Endocrine Flashcards
Physiology of thyroid in pregnancy
Relative maternal iodine deficiency
- 2-fold increase in renal loss (increased GFR + decreased reabsorption)
- Active transport of iodine to fetus
Uptake of plasma iodide into the thyroid is increased 3-fold
- Insufficient dietary iodine –> cellular hyperplasia and goitre
Increased hepatic synthesis of thyroid-binding globulin (TBG) leads to:
- Increase in total thyroxine (T4)
- Increase in total tri-iodothyronine (T3)
- Free T4 (FT4) levels remain unchanged
HCG has weak thyroid stimulating activity as structurally similar to TSH
Normal increase in HCG in early pregnancy may cause a small transient increase in free T4 with subsequent TSH suppression
Iodine deficiency in pregnancy
Inadequate iodine –> inadequate thyroid hormone production –> hypothyroidism
most common cause of mental retardation and irreversible brain lesions
Thyroid hormone is essential for normal maturation of the central nervous system, particularly its myelination
For the first 12/40, the fetus is completely dependent upon maternal T4
Re-emergence of iodine deficiency appears to be due to:
Increased consumption of commercially-prepared foods
Declining use of iodine-containing sanitizers by the dairy industry
Less salt being used in home prepared foods as a response to the health messages to reduce salt intake
The iodine content of vegetables, fruits and grains generally reflect the iodine level of the soil in which they were grown
- Iodine content of NZ soil is low
Dietary sources of iodine
- Seafood (fish, shellfish, seaweed)
- Commercially prepared bread
- Iodised salt
- Milk
- Eggs
It is difficult for most New Zealanders to obtain adequate iodine from their normal diet, which is why commercially prepared bread must now have iodine added to it
RDI if pregnant, planning a pregnancy, or breast feeding: 150 micrograms/day
Primary hyperparathyroidism background
Increased PTH secretion –> increased serum Ca, however clinical hypercalcaemia only occurs in severe cases as pregnancy is a low Ca state
Causes: parathyroid adenomas or hyperplasia
Malignancy
MANAGEMENT Mainly conservative - Phosphate supplements - Low calcium diet - Hydration May require parathyroid surgery - Perform in second trimester
If untreated, risk of:
- PET
- Miscarriage
- FGR
- IUFD
- Neonatal hypocalcaemia through fetal PTH suppression
Graves pathogenesis
95% of thyrotoxicosis
0.1-1% of all pregnancies
Autoimmune disorder
Thyroid-stimulating hormone receptor-stimulating immunoglobulins / antibodies (TSI) –> growth of thyroid gland and hyperthyroidism
Genetic predisposition (50% of patients have a family history of autoimmune thyroid disease)
Environmental factors: smoking, high iodine intake, stress
If thyrotoxicosis occurs for the first time in pregnancy, it usually occurs late in the first or early second trimester
Diffuse, firm goitre
50% have ophthalmopathy
Pretibial or localised myxedema
Pregnancy effect on Graves
First trimester - Exacerbation may occur
- Increased HCG or decreased absorption of medication due to vomiting
Second / third trimester - Improvement in Graves’ disease
- Relative immunosuppression
Post-partum - Exacerbation may occur
- Especially if there has been improvement during pregnancy
Effect of thyrotoxicosis of pregnancy - maternal risks
Good pregnancy outcome if good control on medication or previous treated Graves’
If severe and untreated, thyrotoxicosis is associated with inhibition of ovulation and infertility
Poorly controlled disease may have:
- HTN
- PET
- Placental abruption
Arrhythmias - sinus tachycardia, supraventricular tachycardia, AF
Heart failure and ‘thyroid storm/crisis’ have maternal mortality of 25%
- Highest risk of thyroid storm at delivery
Effect of thyrotoxicosis of pregnancy - fetal risks
If untreated or newly diagnosis in pregnancy, increased risks of:
- Miscarriage
- Fetal growth restriction
- Preterm labour and birth
- Perinatal mortality
- Stillbirth
Transplacental TSI –> fetal or neonatal thyrotoxicosis in 1%
Higher risk if:
- Poorly controlled disease or high TSI titres
- Active disease in the third trimester
