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?