Endocrine Disorders in Pregnancy: Changes in Glucose Metabolism and Thyroid Physiology

Question 1

Insulin Resistance of Normal Pregnancy and difference between trimesters for insulin sensitivity

Answer 1

Physiologic adaptation to ensure adequate nutrients to fetus

Placental hormones reprogram maternal physiology to become insulin resistant

Normal pregnancy: 50% decrease in insulin mediated glucose disposal

Women must increase insulin secretion by 2-3 X to maintain euglycemia

~80% energy needs of fetus from glucose

Insulin sensitive 1st trimester:
Insulin requirements decreased in pre-existing DM
Women at risk for severe nocturnal hypoglycemia 1st trim

Insulin resistance late 2nd and 3rd with increased hPL, hPGH, TNFα

Women with pre-existing diabetes will double to triple their insulin requirements in 2nd and 3rd trimester

Question 2

Normal Metabolic Changes in Pregnancy

Answer 2

Glycogen stores depleted rapidly due to fetal-placental growth requirements

Pregnant women shift from carb to fat metabolism within 12 hrs due to depleted glycogen

Pregnant women utilize fat as fuel to conserve glucose for fetal-placental unit resulting in increased ketones

Prolonged fasting increased starvation ketosis (accelerated starvation of pregnancy)

High risk of DKA in pregnancy

Question 3

Oral Glucose Tolerance Test in pregnant women

Answer 3

Pregnant women have lower FBG but slightly higher postprandial glucoses and hyperinsulinemia

Question 4

When are mothers anabolic vs catabolic in general during pregnancy?

Answer 4

Early mother: anabolic with lipogenesis

Late mother: catabolic with lipolysis

Question 5

Gestational Diabetes (GDM)

Answer 5

Glucose intolerance recognized for the first time during pregnancy (should only show up in 2nd or 3rd trimester)

If 1st trimester (NOT GDM):
Undiagnosed Type 2 (or Type 1) with increased A1C have risk for major malformations (3-10 weeks)

Most women diagnosed before 24 weeks have IGT (pre-diabetes) and are at very high risk for developing Type 2 postpartum

Prevalence has doubled in 10 years due to obesity epidemic

Question 6

Why do obese women without GDM have larger babies?

Answer 6

They have higher glucose levels than normal women, even when not criteria for GDM

Question 7

Pathophysiology of GDM

Answer 7

Vast majority are overweight and insulin resistant

Marked decrease in insulin mediated glucose disposal

Impaired glucose transport into skeletal muscle and adipose tissue

Inability for Beta-cell cell to compensate for insulin resistance despite hyperinsulinemia leading to hyperglycemia

Both first phase and second phase of insulin secretion impaired in GDM

Hepatic overproduction of glucose leads to increased Feta Blood Glucose

Thin GDM women often GAD ab positive are at risk of developing autoimmune DM (Type 1)

Question 8

Why is GDM a Problem for the Mother?

Answer 8

Intensive monitoring glucoses, diet restrictions, insulin or meds, visits q 2 wks, financial burden

Higher risk infection, C-section, Preeclampsia

~50% Maternal risk of developing Type 2 DM in 5-10 years

Question 9

Postpartum Management GDM Women

Answer 9

Target GDM women for primary prevention postpartum given ~50% risk of DM in 5-10 yrs (80% if IGT)

Do oral glucose test post-partum
If pre-diabetes: diet, exercise

Preconception counseling; wt loss, DM evaluation

CONTRACEPTION!! 50% pregnancies unplanned!!

Breast feeding decreases risk of Type 2 DM

Question 10

Diabetic Effects on the Fetus

Answer 10

Mother’s glucose from hyperglycemia transfers to baby but mother’s insulin doesn’t

Baby responds to glucose by increasing insulin

High insulin causes increased growth and metabolic rt leading to increased trauma, c-sec, increased childhood obesity and diabetes

Can also get hypoglycemia after birth because mother’s glucose disappears but takes a while for insulin to decrease

Associated problems for baby:

Head to body disproportion

Increase in mortality from severe maternal hyperglycemia leading to fetal hyperinsulinemia leading to increase in fetal metabolic rate and fetal hypoxemia

Cardiac septal hypertrophy

Neonatal RDS from hyperinsulinemia which inhibits cortisol production of Type II cells leading to decreased lecithin

Neonatal hypoglycemia from fetal hyperinsulinemia

Question 11

How does the intrauterine environment have Long Term Implications on metabolic factors for the baby?

Answer 11

Metabolic factors in the intrauterine environment have a profound effect on prenatal development and enhanced susceptibility to later chronic disease

Type 1 and 2 DM, GDM lead to increased fetal insulin and leptin, neonatal adiposity, and enlargement of the pancreas, heart

High fetal insulin/leptin levels affect appetite regulation in the hypothalmus as well energy expenditure and mitochondrial oxidative capacity leads to neonatal obesity and impaired glucose tolerance in childhood

Epigenetic mechanisms (how your genes are expressed) appear to mediate most of these effects through intrauterine environmental influences and postnatally

Question 12

Childhood Obesity and Diabetes

Answer 12

Obesity has tripled children in last 2 decades

1/3 of children 6-19 are overweight; 20% are obese

~30% girls 11-15 are obese

Type 2 DM up by >300% in adolescents

Childhood Type 2 DM diabetes has tripled; 1:3 children will develop DM in their lifetime

Question 13

Normal Thyroid Function and Physiology during Pregnancy

Answer 13

TSH: nl or slight decrease 1st, 2nd trim due to increased hCG

TBG: increases 2-3 fold due to Estrogen

TT4 and TT3 increased by 50%

fT4 ,fT3 within nl range

Gland increase by 15%; goiter pathologic

Mother increases synthesis of thyroid hormone which requires increased iodine due to increased TBG, plasma vol, and GFR. Limited passage of T4

Thyroid Requirements increases in Pregnancy

Question 14

Fetal Thyroid Function

Answer 14

T4 observed in embryonic circulation as early as 4 wks post implantation

Essential for normal early neurogenesis

Fetus dependent on mom’s T4 1st trim; Fetal thyroid begins to concentrate iodine and make T4 at 8-10 wks
T4 transporters in fetal brain 1st trim; not T3 which remains low. Do not use T3 in pregnancy.

