Managing Endocrine Issues in Pregnancy Jennifer Smith MD, PhD Maternal Fetal Medicine The Perinatal Center September 18, 2019
Managing Endocrine Issues in Pregnancy
Jennifer Smith MD, PhDMaternal Fetal MedicineThe Perinatal Center
September 18, 2019
Objectives
Discuss management of thyroid disease in pregnancy
Discuss management of obesity and diabetes in pregnancy
Discuss ways to optimize pregnancy outcomes in women with pre-existing endocrine diseases
Thyroid Disease in Pregnancy
Control of thyroid hormone production
Thyroid Disease: Thyroid Hormone Biosynthesis
Thyroid changes in pregnancy
Interpreting Thyroid Labs in Pregnancy
TSH: Normal Values in Pregnancy● American Thyroid Association
○ Trimester specific ranges■ First trimester 0.1-2.5 mIU/L■ Second trimester 0.2-3.0 mIU/L■ Third trimester 0.3-3.0 mIU/L
Thyroid function in the fetus● T4 transferred across the placenta throughout the entire
pregnancy
● Fetal thyroid gland begins concentrating iodine and synthesizing thyroid hormone at about 12 weeks gestation
Thyroid nodules in pregnancy● Thyroid function tests
○ Usually normal in thyroid cancer● Thyroid ultrasound● FNA
○ Pregnancy does not alter cytologic diagnosis○ Surgery in pregnancy does not affect survival
with well differentiated thyroid cancer● Radionuclide scintigraphy or radioiodine uptake
determination should not be performed during pregnancy
Thyroid cancer in pregnancy● Prevalence 14/100,000 pregnancies
● Papillary○ Most common type○ Monitor with serial sonography
■ If significant growth or cervical lymphadenopathy then consider surgery in the second trimester
● Medullary or anaplastic○ Should be managed surgically in the second
trimester
Causes of hypothyroidism
● Hashimoto’s thyroiditis○ Glandular destruction by anti-thyroid
peroxidase antibodies● Iodine deficiency
○ Cretinism■ Most common cause of preventable mental
retardation in the world● Thyroidectomy● Radioactive iodine therapy● Radiation to the head and neck
Overt hypothyroidism
● 2-10 per 1,000 pregnancies
● Increased TSH and decreased free T4
● Signs and symptoms○ Fatigue, constipation, cold intolerance, muscle
cramps, and weight gain○ Edema, dry skin, hair loss, prolonged relaxation
phase of DTRs○ Goiter
■ More common in Hashimoto’s thyroiditis
Overt Hypothyroidism
● Adverse pregnancy outcomes:○ miscarriage, preeclampsia, preterm birth,
abruption, fetal death○ Lower IQ○ Delay in motor skill development, attention, and
language development
Subclinical hypothyroidism
● Elevated TSH with normal free T4
● Prevalence 2-5% in pregnancy
● Unlikely to progress to overt hypothyroidism
Subclinical hypothyroidism● Miscarriage
○ Increase in miscarriage risk as maternal TSH increased■ Augmented by presence of TPOAb
● Cut-off for treatment benefit○ TSH 4 if TPOAb negative○ TSH 2.5 if TPOAb positive
Subclinical hypothyroidism● Premature delivery
○ Increased risk of <34 week delivery and <37 week delivery with TSH> 97.5 percentile (Korevaar, 2013)■ If remove TPOAb positive women, no longer
see effect
● Likely no association with preeclampsia/hypertensive disorders
● Possible increase in abruption
Hypothyroidism in pregnancy:Clinical Recommendations
● Indicated testing○ Personal history of thyroid disease○ Symptoms of thyroid disease
● No indication for universal screening
Screening for hypothyroidism in pregnancy (2017 ATA Guidelines)
● History of thyroid dysfunction● Known thyroid antibodies● Goiter● History of thyroid surgery● History of head and neck irradiation● Age >30● Type 1 DM or other autoimmune disorders● History of pregnancy loss, preterm delivery, or infertility● >= 2 prior pregnancies● Family history of autoimmune disease or thyroid
disease● BMI>40● Amiodarone or lithium use● Reside in an area of iodine deficiency
Hypothyroidism: Treatment in Pregnancy
● Levothyroxine (Synthroid)○ T4
● Liothyronine (Cytomel)○ T3
