A joint webinar series of the Philippine Thyroid Association (PTA) & the Philippine Society of Maternal-Fetal Medicine, Inc. delivered via Zoom.

1. May 27, 2020 4:00 pm via Zoom
The Role of Maternal Thyroid
Status on Pregnancy Outcomes
Jeremy F. Robles, MD, FPCP, FPSEDM
International Thyroid Awareness Week (ITAW) 2020
A joint webinar series of the Philippine Thyroid Association (PTA) &
the Philippine Society of Maternal-Fetal Medicine, Inc.

2. Objectives
• Discuss the changes in maternal thyroid physiology during normal pregnancy
(PSMFM)
• Describe the effect of maternal thyroid dysfunction on maternal and fetal
outcomes (PTA)
• Outline the management of thyroid dysfunction to improve maternal and fetal
outcomes (PTA)

4. Changes in thyroid hormones with pregnancy
TSH dips in the first trimester then
slowly goes up in the second and
third trimester.
FT4 slightly increases ion the first
trimester then gradually decreases
in the second and third trimester.
Yalamanchi S, Cooper DS. Thyroid
disorders in pregnancy. Curr Opin
Obstet Gynecol. 2015;27(6):406‐
415.
α-subunit of hCG is homologous to TSH

5. Physiological adaptation to pathological alterations of the thyroidal economy
during pregnancy
• Iodine intake needs to be increased
during early pregnancy.
• Physiologic changes that take place
in maternal thyroid economy lead to
an increase in thyroid hormone
production of ~50% above
preconception baseline.
• Target 250 ug/day iodine intake for
pregnant and lactating mother.
Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine
adaptation from physiology to pathology. Endocr Rev. 1997;18(3):404‐433.

6. Iodine Status in Filipino Women of Childbearing Age
• The study observed that while the
national estimate of UIC was above the
threshold value, pockets of deficiency
were nonetheless observed.
• Households with adequately iodized
salt had better iodine status than those
with levels below the mandated
fortification levels.
• Knowledge about the importance of
iodine has been identified as an
essential determinant of iodine nutrition.
Serafico ME, Ulanday JRC, Alibayan MV, Gironella GMP, Perlas LA. Iodine Status in
Filipino Women of Childbearing Age. Endocrinol Metab (Seoul). 2018;33(3):372‐379.

7. Passage of T4 and T3 from the maternal to fetal circulation
• Placenta acts as an exchange unit
for nutrients and waste products.
• Placenta regulates the amounts of
thyroid hormones passing from the
mother to the fetus.
• Human placental development is
itself is responsive to thyroid
hormone from early in gestation with
evidence of trophoblastic expression
of thyroid hormone receptors
Chan, S., Vasilopoulou, E. & Kilby, M. The role of the placenta in thyroid hormone
delivery to the fetus. Nat Rev Endocrinol 5, 45–54 (2009).

8. Spectrum of Thyroid Diseases in Pregnancy
HYPOTHYROIDISM
OVERT HYPOTHYROIDISM
SUBCLINICAL HYPOTHYROIDISM
ISOLATED HYPOTHYROXINEMIA
HYPERTHYRODISM
OVERT HYPERTHYROIDISM
SUBCLINICAL HYPERTHYROIDISM
HCG RELATED HYPERTHYROIDISM

9. Among the 616 pregnant Filipino women recruited in the study, 595 (97%) were
TPO-antibody negative. It is noted that TSH rises with age of gestation. FT4
decreases and is at its lowest in the 2nd trimester and rises in the 3rd trimester. FT3
is the same in the 1st and 2nd trimesters & decreases in the 3rd trimester.
Trimester-Specific Reference Interval for Thyroid Function Tests in
Pregnant Filipino Women
Patal, P., et. Al. (2016). Trimester-Specific Reference Interval for Thyroid Function Tests in
Pregnant Filipino Women. Journal of the ASEAN Federation of Endocrine Societies, 31(1), 18.

10. Maternal & Fetal Outcomes
for pregnant with Thyroid
Disease

11. Thyroid function & thyroid disorders during pregnancy: a review & care pathway
Development of central nervous system and thyroid function
Delitala AP, Capobianco G, Cherchi PL, Dessole S,
Delitala G. Thyroid function and thyroid disorders
during pregnancy: a review & care pathway. Arch
Gynecol Obstet. 2019;299(2):327‐338.
* Data demonstrates that
the maternal low T4 levels
during the 1st trimester of
pregnancy are likely
correlated with the risk of
developing adverse fetal
outcomes.
* Overt and subclinical
dysfunctions of the
thyroid disease should be
treated appropriately in
pregnancy, aiming to
maintain euthyroidism.

