Endocrine Disorders in Pregnancy: Changes in Glucose Metabolism and Thyroid Physiology Flashcards
Insulin Resistance of Normal Pregnancy and difference between trimesters for insulin sensitivity
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
Normal Metabolic Changes in Pregnancy
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
Oral Glucose Tolerance Test in pregnant women
Pregnant women have lower FBG but slightly higher postprandial glucoses and hyperinsulinemia
When are mothers anabolic vs catabolic in general during pregnancy?
Early mother: anabolic with lipogenesis
Late mother: catabolic with lipolysis
Gestational Diabetes (GDM)
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
Why do obese women without GDM have larger babies?
They have higher glucose levels than normal women, even when not criteria for GDM
Pathophysiology of GDM
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)
Why is GDM a Problem for the Mother?
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
Postpartum Management GDM Women
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
Diabetic Effects on the Fetus
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
How does the intrauterine environment have Long Term Implications on metabolic factors for the baby?
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
Childhood Obesity and Diabetes
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
Normal Thyroid Function and Physiology during Pregnancy
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
Fetal Thyroid Function
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
Iodine deficiency
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
Maternal Hypothyroidism
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
Hyperthyroidism in Pregnancy
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
Do we use T3 in pregnancy?
NO! Because doesn’t protect baby’s brain
Gestational Hyperthyroidism and HG
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
Grave’s Disease in pregnancy
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
Fetal and Neonatal Grave’s
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
Do antithyroid drugs cross placenta?
Yes so be careful in treating a pregant women
Postpartum Thyroiditis
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
- 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
What hormones are responsible for insulin resistance of pregnancy
hPL
hPGH
What hormone makes prolif retinopathy worse
estrogen
Which hormone causes TSH to be suppressed?
hCG
Which hormone cause TT4, TT3 to be elevated?
estrogen
because of increased thyroid hormone binding
Which hormone causes hyperthyroid sxs: increased HR, decreased SVR, increased C.O., heat intolerance?
hCG
Which hormone causes GERD, constipation, increased risk pyelo
progesterone
Which hormone causes 50% women with HG to become hyperthyroid?
hCG
Which hormone causes Grave’s to improve 3rd trimester
progesterone
Which hormone increases lipolysis and insulin secretion in pregnancy
hPL