● Dessicated thyroid hormone (Nature-throid, Armour thyroid, Westhroid)○ T3 and T4
Treating hypothyroidism in pregnancy
○ T4 is very important for developing fetal brain■ Neuronal migration, myelination, structural
changes in the fetal brain○ T3 does not cross fetal blood-brain barrier
(NatureThroid, Armour thyroid, Cytomel)
Treating hypothyroidism in pregnancy: Levothyroxine
● 1.6 mcg/kg levothyroxine daily full replacement dose○ Be sure take on empty stomach with water
● 50-85% of women already on replacement therapy will need to increase dose in pregnancy○ More likely in women without endogenous thyroid tissue than
women with Hashimoto’s thyroiditis
○ Increase daily dose by 20-25% or add 2 additional tablets per week
● Goal TSH <2.5
Hypothyroidism: Postpartum considerations
● Women with postpartum depression should be screened for hypothyroidism
● Decrease levothyroxine dose to pre-pregnancy dose
● Thyroid function testing 6 weeks postpartum○ 50% of women with Hashimoto’s thyroiditis will
need dose increases postpartum
Hyperthyroidism
Gestational transient thyrotoxicosis
● Limited to first half of pregnancy
● 1-3% of pregnancies
● Elevated FT4 and low TSH
● Occurs with markedly elevated levels of HCG■ Hyperemesis gravidarum ■ Gestational trophoblastic disease■ Multiple gestations
● Treatment is supportive
Subclinical hyperthyroidism
● Low TSH with normal free T4○ Not associated with adverse pregnancy
outcomes○ No indication for therapy
Overt Hyperthyroidism● 0.2 % pregnancies
○ Graves disease (95%)○ Toxic multinodular goiter○ Toxic adenoma○ Thyroiditis○ Struma ovarii○ TSH secreting adenoma○ Thyroid cancer metastases○ TSH receptor germline mutations○ Molar pregnancy, multiple gestation, and
choriocarcinoma
Hyperthyroidism: diagnosis● Signs and symptoms
○ Nervousness, tremors, tachycardia, frequent stools, excessive sweating, heat intolerance, weight loss, goiter, insomnia, palpitations, and hypertension
○ Graves disease: ophthalmopathy and pretibial myxedema
● Decreased TSH and increased free T4, TSH receptor antibodies (TRAb)
Hyperthyroidism: Risks in pregnancy
● Increased risk of preterm delivery, low birth weight, and fetal loss
● Increased risk of severe preeclampsia
● Increased risk of maternal heart failure
Hyperthyroidism: Graves disease
Treatment of Graves disease● 131-I treatment
○ Should not be used in pregnancy or breastfeeding
● Thyroidectomy○ If needed, best to do in the second trimester
● Antithyroid drugs○ Propylthiouracil
■ 200-400 mg/day○ Methimazole
■ 12-20 mg/day
● Reduce iodine
organification and coupling of monoiodotyrosine and diiodotyrosine
Antithyroid Medications
Hyperthyroidism: Monitoring therapy
● Check thyroid levels every 2-4 weeks initially, once stable can monitor q 4-6 weeks
● Antithyroid drugs are more potent in the fetus than the mother○ Maintain maternal FT4 levels at or just above
upper limit of normal
Antithyroid medications: Maternal side effects● Will occur in 3-5% of patients
○ Rash ○ Agranulocytosis (0.15%)○ Liver failure (<0.01%)
■ PTU ● Limit use to first trimester, women with
allergy to methimazole, or women with thyroid storm
Graves disease: effects on fetus● Thyroid stimulating antibodies cross placenta
○ Measurable in 95% of patients with active Graves hyperthyroidism
● Maternal T4 crosses placenta
● Fetus is at risk for:○ Fetal Hyperthyroidism (risk 1-5%)○ Neonatal hyperthyroidism○ Fetal hypothyroidism○ Neonatal hypothyroidism○ Central hypothyroidism
Graves disease: Risks to the fetus
○ Tachycardia
○ Hydrops
○ Goiter
Antithyroid medications:Fetal Risks
● Methimazole■ Aplasia cutis■ VSD■ Choanal/esophageal atresia
● Abdominal wall defects
● Propylthiouracil (PTU)○ Face and neck cysts and GU differences in males
● Beta-blockers (Propranolol)○ Neonatal hypoglycemia and fetal growth restriction
Graves disease: Neonatal Risks● Neonates can have transient hypothyroidism