12. Thyroid Diseases & Adverse Pregnancy Outcomes in a Contemporary US Cohort
Tuija Männistö, Pauline Mendola, Jagteshwar Grewal,
Yunlong Xie, Zhen Chen, S. Katherine Laughon,
Thyroid Diseases and Adverse Pregnancy Outcomes
in a Contemporary US Cohort, The Journal of Clinical
Endocrinology & Metabolism, Volume 98, Issue 7, 1
July 2013, Pages 2725–2733
Primary
Hypothyroidism
Iatrogenic
Hypothyroidism
Thyroid diseases are
associated with
significant increases in
morbidity during
pregnancy.
Adverse outcomes
could be mitigated and
possibly prevented by
adequate management
of thyroid diseases.
Hyperthyroidism

13. Effects of thyroid diseases on pregnancy outcomes
Zhou, M., Wang, M., Li, J., Luo, X., & Lei, M. (2019). Effects of
thyroid diseases on pregnancy outcomes. Experimental and
Therapeutic Medicine, 18, 1807-1815.

14. Effects of thyroid diseases on pregnancy outcomes
Zhou, M., Wang, M., Li, J., Luo, X., & Lei, M. (2019). Effects of
thyroid diseases on pregnancy outcomes. Experimental and
Therapeutic Medicine, 18, 1807-1815.

15. Effects of thyroid diseases on pregnancy outcomes
Zhou, M., Wang, M., Li, J., Luo, X., & Lei, M. (2019). Effects of
thyroid diseases on pregnancy outcomes. Experimental and
Therapeutic Medicine, 18, 1807-1815.

16. Effects of thyroid diseases on pregnancy outcomes
Zhou, M., Wang, M., Li, J., Luo, X., & Lei, M. (2019). Effects of
thyroid diseases on pregnancy outcomes. Experimental and
Therapeutic Medicine, 18, 1807-1815.

17. Effects of thyroid diseases on pregnancy outcomes
Zhou, M., Wang, M., Li, J., Luo, X., & Lei, M. (2019). Effects of
thyroid diseases on pregnancy outcomes. Experimental and
Therapeutic Medicine, 18, 1807-1815.

18. Thyroid Function in Pregnancy and Its Influences on Maternal and Fetal Outcomes
Saki F, Dabbaghmanesh MH, Ghaemi SZ, Forouhari S, Ranjbar Omrani
G, Bakhshayeshkaram M. Thyroid function in pregnancy and its
influences on maternal and fetal outcomes. Int J Endocrinol Metab.
2014;12(4):e19378. Published 2014 Oct 1.
HYPERTHYROIDISM

19. Thyroid Function in Pregnancy and Its Influences on Maternal and Fetal Outcomes
Saki F, Dabbaghmanesh MH, Ghaemi SZ, Forouhari S, Ranjbar Omrani
G, Bakhshayeshkaram M. Thyroid function in pregnancy and its
influences on maternal and fetal outcomes. Int J Endocrinol Metab.
2014;12(4):e19378. Published 2014 Oct 1.
HYPOTHYROIDISM
.

20. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity
With Preterm Birth A Systematic Review and Meta-analysis
Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, et al. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With
Preterm Birth: A Systematic Review and Meta-analysis [published correction appears in JAMA. 2019 Nov 5;322(17):1718]. JAMA. 2019;322(7):632‐641.

21. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity
With Preterm Birth A Systematic Review and Meta-analysis
Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, et al. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth:
A Systematic Review and Meta-analysis [published correction appears in JAMA. 2019 Nov 5;322(17):1718]. JAMA. 2019;322(7):632‐641.

22. Hyperthyroidism during Pregnancy
• Overt hyperthyroidism (Grave’s Disease), associated with increased rates
of Spontaneous abortion, Premature labor, Low birth weight, Stillbirth,
Preeclampsia, Heart failure. Very rare cases of thyroid storm precipitated by
labor, infection, preeclampsia, or cesarean section.
• Subclinical Hyperthyroidism, mixed data
• Free T4 in the upper-normal quintile No evidence of adverse pregnancy
outcomes
UPTODATE 2020
Maternal and Fetal Outcomes

23. Hypothyroidism during Pregnancy
• Overt hypothyroidism - increased rate of 1st trimester spontaneous abortion, Preeclampsia
& gestational hypertension, Placental abruption, Non-reassuring fetal heart rate tracing,
Preterm delivery, including very preterm delivery (< 32 weeks), Low birth weight, Increased
rate of cesarean section, Postpartum hemorrhage, Perinatal morbidity & mortality and
Neuropsychological & cognitive impairment in the child
• Subclinical hypothyroidism - increased risk for severe preeclampsia, preterm delivery,
placental abruption, neonatal respiratory distress syndrome, and/or pregnancy loss. Risk of
pregnancy-specific complications was apparent in TPO-positive women with TSH >2.5 mU/L
but was not consistently apparent in TPO-negative women until TSH values exceeded 5 to
10 mU/L
• Cognitive impairment & Effect of Levothyroxine replacement - mixed data
• Cognitive development - insufficient data
UPTODATE 2020
Maternal and Fetal Outcomes