- May also occur in treated Graves’, following thyroidectomy or radioactive iodine
Perinatal mortality without treatment is 25%
Medications for hyperthyroid
- High doses may –> fetal hypothyroidism
- Carbimazole rarely causes aplasia cutis (patches of absent skin at birth, mainly on the scalp)
Doses of PTU <150mg/day and carbimazole <15mg/day are unlikely to cause problems in the fetus
Risks of PTU - maternal liver failure, 1 in 10,000
Suggest PTU first trimester, then switch to carbimazole
BETA BLOCKERS
- for symptoms of tachycardia and tremor, discontinue once anti-thyroid drugs take effect
Radioactive iodine CI in pregnancy and breastfeeding (avoid pregnancy for 4-6/12 after Rx)
Monitoring for hyperthyroid in pregnancy
TFTs monthly in newly diagnosed patient
3-monthly TFTs in stable patient
Measure maternal TSI titre early and late in pregnancy
Serial growth scans for growth, HR and goitre
Cord blood for TFTs
USS features of fetal thyrotoxicosis
Thyroid enlargement FGR Hydrops Presence of goitre Advanced bone age Tachycardia Cardiac failure
Key points of neonatal thyrotoxicosis
Results from transplacental passage of TSIs
Onset may be delayed for 14 days if the mother was on thionamides
Transient condition, lasting 2-3 months
Mortality rate up to 15% if untreated
Antithyroid treatment should begin promptly but only short term
Symptoms: Weight loss, tachycardia, irritability Hepatosplenomegaly Heart failure (faire) Goitre)
Gestational hyperthyroidism
1-3% of women in early pregnancy
Develops in early pregnancy and resolves before 20/40
HCG is structurally similar to TSH –> stimulates TSH receptor –> increased thryoid hormone production –> suppresses TSH
Women do not always have overt signs of hyperthyroidism
By definition, have negative thyroid receptor antibodies
~50% of cases occur with hyperemesis gravidarum
Subclinical hypothyroidism implications
Results for large cohorts and meta-analyses have not been consistent in demonstrating an association between SCH and adverse pregnancy outcomes
Increased risk of clinical hypothyroidism within 5 years, especially if thyroid autoantibodies
Association with childhood developmental delay has not been confirmed in prospective cohort data
No studies show thyroxine influences outcome
Routine screening and treatment not recommended
Overt hypothyroidism diagnosis
TSH >reference range with decreased T4, or
TSH >10mIU/L, irrespective of the level of FT4
Treat in pregnancy
Pathophysiology - hypothyroid
Autoimmune disease associated with thyroid peroxidase (microsomal) autoantibodies (TPA) –> lymphoid infiltration –> fibrosis and atrophy of the thyroid gland
- Hashimoto’s thyroiditis - Main cause of hypothyroidism in NZ and Australia, A/w other autoimmune diseases, e.g. T1DM
- Atrophic thyroiditis
Iatrogenic
- After radio-iodine
- Thyroidectomy
- Drugs - amiodarone, lithium, iodide, thionamides
Secondary hypothyroidism
- Sheehan syndrome (postpartum pituitary necrosis after PPH)
Transient
- Subacute de Quervain’s thyroiditis
- Postpartum thyroiditis
Iodine deficiency itself is associated with hypothyroidism and goitre
Hypothyroidism effects on pregnancy
Adequately treated hypothyroidism is not a/w any adverse maternal, fetal or neonatal complications TPA (thyroid peroxidase antibodies) does not affect the fetus Under treated women at risk of - Miscarriage - PET - Abruption - PPH - Anaemia - Low birth weight - Prematurity - Perinatal mortality - Stillbirth - Impaired neurological development - Low offspring IQ Congenital cretinism - syndrome of growth restriction, deafness, neuropsychological impairment, resulting from severe iodine deficiency or untreated congenital hypothyroidism
Antenatal management of hypothyroidism
Pregnant women receiving thyroxine will often require a 30-50% increase in their thyroxine dose from early in the first trimester
The goal for treatment of overt hypothyroidism should be to maintain serum TSH values within the lower half of trimester-specific pregnancy ranges
Iron or aluminium hydroxide antacids interfere with thyroxine absorption
In euthyroid women, check TFTs once each trimester
