrician
Breastfeeding safe when taking PTU/methimazole

14. Treatment of Hyperthyroidism
Beta-blockers can be used for symptomatic relief (usually Propanolol)
Reserve thyroidectomy for women in whom thioamide treatment unsuccessful
Iodine 131 contraindicated (risk of fetal thyroid ablation especially if exposed after 10 weeks); avoid pregnancy/breastfeeding for 4 months after radioactive ablation

15. Hypothyroidism
Symptoms: fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, slow reflexes, weight gain, intellectual slowness, voice changes, insomnia
Can progress to myxedema and coma
Subclinical hypothyroidism: elevated TSH, normal FTI in asymptomatic patient
Associated with other autoimmune disorders
Type 1 DM -> 5-8% risk of hypothyroidism; 25% postpartum thyroid dysfunction

16. Hypothyroidism: Fetal & Neonatal Effects
Higher incidence of LBW (due to medically indicated preterm delivery, pre-eclampsia, abruption)
Iodine deficient hypothyroidism -> congenital cretinism (growth failure, mental retardation, other neuropsychological deficits)

17. Cretinism Due to severe dietary iodine deficiency
Severe hypothyroidism in BOTH Mom and fetus
Impaired cognitive development
Poor growth
Iodine deficiency is considered the most common cause of preventable brain damage in the world today (WHO 1994).
Figure 5. Myxedematous endemic cretinism in the Democratic Republic of Congo. Four inhabitants aged years : a normal male and three females with severe longstanding hypothyroidism with dwarfism, retarded sexual development, puffy features, dry skin and hair and severe mental retardation.

18. Causes & Diagnosis of Hypothyroidism
Hashimoto’s (chronic thyroiditis; most common in developed countries) & iodine deficiency -> both associated with goiter
Subacute thyroiditis -> not associated with goiter
Thyroidectomy, radioactive iodine treatment
Iodine deficiency (most common worldwide; rare in US)

19. Spectrum Mild “subclinical” hypothyroidism 1:50 pregnancies
Severe “overt” hypothyroidism :500 pregnancies

20. What if the mom’s thyroid doesn’t work? ~2% of all pregnancies
Subclinical Overt Hypothyroidism
Spontaneous abortion5, % 60%
Preeclampsia1,2,4,6,9 0-17% 0-44%
Abruption2,3,4,6,7 0% 0-19%
Stillbirth/fetal loss1,2,3,6 0-3% 0-12%
Anemia2,3 0-2% 0-31%
Postpartum hemorrhage2,3,4 0-17% 0-19%
Preterm birth2,3,7,8 0-9% 20-31%
“Maternal hypothyroidism is associated with increased rate of pregnancy complications, and the risk is greatest in overt hypothyroidism compared to subclinical hypothyroidism.” LaFranchi, Thyroid 2005
1Montoro et al, Ann Intern Med 1981; 2Davis et al, Obstet Gynecol 1988; 3Leung et al,
Obstet Gynecol 1993; 4Wasserstrum et al, Clin Endocrinol 1993; 5Glinoer, Thyroid Today, 1995
6Allan et al, J Med Screen 2002; 7Abalovich et al, Thyroid 2002; 8Stagnaro-Green et al, Thyroid, 2005; 9Sahu et al, Arch Gynecol Obstet 2009

21. Recent Developments Hypothyroidism for Subclinical
MATERNAL HEALTH Negro R et al, Universal Screening vs Case Finding for Detection and Treatment of Thyroid Dysfunction During Pregnancy, J Clin Endocrinol Metabolism :1699
Raphael also took part in painting pregnant women, with his simply titled Portrait of a Pregnant Woman (La Donna Grivada 1506).
FETAL HEALTH
Lazarus J et al. Controlled Antenatal Thyroid Screening (CATS) Study. 14th International Thyroid Congress, Sept 2010

22. Maternal Adverse Outcomes: Negro 2010
PRIMARY ENDPOINT:
NO BENEFIT to pregnancy outcome
Overall, universal screening c/w case finding did NOT result in fewer AEs
Ultimate rationale was to assess the potential reduction in preg AEs after T4 Rx in hypothyroid women c/w hypothyroid women not receiving T4Rx
This blinded intervention only occurred in the non high risk women when comparing universal screening group to case finding, where they would NOT be treated
Basically the analysis revolves around 34 untreated hypothyroid women in the case finding and 44 hypothyroid women treated in the Universal screen
AEs in 15/44 35% of universal screen, but in 31/34 91 % of case finding
Hypothyroid defined as TSH >2.5, no assessment of number of SCH versus Overt, NUMBER IN SCREEN 2.8%, IN CASE FINDING 2.4%
Women Rxed by 12th gestational week
TPOAb + euthyroid women,no Rx but retested 2nd and 3rd trimester
High risk for thyroid dysfnc: FHx autoimmune thyroid dz, goiter, signs/Sx of thyroid dz, type 1 DM or autoimmune Dz, hx neck XRT, prior miscarriages, prior preterm delivery
All women in universal screen and “high risk” women in case finding had TFTs (TSh FT4, TPOAb tested immediately; others the low risk case finding had it tested postpartum
Results: No significant differences were seen in adverse outcomes between the case-finding and
universal screening groups. Adverse outcomes were less likely to occur among low-risk women in
the screening group than those in the case-finding group.
Conclusions: Universal screening compared with case finding did not result in a decrease in adverse
outcomes. Treatment of hypothyroidism or hyperthyroidism identified by screening a low-risk
group was associated with a lower rate of adverse outcomes. (J Clin Endocrinol Metab 95:
1699–1707, 2010)