24. Isolated Maternal Hypothyroxinemia
• Pregnancy outcomes – mixed data, some studies show increased preterm labor,
macrosomia and GDM. (FASTER consortium and Generation R study)
• Cognitive outcomes – mixed data, studies show lower mean intelligence,
psychomotor, or behavioral scores compared with children born to women with normal
thyroid function during gestation. Other studies have shown an increased frequency of
autism & attention deficit disorder in offspring of hypothyroxinemic women. Avon
Longitudinal Study of Parents & Children, no difference in National Curriculum Test
scores between children born to mothers with 1st trimester isolated hypothyroxinemia.
• Effect of thyroid hormone replacement – No significant differences in
neurodevelopmental or behavioral outcomes in the children at five years of age. No
significant differences in the frequencies of preterm delivery, preeclampsia, gestational
hypertension, miscarriage rate, or other maternal or fetal outcomes.
UPTODATE 2020
Maternal and Fetal Outcomes

25. Managing
Hyperthyroidism in
Pregnancy

26. Approach to Hyperthyrodism in Pregnancy
UPTODATE 2020
Grave’s Disease
TRAb (+)
TSH receptor antibodies
Confirmatory 96-97%
Thyroid UTZ
Doppler studies with
high blood flow
TSH <0.1 mU/L
Gestational transient
Hyperthyroidism
Hyperemesis Gravidarum
Trophoblastic hyperthyroidism
hCG Mediated
Hyperthyroidism
TSH 0.1 - 2.5 mU/L
No further work -up
TSH > 2.5 mU/L
See Hypothyrodism
In high risk women check for TSH and
FT4 once pregnancy is confirmed
free T4 and/or free T3 (or total T4 and/or total T3)
measurement that exceeds the normal range for
pregnancy
Both conditions resolve
spontaneously
Further management
warranted
Fetal & neonatal Graves' disease —
1-5 % of neonates born to women with
Graves' disease have hyperthyroidism due to
transplacental transfer of TSH-receptor-
stimulating antibodies.

27. Treatment of Hyperthyroidism in Pregnancy
Goal of treatment is to maintain persistent but mild hyperthyroidism in the mother in an attempt to
prevent fetal hypothyroidism since the fetal thyroid is more sensitive to the action of antithyroid drugs
• Control of symptoms can be done with metoprolol 25 to 50 mg daily or propranolol
20 mg every 6 to 8 hours.
• PTU for the first trimester, Methimazole thereafter
• PTU 50 mg two to three times daily or Methimazole 5 to 10 mg daily
• Lowest dose of thionamide necessary to control thyroid function
• Thyroid function tests every four weeks throughout pregnancy
• Adverse effect: PTU - abnormal liver function tests
• If cannot tolerate thionamides, consider surgery in the second trimester
UPTODATE 2020

28. NO TREATMENT REQUIRED
Goal of treatment is to maintain persistent but mild hyperthyroidism in the mother in an attempt to
prevent fetal hypothyroidism since the fetal thyroid is more sensitive to the action of antithyroid drugs
• Transient, subclinical hyperthyroidism in the first trimester of pregnancy,
because it is considered a normal physiologic finding and therefore does not
require therapy.
• Gestational transient thyrotoxicosis or hCG-mediated, overt hyperthyroidism,
because it is usually transient and mild.
• Hyperemesis gravidarum-associated hyperthyroidism, because it is usually mild
and subsides as hCG production falls (typically by 16 to 18 weeks gestation).
• Subclinical and mild, asymptomatic, overt hyperthyroidism due to Graves'
disease, toxic adenoma, or toxic multinodular goiter.
UPTODATE 2020

29. Managing
Hypothyroidism
in Pregnancy

30. Approach to Hypothyrodism in Pregnancy
Clinical Evaluation: Risk Factors
* History of hypothyroidism/hyperthyroidism or current
symptoms/signs of thyroid dysfunction
* Known thyroid antibody positivity or presence of a goiter
* History of head or neck radiation or prior thyroid surgery
* Age >30 years
* Type 1 diabetes or other autoimmune disorders
* History of pregnancy loss, preterm delivery, or infertility
* Multiple prior pregnancies (‡2)
* Family history of autoimmune thyroid disease or
thyroid dysfunction
* Morbid obesity (BMI ‡40 kg/m2)
* Use of amiodarone or lithium, or recent administration of
iodinated radiologic contrast
* Residing in an area of known moderate to severe
iodine insufficiency
2017 Guidelines of the American Thyroid Association for the Diagnosis and
Management of Thyroid Disease During Pregnancy and the Postpartum
Overt hypothyroidism

