The Biochemistry of Pregnancy

Dr. Gill Burrows Consultant Chemical Pathologist Stepping Hill Hospital

Normal pregnancy
• • • • • Fluid and electrolyte homeostasis Acid base changes Carbohydrate metabolism Calcium homeostasis Lipoprotein metabolism

• Endocrine changes

Disorders of pregnancy
• Hypertensive disorders
– Pre-eclampsia – HELLP

• • • •

Diabetes mellitus Hyperlipidaemia Jaundice Acute endocrinopathies

Fluid and electrolyte homeostasis
• Markers of physiologic changes
– weight gain – haemodilution – reduced plasma osmolality – reduced sodium concentration

• Causes
– increased fluid volume – redistribution of fluid between ICF and ECF – sodium retention by kidney (~900 mmol)
– increased TBW by 8.5 L – increased plasma vol by 1.2 L

Fluid and electrolyte homeostasis
• Activated renin-angiotensin system (despite increased plasma volume)
– ? Due to fall in vascular resistance – ? New set point of fluid volume homeostasis

• Known resistance to pressor and renal effects of angiotensin - with increased adrenal response

Fluid and electrolyte homeostasis
• Osmoregulation
– resetting of osmotic control at a lower osmolality – osmotic threshold for
• thirst decreased by 9 mmosmol/kg • AVP secretion by 6 mosmol/kg

– decreased osmolality seen by 5/40, maximal at 10/40 – ? mechanisms

Disorders associated with fluid and electrolyte homeostasis
• Hyperemesis gravidarum • Pre-eclampsia

Acid-base changes
• Hyperventilation results in reduced PaCO2 (from ~39 mm Hg to 31 mm Hg) • pH increases slightly to 7.42-7.44 • HCO3- decreases by ~ 4 mmol/L • Respiratory alkalosis with metabolic compensation

Disorders of acid-base metabolism
• As for non-pregnant patients • Metabolic acidosis
– DKA – lactic acidosis

• Metabolic alkalosis
– hyperemesis gravidarum

Carbohydrate metabolism
• Important for:
– increasing adipose tissue in mother in early pregnancy - to be used for energy in late pregnancy and lactation – foetoplacental unit - foetus requires maternal glucose

Carbohydrate metabolism - early pregnancy
• Basal hepatic glucose metabolism • No change • Postprandial hepatic glucose metabolism • increased glucose • increased insulin • ? Degree of insulin insensitivity

Carbohydrate metabolism - late pregnancy
• Basal hepatic glucose metabolism • increased hepatic glucose production (despite increased insulin) • decreased serum glucose • Postprandial hepatic glucose metabolism • increased insulin response to glucose load • insulin insensitivity

Gestational diabetes
• 3-5 % of pregnant women • defined as ‘ abnormal GTT which is diagnosed or first recognised during gestation’ • confers an increased risk of developing diabetes in later life

Gestational diabetes
• Reduced suppression of hepatic glucose production - decreased hepatic insulin sensitivity • insulin insensitivity at conception

Gestational diabetes
• Diagnosis - European Diabetes Policy Group 1999
– Venous plasma glucose > 6.0 mmol/L
• perform 75 g oral GTT • manage as diabetes if
– fasting plasma glucose >= 7.0 mmol/L OR – 2 hr plasma glucose >= 7.8 mmol/L

Calcium metabolism
• Maintenance of ionised calcium within narrow limits is important for maternal and foetal health • State of “physiologic absorptive hypercalciuria” • Requirement increased by 30%

Lipoprotein metabolism
• Increased triglycerides (~1.7 mmol/L) • Increased LDL cholesterol (~ 1 mmol/L) • HDL - increased 1st trimester, peak at mid-gestation, fall in 3rd trimester • Maternal fuel • placental steroidogenesis • ? Apo A-1 important in foetal development

Disorders of lipoprotein metabolism
• Hyperchylomicronaemia
– Type I
• lipoprotein lipase deficiency • apo CII deficiency