related to maternal medication use
● 1-5% of neonates will have hyperthyroidism or neonatal Graves disease○ Can have delayed presentation as maternal
antibodies are cleared less rapidly than thioamides in neonates, which can result in delayed presentation of neonatal Graves disease
● Neonates at highest risk are women with a history of surgery or 1-131 prior to pregnancy and did not require thioamide therapy
Thyrotoxicosis in the postpartum period
● Relapse of Graves disease● Postpartum thyroiditis
○ Prevalence 5%○ Occurrence of thyroid dysfunction in the first
postpartum year○ Inflammatory, autoimmune condition
■ Thyrotoxicosis followed by hypothyroidism○ Associated with depression
Conclusions: Thyroid Disease in Pregnancy● Thyroid disease should be well controlled prior to
conception
● Treatment of overt hypothyroidism improves pregnancy outcomes○ Decreases miscarriage risk○ Decreases preterm delivery
● Treatment of subclinical hypothyroidism does not seem to improve outcomes○ Subclinical Hypothyroid during Early Pregnancy
(SHEP) trial results 2018-2020
Conclusions: Thyroid Disease in Pregnancy
● Treatment of hyperthyroidism improves pregnancy outcome
● Women with active Graves disease or a history of Graves disease require special attention during pregnancy
● Thyroid dysfunction may be involved in postpartum depression
Obesity in Pregnancy
Maternal Weight Gain in Pregnancy
Fetus 7-8 lbFat Stores 6-8 lbIncreased Blood volume 3-4 lbIncreased fluid volume 2-3 lbAmniotic fluid 2 lbBreast enlargement 1-3 lbUterine hypertrophy 2 lbPlacenta 1.5 lb
Total=24.5-31.5 lb
Body Mass Index (BMI)
Class I
Class IIClass III
Adult Obesity in the United States – The State of Obesity
National Institute of Diabetes and Digestive and Kidney ...
Obesity in Pregnancy: Maternal Risks
● Gestational diabetes● Preeclampsia● Cesarean delivery● Infectious morbidity● Anesthesia complications● Prolonged operating times● Increased blood loss● Increased risk of thromboembolism● Decreased successful VBAC
Obesity in Pregnancy: Fetal and Neonatal risks
● Increased risk of congenital anomalies○ neural tube defects○ congenital heart defects○ facial clefting
● Increased risk of stillbirth○ 2.1-4.3 fold greater
● Increased risk of miscarriage
● Growth abnormalities
● Increased risk of childhood obesity
Treatment of Obesity: Non-surgical
● behavioral changes● diet ● exercise● pharmacotherapy
Treatment of Obesity: Bariatric surgery
Types of Bariatric surgery:● restrictive
○ gastric band, vertical gastroplasty○ reduce stomach capacity
Treatment of Obesity: Bariatric Surgery
● Malabsorptive Procedure○ reduce gastric volume and disrupt proper
absorption
https://www.beliteweight.com/weight-loss-surgery-procedures/gastric-bypass-roux-en-y/
Pregnancy after Bariatric Surgery
● avoid pregnancy for 12-24 months after surgery (this is the starvation phase)
○ oral contraceptives are not recommended
● Increased fertility rates○ improves PCOS, anovulation, irregular menses
● Many pregnant patients after bariatric surgery are still obese (up to 80%)
Pregnancy after Bariatric Surgery
● Nutritional deficiencies○ protein○ iron○ folate
■ possible increased risk of neural tube defects
○ calcium○ Vitamin B12○ Vitamin D○
Pregnancy after Bariatric Surgery
● Decreases risk of gestational diabetes
● Reduces risk of hypertensive disorders of pregnancy
● Decreases risk of indicated preterm delivery
● Reduces risk of large for gestational age fetus
Diabetes in Pregnancy
● Diabetes effects 8% of all pregnancies in the United States○ 90% of these are
gestational diabetes○ numbers are on the
rise
Glucose Regulation during Pregnancy
● Maternal tendency for fasting and inter-prandial hypoglycemia○ Facilitated diffusion of glucose to the fetus
www.glowm.com
Glucose Regulation during Pregnancy
● Increased insulin resistance○ Estrogens, progesterone, human placental lactogen, and chorionic