31. Management of Hypothyroidism in Pregnancy
Subclinical Hypothyrodism Overt Hypothyrodism
UPTODATE 2020

32. Treatment of Hypothyroidism in Pregnancy
Goal of treatment is to restore euthyroidism as soon as possible
• TSH >4 mU/L or (above population and trimester-specific upper limit of normal), with
low trimester specific FT4 – Full replacement dose (Levothyroxine 1.6 mcg/kg per day)
• TSH >4 mU/L, normal free T4 – Intermediate dose (Levothyroxine 1 mcg/kg per day)
• TSH 2.6 to 4 mU/L – If a decision has been made to treat euthyroid women with TPO
antibodies, low dose (Levothyroxine 50 mcg daily)
• LT4 should be taken on an empty stomach, ideally an hour before breakfast, but few
patients are able to wait a full hour.
• Maintain TSH in the lower half of the trimester-specific reference range. A goal TSH of
<2.5 mU/L is reasonable. Titrate with 12-25 mcg per day as needed.
UPTODATE 2020

33. Treatment of Hypothyroidism in Pregnancy
Goal of treatment is to restore euthyroidism as soon as possible
• TSH can be monitored less often (at least once each trimester) in the latter
half of pregnancy, as long as the dose is unchanged.
• Post-pregnancy adjustments, majority of women who were started on
levothyroxine for TSH between 2.5 and 4.0 mU/L do not need to continue
levothyroxine treatment. Continue treatment for overt hypothyrodism.
• Preexisting hypothyroidism, hypothyroid women who are newly pregnant
should preemptively increase their levothyroxine dose by approximately 30
percent and notify their clinician promptly.
UPTODATE 2020

34. Synthesis of data and
Insights on
Management

35. Trimester-Specific Reference Interval for Thyroid Function Tests in
Pregnant Filipino Women
• Trimester specific reference interval for Filipino Pregnant women gives us a better
understanding of the values we encounter among our patients.
• Thyroid hormones interplay with hormones of pregnancy to achieve an equilibrium
suited for the development of the fetus.
• Sufficient iodine levels is essential for pregnancy.

36. Spectrum of Thyroid Diseases in Pregnancy
HYPOTHYROIDISM
OVERT HYPOTHYROIDISM
SUBCLINICAL HYPOTHYROIDISM
ISOLATED HYPOTHYROXINEMIA
HYPERTHYRODISM
OVERT HYPERTHYROIDISM
SUBCLINICAL HYPERTHYROIDISM
HCG RELATED HYPERTHYROIDISM
• Extreme hormone derangements of hyperthyroidism and hypothyroidism are
associated with poor maternal and fetal outcomes that warrant immediate treatment.
• Subclinical thyroid disease warrants further work-up and follow-up. Medications may
be needed for high risk pregnancies based on assessments.
• Isolated hypothyroxinemia remains a controversy. Assess patients individually.

37. Insights on Management
• Work-up for suspected Hypothyroid pregnant patients (Overt Hypothyroid TSH >4 mU/L)
• TSH, FT4, TPOAb, Thyroid ultrasound
• Work-up for suspected Hyperthyroid pregnant patients (Overt Hyperthyroid TSH<0.1 mU/L)
• TSH, FT4, TRAb if strongly suspecting Grave’s Disease, Thyroid ultrasound
• Follow up labs due every 4 weeks. Follow TRAb results each trimester for Grave’s patients.
• Hypothyroidism Treatment:
• Levothyroxine 1.6 mg/kg dose for overt hypothyroidism ; 1 mg/kg for subclinical hypothyroidism
• Assess for history of miscarriage and TPOAb presence - consider levothyroxine treatment
• Hyperthyroidism Treatment: PTU 1st Trimester , Methimazole for 2nd & 3rd Trimester
• Lowest posible dose to achieve mild maternal hyperthyroidism

38. May 27, 2020 4:00 pm via Zoom
The Role of Maternal Thyroid
Status on Pregnancy Outcomes
Jeremy F. Robles, MD, FPCP, FPSEDM
International Thyroid Awareness Week (ITAW) 2020
A joint webinar series of the Philippine Thyroid Association (PTA) &
the Philippine Society of Maternal-Fetal Medicine, Inc.
Mother and Child Sculpture by Napoleon V. Abueva