– Type V – May cause
• eruptive xanthomas • pancreatitis

Endocrinology of foeto-placental unit
• Placental peptide hormones • hCG • hPL • others
– trophic hormones – releasing hormones – pregnancy specific hormones

• Steroid hormones • Oestrogens • Progesterone

Human chorionic gonadotrophin
• Produced by blastocyst, then syncitiotrophoblast • 2 chain glycoprotein • detectable by day 9 • x2 every 2 days to a peak 8-10/40 after LMP • Plateaus at 18-20/40 • Functions
– prevents regression of corpus luteum – stimulates secretion of oestrogen and progesterone – stimulates foetal adrenal – stimulates Leydig cells of foetal testes

Human placental lactogen
• Produced by syncitiotrophoblast • detectable by 4 weeks after ovulation • plasma concentration proportional to functional placental mass • Functions:
– affects fat and CHO metabolism – mobilises FFA – inhibits gluconeogenesis – inhibits peripheral uptake of glucose – increases uptake of amino acids and ketones by placenta

Weeks gestation hCG hPL 5 22 120 10 105 15 30 20 18 25 19 100 30 20 35 19 40 18 80 hCG (IU/mL)

hCG and hPL in pregnancy
0.5 2 3 4 5 6.8 7 8 7 6 5 4 3 2

hPL (ug/mL)

60

hCG hPL

40

20 1 0 1 2 3 4 5 6 7 8 Weeks gestation (/5) 0

Steroid hormones - oestrogen
• In early pregnancy
– FSH stimulates testosterone and androstenedione secretion from theca cells – testosterone and androstenedione aromatised by granulosa cells of corpus luteum – oestrogen induces FSHand LH receptors of granulosa cells

Steroid hormones - oestrogen
• In later pregnancy
– androgens produced by foetal adrenal cortex are converted into oestriol by the placenta – production of steroids by foetal adrenal cortex at term is 5-6 x that of an adult – increase in maternal serum oestradiol throughout pregnancy

Steroid hormones - oestrogen
• Functions
– myometrial and endometrial growth – growth of alveoli and breast ducts – angiogenesis – protein synthesis and cholesterol metabolism – sodium and water retention

Steroid hormones progesterone
• Produced by corpus luteum for first 10 weeks, then syncitiotrophoblast • Increases throughout pregnancy • functions include – decidualisation of endometrium – relaxation of smooth muscle – vasodilatation – hyperventilation – increased thirst, appetite, fat deposition

Thyroid function
• Increase in TBG - 2-3x – increased hepatic synthesis – increased sialylation • raised total T4 and T3 – increased TBG • decreased FT4 • thyroid stimulation by hCG • increased iodide loss in urine

Thyroid dysfunction in pregnancy
• Hyperthyroidism • 0.2 % • Graves disease • Pregnancy specific
– hyperemesis gravidarum – trophoblastic disease

• Hypothyroidism • 0.3-0.7 % • Autoimmmune thyroiditis • Iodine deficient goitre

Hypertensive disorders of pregnancy
• Pre-existing hypertension • Pre-eclampsia • HELLP • commonest severe complication of pregnancy • 5-15 % associated with proteinuria

Pre-eclampsia
• Increased incidence
– increased age – primigravida – genetic predisposition – obesity – twins

• Reduced incidence in smokers

Pre-eclampsia
• Loss of the insensitivity of the arterial system to angiotensin II
– endothelial damage – placental ischaemia – impaired vasodilatation – reduced GFR – reduced renal blood flow – reduced plasma volume

HELLP
• • • • Haemolysis Elevated Liver enzymes Low Platelets Incidence - ? 20% of severe preeclampsia • Presentation
– nausea, vomiting, flu-like illness – RUQ pain – hypertension or proteinuria may be slight

HELLP
• Haemolysis • Blood film • LDH > 600 IU/L • AST > 70 IU/L • Platelets < 100 000/uL

• Raised liver enzymes • Low platelets

Jaundice in pregnancy
• 1 in 2000 pregnancies
– viral hepatitis – intrahepatic cholestasis of pregnancy – drug treatment – HELLP – acute hepatic failure

Reference ranges