Following any dose adjustments, recheck every 4-6 weeks
In women on thyroxine following treatment of Graves’ disease, TSI should be measured in early and late pregnancy to predict fetal or neonatal thyrotoxicosis
If newly diagnosed or undertreated, do serial scans for growth and goitre
Postpartum management of hypothyroid
Check TFTs if thyroxine dose was adjusted
Up to 75% develop postpartum thyroiditis
Postnatal depression commoner in women with thyroid antibodies
TSH is measured in all neonates with a Guthrie card
Aetiology of postpartum thyroiditis
5-10% of pregnancies
Occurs in up to 75% of patients with thyroid peroxidase (micrsomal) autoantibodies (TPA)
25% have a first degree relative with authoimmune thyroid disease
Incidence is 3-fold higher in T1DM
Clinical features of postpartum thyroiditis
Usually presents 3-6/12 after delivery
Symptoms usually vague and attributed to puerperium
Biphasic
- Transient hyperthyroidism from increased release of preformed T4 (instead of increased production), followed by prolonged hypothyroidism as thyroid reserve depleted
Monophasic
- Transient hyperthyroidism or hypothyroidism
Small, painless goitre in 50%
Diagnosis of postpartum thyroiditis
TFTs to distinguish hyper and hypothyroidism
Distinguish from PP Graves’ disease flare, which needs treatment
- Radioactive iodine scan shows increased uptake in Graves’ and reduced uptake in postpartum thyroiditis
- TSI absent in postpartum thyroiditis
Stop breastfeeding for 24h after radioactive scan
Management of postpartum thyroiditis
Most patients recover spontaneously within 1 year
Need for treatment depends on symptoms not TFTs
Hyperthyroidism –> Beta blocker
Hypothyroidism –> Thyroxine
Repeat TFTs to ensure complete recovery
- avoid conception in this time
Permanent thyroxine replacement recommended with increased TSH level and thyroid antibodies as increased risk of overt hypothyroidism within 5 years
- Long-term annual TFTs
Recurrence and prognosis of postpartum thyroiditis
3-4% remain permanently hypothyroid
10-25% have recurrent PP thyroiditis
20-40% of patients with TPA will develop permanent hypothyroidism within 5 years
Thyroid nodules and cancer in pregnancy
Up to 40% of nodules in pregnancy may be malignant
- Commonest is papillary carcinoma
Features indicating malignancy:
- Previous history of radiation to the neck or chest
- Nodule - fixed, painless, rapid growth
- Lymphadenopathy, voice change, Horner’s syndrome
Physiology of glucose metabolism in pregnancy
Normal pregnancy - state of physiological insulin resistance and relative glucose intolerance
First trimester - insulin sensitivity increases
Second and third trimesters - progressive insulin resistance
- ~50% reduction in insulin sensitivity by the 3rd trimester (chiefly manifested in skeletal muscles)
Placenta produces insulin antagonists and cortisol –> increased glucose production
- Human placental lactogen (HPL)
- Progesterone
- HCG
Increased glucose production is beneficial to the growing fetus
BSLs in normal pregnancy compared to non-pregnant - low fasting levels, high post-prandial
Maternal pancreas compensates for increased peripheral demands (if no diabetes or normal response)
GDM:
- Pancreatic beta-cells are unable to produce sufficient insulin to balance the increased glucose production, or if there is maternal insulin resistance
Incidence of GDM
Common >35,000 women each year diagnosed with the condition or its recurrence in Australia 3000-4000 in NZ ~5% of pregnancies Increasing in prevalence
Risk factors of GDM
Pre-pregnancy BMI >30
Previous macrosomic baby (>4.5kg or >90th centile)
Previous GDM / hyperglycaemia in pregnancy
FHx of diabetes (1st degree relative or sister with GDM)
Minority ethnic family origin with high prevalence of diabetes
- Asian, Indian, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African
PCOS
Medications - corticosteroids, antipsychotics
Maternal age >40
Neonatal morbidity of GDM
Hypoglycaemia Hyperbilirubinaemia Hypocalcaemia Hypomagnesaemia Polycythaemia Respiratory distress Cardiomegaly
Screening for GDM as per RANZCOG
OGTT 75g
GDM (RANZCOG, ADIPS)
fasting =/>5.1 mmol/L