somatomammotropin rise linearly during pregnancy
Creasy and Resnik, Maternal Fetal Medicine
Maternal Glucose Regulation during Pregnancy
● Augmentation in
pancreatic insulin
secretion
○ Insulin production is
more than twice nonpregnant levels
Diabetes in Pregnancy:Management Goals
● Appropriate preconception counseling and management goals
● Optimize glycemic monitoring and diet/insulin therapy
● Appropriately evaluate mother and fetus for complications of diabetes
● Peripartum and postpartum glycemic control
Types of Diabetes in Pregnancy
Gestational diabetes
Pre-existing DiabetesType IType II
www.deo.ucsf.edu/types-of-diabetes/type-1.html
Pancreatic beta-cell injury stage
Pre-diabetic stage-Loss of first phase
insulin response
Overt diabetes stage-Absolute insulin
deficiency
Pre-existing Diabetes: Type I
Pre-existing Diabetes: Type II
● Most common type of diabetes in reproductive age women
● Risk Factors○ Obesity○ Increasing age○ Race
■ African Americans■ Native Americans
●
● Complicating Factors○ More likely to have chronic
hypertension and other medical problems
www.deo.ucsf.edu/types-of-diabetes/type-1.html
Gestational DM
● Glucose intolerance with onset or first recognition during pregnancy
● Due to increased insulin resistance during pregnancy, all pregnant women are at risk of developing gestational diabetes
Gestational Diabetes: Women at Risk
● Prior history of gestational diabetes
● History of infant >9 pounds
● Family history of Type II DM (first degree relative)
● Polycystic ovarian syndrome
● BMI >30 kg/m2
● Ethnicity: Hispanic, Native American, Southeast Asian
*Screen at first visit with glucola*
Blood Glucose in Pregnancy: What is normal?
Cousins et al., Am J Obstet Gynecol, 1980
Diabetes in Pregnancy:Goals of Treatment
● Achieve normal blood glucose and hemoglobin A1C levels
● Prevent and/or minimize maternal and perinatal morbidity/mortality
Hemoglobin A1C During Pregnancy
● Normal A1C levels are lower for pregnant patients (Mosca et al, 2006)
○ 4.0-5.5 % for pregnant non-diabetics
○ 4.8-6.2 % for non pregnant controls
●● Assess every 4-6 weeks during pregnancy
● Pregnancy goal is A1C <6 %
● Not recommended for diagnosing gestational diabetes
Blood Glucose Goals in Pregnancy
● Fasting <90● Preprandial <105● One hour postprandial <140● Two hour postprandial <120
● 3AM if nighttime hypoglycemia is a problem
■ Avoid blood sugars less than 60
Why is glucose control important during pregnancy?
Risks of Diabetes in Pregnancy
● Fetal○ Miscarriage○ Congenital anomalies○ Intrauterine fetal
demise○ Growth disturbances
● Neonatal○ Hyperbilirubinemia○ Hypoglycemia○ Obesity○ Diabetes
● Maternal○ DKA○ Worsening end organ
damage■ Retinopathy■ Nephropathy
○ Pregnancy induced hypertension
○ Preeclampsia○ Polyhydramnios○ UTI/pyelonephritis
Diabetes in Pregnancy: Maternal Morbidity
Complication GDM (%) B, C (%) D,F,R (%)
Preeclampsia 10 8 16
Hypertension 15 15 31Polyhydramnios 5 18
Preterm labor 8 5 10Cesarean delivery
12 44 57
Creasy and Resnik, Maternal Fetal Medicine, 2004
Diabetes in Pregnancy:Fetal Risks
○ Miscarriage
○ Congenital anomalies
○ Intrauterine fetal demise
○ Growth disturbances
Taylor, R. et al. BMJ 2007;334:742-745
Pre-existing Diabetes: Risk of Congenital Malformations
Congenital Malformations
Diabetes in Pregnancy: Perinatal Morbidity
● Fetal hyperinsulinemia
○ Drives catabolism of the oversupply of glucose which depletes fetal oxygen stores■ Episodic hypoxia leads to Increased adrenal catecholamines
● Cardiac hypertrophy● Increased risk of intrauterine demise● Stimulation of erythropoietin● Postnatal hyperbilirubinemia
○ Promotes storage of excess nutrients■ Macrosomia
● Increased risk of birth injury
Gabbe 2007
Pre-existing Diabetes: Perinatal Mortality
Gestational Diabetes: Dietary Management