Production independent by ~ 16-18 weeks but needs adequate iodione

Fetus independent of mom’s status late 2nd and 3rd trim

Question 15

Iodine deficiency

Answer 15

Iodine requirements increase during pregnancy

Leading preventable cause of mental retardation

Cretinism is due to both maternal and fetal iodine deficiency

30% of world pop at risk for iodine def

Only 50% U.S. households use iodinized salt; NOT in most prenatal vitamins

Question 16

Maternal Hypothyroidism

Answer 16

Most cases due to Hashimoto’s

Nl preg: increased T4 by 30-50%

Most women require a 25% increase in thyroid hormone supplements early in gestation

Hypo leads to increased Neurodev delay in offspring, preg loss, preterm delivery, preeclampsia, LBW, abruptio placenta

T4 needed for trophoblast function

Question 17

Hyperthyroidism in Pregnancy

Answer 17

Prevalence ~1%

Causes:
Grave's ~85%
hCG-induced hyperthyroidism (hyperemesis gravidarum)
Toxic multinodular goiter
Toxic adenoma
Iodine-induced from autonomous goiter
Subacute thyroiditis
Over-replacement with thyroid hormone

Question 18

Do we use T3 in pregnancy?

Answer 18

NO! Because doesn’t protect baby’s brain

Question 19

Gestational Hyperthyroidism and HG

Answer 19

Vomiting with wt loss/requiring fluid resusitation

Elevated fT4 levels usually fall by 16-18 weeks so no need to treat

hCG activity high degree of affinity for the TSH receptor and hepatic clearance correlate with the degree of post-translational glycosylation

Question 20

Grave’s Disease in pregnancy

Answer 20

Usually presents 1st trim

Improves 3rd trim due to immune suppression of pregnancy; 70% rebound post-patrum

Thyroid stimulatory immunoblobulin (TSI) levels often normalize later in pregnancy

Maternal risks: CHF, wt loss, preeclampsia, a fib, storm

Fetal risks: Fetal tach, IUGR, premature

Rx: PTU or MMI to titrate fT4 and T3 upper limits of nl range because normalization of free T4 may cause fetal hypothyroidism

Question 21

Fetal and Neonatal Grave’s

Answer 21

Very rare that the maternal Ab cross to baby, but can happen

2-5%–assoc with high levels TSI (TSH Receptor abs)

Fetal thyroid can respond to TSI by 18-20 wks

Fetal tach, IUGR–rarely cardiac failure, HSM, goiter, craniosynostosis

Neonatal sxs more common; irritability, failure to thrive, diarrhea, hyperkinesis, jaundice, tachycardia

May take 5-10 days to present; Rx with thioamides until TSI levels normalize

Question 22

Do antithyroid drugs cross placenta?

Answer 22

Yes so be careful in treating a pregant women

Question 23

Postpartum Thyroiditis

Answer 23

Occurs in ~5% population

Up to 20% prevalence in Type 1 DM

Associated with high levels of antiperoxidase (TPO) abs

Histology identical to Hashimoto’s thyroiditis

High recurrence in subsequent pregnancies

2 phases:
1. Hyperthyroid phase: 2-4 mos Postpartum
Often clinically silent: weight loss, palpitations, nervousness, insomnia. Due to destruction of the thyroid gland and release of thyroid hormone

Treatment: Beta-blockers. Differentiate from post-partum exaccerbation of Grave’s

2. Hypothyroid phase: 4-8 mos postpartum
   Often unrecognized: fatigue, depression, weight gain
   Due to continued destruction of gland

Treatment: Thyroid hormone for 6-12 months. Recheck TSH after withdrawing thyroid hormone for 6 weeks
Permanent hypothyroidism in 10-40%. Need long-term follow-up

Question 24

What hormones are responsible for insulin resistance of pregnancy

Answer 24

hPL

hPGH

Question 25

What hormone makes prolif retinopathy worse

Answer 25

estrogen

Question 26

Which hormone causes TSH to be suppressed?

Answer 26

hCG

Question 27

Which hormone cause TT4, TT3 to be elevated?

Answer 27

estrogen

because of increased thyroid hormone binding

Question 28

Which hormone causes hyperthyroid sxs: increased HR, decreased SVR, increased C.O., heat intolerance?

Answer 28

hCG

Question 29

Which hormone causes GERD, constipation, increased risk pyelo

Answer 29

progesterone

Question 30

Which hormone causes 50% women with HG to become hyperthyroid?

Answer 30

hCG

Question 31

Which hormone causes Grave’s to improve 3rd trimester

Answer 31

progesterone

Question 32

Which hormone increases lipolysis and insulin secretion in pregnancy

Answer 32

hPL