2h =/>8.5 mmol/L
Reasons RANZCOG no longer recommends 2-step process (polycose +/- OGTT)
- Misses 25% of cases and results in almost 30% of patients being ‘chased up’ and recalled for a second test
- Diagnosis and therapy of GDM is delayed
Booking HbA1c =/>48mmol/mol –> T2DM
Indicates the average blood glucose levels over the previous 6-8 weeks
Reliable method of detecting undiagnosed diabetes in the first 20/40
Patient education for GDM
Majority of women will need metformin or insulin if changes in diet and exercise do not control GDM effectively
If not detected and controlled, there is a small increased risk of serious adverse birth complications
- E.g. shoulder dystocia
Diagnosis of GDM will lead to increased monitoring, and may lead to increased interventions
Risks - LGA, birth trauma, IOL, CS
Neonates - hypoglycaemia, diabetes / obesity in later life
Treatment target for BSL control
Fasting <5 mmol/L
2h <6.7 mmol/L
Poor glycaemia control = 10% above treatment targets in one week (MoH NZ)
Delivery for GDM
If normally grown fetus with good BSL control throughout pregnancy, then should not be routinely offered elective birth before 40 completed weeks
If >90th centile or maternal / fetal comorbidities, plan delivery for 38-39/40
Offer elective LSCS to avoid birth trauma to women at 39+0 with GDM and EFW >4.5kg (UTD)
NNT 443 to prevent 1 permanent brachial plexus injury (UTD)
PN management of GDM
Stop all medication for diabetes immediately after delivery
Monitor BSLs post-partum to exclude persisting hyperglycaemia
Breastfeeding
- Benefits both mother and child
- Improves maternal glucose metabolism
Contraception
Screen for depression
Increased risk of GDM in future pregnancies and T2DM in later life
- Risk of recurrence - studies have quoted an incidence of >30%
- Chance of developing T2DM - risk of developing T2DM 1.5-10% per year
Offer lifestyle advice
HbA1c at 3/12 post-partum, then annual thereafter
Antenatal management for DM
5mg folic acid Retinal screening at booking and 28/40 - Can deteriorate in pregnancy and with quick correction of BSL Assess diabetic nephropathy Baseline PET screen and assess risk Aspirin and calcium - PET 10-20% VTE prophylaxis if nephrotic range TFTs if T1DM MSS1 Detailed anatomy scan Serial growth from 28-36/40
Fetal risks for DM
Miscarriage (2-3 fold) Major congenital abnormality (2-4 fold) Congenital heart defects (3-fold) NTD (3-fold) Situs inversus Sacral agenesis (rare but specific) Macrosomia FGR PTB Polyhydramnios Stillbirth Polycythaemia, jaundice Neonatal hypoglycaemia
Macrosomia in DM
2-fold increased risk
Birth weight >4kg or >90th centile for gestation
Pedersen hypothesis:
- Insulin is anabolic and growth-promoting
- Maternal hyperglycaemia –> fetal hyperglycaemia –> fetal pancreatic beta cell hyperplasia and hyperinsulinaemia –> macrosomia, organomegaly, accelerated skeletal maturation
No difference in birth weight between T1 and T2DM
30% increased risk of macrosomia if mean postprandial BG >6.7
Increased risk of traumatic delivery
- 10-fold increased risk of Erb’s palsy
- Shoulder dystocia 8% vs. 3% general population
Intrapartum DM management
T1DM / T2DM with no other complications to have elective birth between 37+0 and 38+6
Can consider <37+0 if metabolic or other maternal or fetal complications
BSL every hour
Ensure it maintained between 4-7 mmol/L
Consider IV dextrose and insulin infusion in all T1DM from the onset of established labour
Typically insulin requirements decrease during labour
- Energy use
- Fasting status
Neonatal care if DM
Recommend women with diabetes birth in hospital
Skin to skin and breastfeeding encouraged
BSL testing of infant at within 1-2h of birth
Hyperinsulinaemia - inhibits the normal stimulatory effect of cortisol on lecithin synthesis and is the reason RDS is more common in babies of diabetic mothers
Diabetes insipidus - definition and causes
Disorder characterised by polyuria and polydipsia from the loss of urine concentrating ability of the kidneys
Gestational
Central - Sheehan syndrome, tumour, trauma, neurosurgery
- Inadequate ADH production
Nephrogenic - CKD, lithium, inherited