23. Cognitive Development: CATS 2010
Cognitive development and Maternal Hypothyroidism
PRIMARY ENDPOINT:
NO difference in IQ scores
Controlled antenatal thyroid screening study
22,000 women: ½ screened (TSH, FT4) at mean 12.5 weeks gestation, ½ not screened
Intervention: LT4 0.15mg/day if TSH >2.5mIU/L
Outcome: IQ testing at 3 years
Cardiff screened
Turin 5500
Mean age at testing 12.5 weeks
Rx 0.15mg
The prospective, randomized, controlled trial compared hypothyroid screening vs. no screening plus levothyroxine, if needed, in more than 22,000 singleton pregnancies at less than 16 weeks gestation. The primary outcome was the child’s IQ at age 3.2 years and at age 3.6 years and the percentage of children with an IQ of less than 85, using the WPPSI-III child intelligence assessment score.
Women in the screening group had their serum samples analyzed and thyroid-stimulating hormone and free thyroxine (T4) assayed before 16 weeks gestation; if TSH was greater than the 97th percentile or if free T4 was less than the 25th percentile, the women were assigned to 150 mcg (0.15 mg) of levothyroxine. Assessment was conducted 6 weeks later with another serum thyroid hormone measurement, at 9 weeks and then postdelivery. The control group did not have its sera analyzed at the first visit but, rather, after delivery. If TSH or free T4 were abnormal, the women were advised to seek attention from a family physician.
The study was conducted at two sites: Cardiff and Turin, Italy. The researchers noted some discrepancies between the groups at baseline, including heavier women and a higher prevalence of smokers in Cardiff (21.4% vs. 8.4%) and older mothers in Turin (32 years vs. 29 years). There was no significant difference in thyroid hormone levels at baseline.
Lazarus presented preliminary data on 390 children in the screening group and 404 children in the control group.
According to the main results of the intent-to-treat analysis, child intelligence scores were similar in the screening and control groups. The average IQ score was 99.3 in the screening group vs. 100 in the control group (difference of 0.7; 95% CI, –1.2 to 2.5). More than 15% of children in the control group had an IQ of less than 85 vs. 11.5% in the screening group (difference of 4.1; 95% CI, –0.7 to 8.8).
When the researchers conducted an on-treatment analysis of women who actually took their assigned levothyroxine, IQ scores remained similar between the groups. However, the percentage of children with an IQ below 85 was significantly different - 9.5% in the screening group compared with 15.6% in the control group.
Courtesy of John Lazarus ITC 2010

24. However, secondary analyses for both studies suggest a benefit
Negative results could be due to screening and intervention at end of 1st trimester—TOO LATE
What to do

25. 2011 Guidelines: Endocrine Society American Thyroid Association
Insufficient evidence to recommend universal screening for thyroid disease in pregnant women
Aggressive detection of women at high risk for thyroid dysfunction

26. Women at risk for hypothyroidism
History of thyroid dysfunction or prior thyroid surgery
Signs or symptoms of thyroid problem
Women older than age 30
Presence of other autoimmune disorders
Type 1 diabetes, rheumatoid arthritis
Family history of thyroid dysfunction
History of miscarriage or preterm labor

27. What is needed . . .
Partnerships with public health, government and professional organizations to insure all prenatal vitamins contain 150mcg of potassium iodine
Exploration of the feasibility of a randomized controlled trial that screens, identifies, and treats thyroid dysfunction in women PRIOR to conception

28. Treatment of Hypothyroidism
Treat with Levothyroxine in sufficient dose to return TSH to normal
Adjust dosage every 4 weeks
Check TSH every trimester

29. ACOG Recommendations
Screening of all pregnant women with a personal history, physical examination, or symptoms of a thyroid disorder.

30. Prolog Question #1
A 33 year-old G3 P2 at 10 weeks GA comes to the office for her 1st prenatal visit. She reports that she had hypothyroidism in the distant past, but was never treated and is asymptomatic. Physical examination is normal. On bimanual examination her uterus is 10 weeks size and FHR is 150 bpm. Her TSH level is 13.1 and, free T4 level is 0.7, and her anti-thyroid peroxidase antibody level is high. The next best step in the patient’s care is:
A) Begin levothyroxine
B) Repeat serum TSH and Free T4 after 20 weeks of gestation
C) Measure serum thyroid-stimulating immunoglobulins
D) Perform ultrasonography of the maternal thyroid

31. Answer A) Begin levothyroxine
Although the patient is asymptomatic she has laboratory evidence of overt hypothyroidism with an elevated TSH and low free T4 level
She also has elevated anti-thyroid peroxidase antibody level which indicates that the likely cause of her hypothyroidism is chronic autoimmune thyroditis (Hashimoto’s disease)
The anti-thyroid peroxidase antibodies also indicate an increased risk of her developing other autoimmune disease, such as adrena insufficiency or type 1 DM.
Hypothyroidism in pregnancy has been associated with pre-eclampsia, GHTN, abruptio placentae, preterm delivery, and neuropsychologic deficits in the child.

32. And if the baby’s thyroid doesn’t work. . . .
Congenital hypothyroidism affects 1:3000 live births in the US
Newborn screening programs in all 50 states
Detection and treatment by 1 month of life results in normal outcomes
THEREFORE, maternal thyroid hormone can protect fetal development in utero