● Diet composition: 40% CHO, 20% protein, 30-40% fat○ 10% of calories for breakfast○ 30% of calories for lunch○ 30% of calories for dinner○ 30% of calories for snacks (3)
● Avoid periods of longer than 4 hours without food intake during the day and longer than 10 hours overnight
● Bedtime snack of 25g (medium apple) of complex carbohydrates helps to decrease risk of nocturnal hypoglycemia
● Allow one to two week trial of dietary changes before instituting insulin or oral hypoglycemic therapy
●● Exercise is good
Treatment of Diabetes in Pregnancy:Oral Hypoglycemic
Biguanides (Metformin)
No oral agents are FDA approved for treating gestational diabetes
Metformin: Evidence in Pregnancy
● Crosses the placenta
● Pregnancy Class B ○ No teratogenic effect in animals and
inadequate evidence to confirm safety in human pregnancy
● First trimester use○ Decreased risk of congenital malformations
(Gilbert et al., 2006)○ In women with PCOS may decrease risk of
miscarriage (Khattab et al., 2006)
Metformin: Evidence in Pregnancy
● Second and third trimester use
○ Continued use during pregnancy in patients with PCOS decreases risk of developing gestational diabetes ten fold (Glueck et al., 2002)
○ Questionable increase in incidence of pre-eclampsia (Hellmuth et al., 1994)
○ Metformin in Diabetes study (Rowan JA et al, 2008)■ Comparable fasting glucose and HgbA1C■ Better weight management■ No increase in adverse pregnancy outcomes compared to
insulin for the treatment of GDM■ Patients preferred over insulin therapy
Metformin use in Pregnancy
● Continue through the first trimester if a patient conceives on Metformin
● May be an adjunct to insulin therapy in cases of extreme insulin resistance
● May be an option in a patient who refuses insulin therapy
● Discuss with patient the lack of information regarding long term outcomes of use during pregnancy
Insulin Treatment
Remains the only FDA approved treatment for diabetes in pregnancy
Insulin in Pregnancy
● First trimester○ Often necessary to reduce insulin dose by
10-25%
● Second and third trimester○ Doses will need to be increased
■ Type I 10-20%■ Type II 30-150%
○ After 35-38 weeks insulin requirements may decline
Insulin Dosing: General Guidelines
Total daily dose of insulin =wt (kg) x factor
Trimester Type 1Type II andGestational
1st 0.5 0.7-0.8
2nd 0.6 0.8-1.0
3rd 0.7 0.9-1.2
Gestational Diabetes: Lifelong risk to the Mother
● ACOG recommends a 2 hour (75 g) GTT at 6-12 weeks postpartum for all women with gestational DM
● Up to 60% of women with insulin requiring gestational DM will become Type II diabetics later in life
● Yearly diabetes screening through their PCP
Diabetes in Pregnancy:Neonatal Complications
Childhood Obesity
Childhood Obesity
https://diabetologia-journal.org/2018/11/13/being-large-for-gestational-age-at-birth-combined-with-diabetes-in-the-mother-is-associated-with-a-near-trebling-of-a-childs-risk-of-obesity/
Diabetes in Pregnancy: Risk in Childhood
Conclusions: Diabetes in Pregnancy
● Early, aggressive treatment of diabetes during pregnancy is important to improve outcomes (maternal, fetal, neonatal, and lifelong)
● Appropriate nutrition management improves glucose control and has potential long term impact on maternal and child health
● Long term follow up of women who had gestational diabetes is recommended
Maternal mortality in the US
Conclusions
● Preconception counseling for chronic medical conditions is very important to improve pregnancy outcomes
● BIRTH CONTROL
Thyroid Disease:Preconception Counseling
● If TSH >2.5, Consider TPOAb testing
● Iodine supplementation
● Good control for at least 3 months prior to conception
Obesity and Diabetes:Preconception Counseling
● Weight loss prior to conception to improve maternal and fetal/neonatal outcomes
● Optimize glucose control for at least 3 months prior to conception
● Optimize management of any co-existent medical problems prior to conception
QUESTIONS?