- Renal resistance of ADH
Dispogenic / psychogenic - excessive water drinking
normal pregnancy and ADH
Gestational diabetes insipidis
Metabolic clearance of ADH increases 4-6 fold because of increase in vasopressinase by the placenta
In normal pregnancy, compensatory increase in ADH production so concentration remains in normal range and patients do not become polyuric
Gestational diabetes insipidus
Transient ADH deficiency in pregnancy or postpartum
- Caused by either increased placental vasopressinase production (e.g. multiple pregnancy), or decreased hepatic degradation of placental vasopressinase
(e.g. PET, HELLP syndrome, acute fatty liver of pregnancy)
Treatment of diabetes insipidus
Hypernatraemia - Replace free water (IV or PO) Desmopression (DDAVP) if central or transient DI - Vasopressin analogue - Safe in pregnancy - PO, SL, or nasal spray
For new onset DI in pregnancy, need to exclude:
- PET
- HELLP syndrome
- Acute fatty liver
Diabetic ketoacidosis in pregnancy
More common, occurs at lower levels of glycaemia, higher risk of mortality
BSL >11mmol/l, venous pH <7.3 or bicarb <15, ketonaemia or ketouria
Potassium level may be falsely elevated or normal
Increased ventilation = state of resp alkalosis –> less ability to buffer
Hormonal changes –> increased insulin resistance
Management of DKA
Aggressive volume replacement, insulin infusion, careful attention to electrolyte balance
Treat precipitating factors
Hourly BSL
2hr K+ monitoring until stable
Glucose <14, add dextrose to insulin
What is acromegaly?
Pituitary adenoma producing excessive growth hormone
Soft tissue hypertrophy
Insidious onset, diagnosis usually age 40-60
Pregnancy implications and management if acromegaly
Tumour may enlarge significantly (larger tumour –> greater risk of growth) –> headaches, visual disturbances due to pressure on optic chiasm
Increased risk of
- HTN
- Diabetes
- Heart disease
GH does not cross the placenta - no risk to fetus
Monitoring
- Visual field exam
- Pituitary MRI is tumour growth suggested
Trans-sphenoidal surgery
- Ideally before conception
Medical therapy - somatostatin analogues (lanreotide, octreotide) are usually discontinued in early pregnancy
Management of hypopituitism / Sheehan’s
Hormone replacement
Steroids
- Similar Rx to adrenal insufficiency
- Increased doses at times of stress, including labour
Thyroxine
Growth hormone - stop prior to pregnancy due to lack of safety data
Vasopressin
Pregnancy outcomes if inadequate Rx:
- FGR
- Miscarriage
- Maternal hypotension
- Hypoglycaemia
- Death
Describe the adrenal gland
Lies above the kidney
Cortex represents ~90% of the normal gland, surrounds the medulla
Corticosteroids from the Cortex
- Aldosterone
- Cortisol
- Adrenal androgens - DHEA, DHEA-sulfate
Catecholamines from the medulla
- Epinephrine
- Norepinephrine
What is addison’s disease?
Primary adrenocortical failure Most cases due to autoimmune destruction Hyponatraemia Hyperkalaemia Hypoglycaemia
Treatment
- Hydrocortisone 20-30mg po in divided doses
- Fludrocortisone 50-200mcg po
If adequately treated, no associated maternal mortality
Fetal morbidity unlikely as the fetus produces and regulates its own adrenal steroids
CAH - pregnancy outcomes
Small increased risk of:
- Miscarriage
- PET
- GDM
- FGR
- CS due to cephalopelvic disproportion
Risk of fetal CAH depends on paternal carrier state
Genetics of CAH
Autosomal recessive
Carrier frequnecy 1 in 60 (white European population)
>90% 21-hydroxylase deficiency
Management of pregnancy with mother having CAH
Maintain adequate replacement of glucocorticoids and mineralocorticoids
- Prednisolone preferred over dexamethasone (latter crosses the placenta)
Serum testosterone and electrolytes - every 6-8 weeks
- To confirm compliance and adrenal suppression
If fetus at risk of CAH, treat with dexamethasone 20mcg/kg daily to avoid virilisation of an affected female ideally <5/40
- Suppresses fetal ACTH and reduce fetal adrenal hyperandrogenism
- Continue until sex determined and paternal status is known
- If female and partner carrier –> CVS
- If fetus affected, continue dexamethasone or offer TOP