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Home , Human placental lactogen, Insulin (medication)

Health in

Peter Ward Pathology North-Sydney Chemical Pathology, Royal North Shore Hospital Health in Pregnancy • Normal pregnancy is characterized by profound changes in almost every system in order to accommodate the demands of the fetoplacental unit. • Large amounts of oestrogens, and corticosteroids produced affect various metabolic, physiological and endocrine systems. • Many normal Reference Intervals are not appropriate for pregnancy.

Health in Pregnancy • Normal pregnancy lasts ~ 40 weeks • Divided into three trimesters each of ~ 13 weeks • By 10 weeks embryo has developed most major structures – now referred to as a • At end of first trimester fetus weight 13g • Rapid foetal growth in T2 (13-26w) – 700g by end of T2 • T3 (26-40w). Organ maturation; growth rate decelerates. Weight ~ 3200g at term

Health in Pregnancy • is the primary link between the mother and fetus. • Placenta keeps the maternal and fetal circulation separate, nourishes the fetus, eliminates fetal waste and produces vital to the pregnancy • Placental production generally increases in proportion to the increase in placental mass. • Exception is hCG (human chorionic ) hCG • hCG is produced by the trophoblast which later develops into the placenta • hCG maintains the corpus luteum, enabling it to produce progesterone until placental progesterone production becomes established (six weeks of gestation). Actions of progesterone prevents menses thus allowing pregnancy to continue. • Serum or urine hCG often used in the diagnosis of pregnancy

hCG • Glycoprotein; dimer • α subunit – common to hCG, LH, FSH & TSH • β subunit –specific, receptor binding • Detectable 6 - 8 days after conception • Concentration doubles every two days • Concentration peaks at 10 weeks and then declines • Levels are very highly variable, and not useful for estimating gestational age

Maternal adaption in pregnancy • Numerous physiological changes occur during pregnancy to accommodate the maternal and foetal needs • Most begin soon after conception and continue until late gestation • These physiologic adaptations result in many significant changes in laboratory test values. Pregnancy related Ref Int !!! • Most proceed normally so little need for laboratory testing Respiratory changes

• Increased ventilation allows maintenance of high-normal pO2 – O2 consumption increases by 20% due to metabolic demands of the placenta, foetus, and maternal organs.

• Mild respiratory alkalosis; fall in pCO2 from 40 mmHg to 27–32 mmHg

– Thought to assist the foetus to eliminate CO2 across the placenta

• Altered set point of central respiratory centres – progesterone effect- increasing the sensitivity of the medulla to CO2

• Arterial pH normal to slightly alkalotic (7.40 – 7.45) after renal compensation

Haemodynamic changes • Increased cardiac output • Decreased systemic vascular resistance and blood pressure • Expansion of plasma volume ( 30-50% ↑ over non - pregnant) • ↑ red blood cell mass (< than plasma volume expansion so mild ↓ in Haematocrit). • P.R.A. ↑, Atrial Natriuretic ↓ - suggests plasma volume underfilling as true volume expansion would result in the opposite (ie ↓ P.R.A. and ↑ANP) Effects of Haemodilution and Changes in Renal function • Many of the biochemical changes in pregnancy are due either to ↑ in blood volume or ↑ Renal Function due to ↑ renal perfusion →↑GFR . – ↑ in volume → dilution of some analytes ie Albumin (34g/L in late pregnancy), Ferritin – ↑Renal Clearance → ↓ serum [Creatinine, Urea] over much of the pregnancy & ↓ [Uric Acid] (Trimester 1,2) – Creatinine decreases by 35 umol/L to 35 – 70 umol/L – eGFR equations are inaccurate during pregnancy; • MDRD underestimates GFR during pregnancy – Urinary excretion increases from 100 mg/day to 180–200 mg/day in the third trimester

Sodium and Water • Water retention: average increase at term of 3 L total • Plasma osmolality falls to a new set point of ~270 mOsm/kg with a proportional decrease in Sodium by 4 – 5 mmol/L – Hyponatremia of pregnancy mediated by hormonal factors and correlates closely with increased hCG production – Physiological responses to changes in osmolality above or below the new set point (ie, thirst and ADH release) are intact. – Correction of the hyponatremia is both unnecessary and ineffective Function Tests • Albumin decreases during the first trimester, due to haemodilution • ALP 2 – 4× normal in third trimester, primarily due to placental synthesis • GGT reduced two fold • ALT and AST minor decreases • Bilirubin is slightly decreased • Total bile acids are increased in second and third trimesters • PT unchanged; increases in late pregnancy.

Other changes • Lipase and LD double • Some transport (TBG, CBG and SHBG) increase markedly Iron, B12 and folate

• Foetal haematopoiesis requires supply of iron, vitamin B12 and folate • Average total maternal iron requirements are ~ 1000 mg – 300 mg for the foetus and placenta, 500 mg for maternal haemoglobin. – 200 mg is shed through the gut, urine, and skin. – Women taking iron supplements have 10 g/L higher Hb Hypothalamic hormones

Hypothalamic hormones may be produced by the placenta • GnRH increases, with unknown physiological significance – Mainly from placenta, possible role in placental growth and function

• CRH increases exponentially throughout pregnancy – Produced by placenta – In Placental HPA axis, CRH is stimulated by , ie, positive feedback loop – Rise in CRH may have possible role in initiation of labour

• GHRH unchanged, but GH is higher due to placental secretion

• decreases with advancing gestation – Inhibits human (hPL), a hormone that causes resistance. – Structure of hPL is 96% homologous with GH and 67% with – Potent growth and lactogenic properties

• TRH unchanged hormones • The anterior lobe enlarges up to 3× due to hyperplasia and hypertrophy of lactotrophs • Prolactin increases, peaking at delivery – Probably due to increasing during pregnancy – Preparation for – Variable magnitude of increase • At term: 4,000 IU/L (700 – 12,000)

Anterior Pituitary hormones

• LH and FSH suppression with decreased response to GnRH – Due to the high estradiol and progesterone – Also due to inhibin A and inhibin B produced by placenta

• GH increased – Pituitary GH production is replaced by placental-GH, which peaks at 35 weeks.

• ACTH increased – Probably due to placental CRH, stimulated by cortisol – Pregnancy is a state of relative hypercortisolism – Increases in serum, salivary, and urinary free cortisol

• TSH is reduced in the first trimester – Due to the thyrotropic effects of hCG – TSH retains its normal circadian rhythm (nocturnal surge), indicating an intact axis – May be elevated at term due to increased iodine clearance and placental degradation of hormone

Calcium metabolism

• Elevated 1,25-(OH)2Vit D • VitD metabolism is uncoupled from calcium

– By second trimester 1,25-di(OH)2Vit D levels increase >2x without change in calcium – May be due to placental 1α-hydroxylase, since increases in 1,25-(OH)2Vit D in pregnancy do not follow PTH

• PTH declines in the early half of pregnancy reaches a nadir and then rises – May be due to inhibition from 1,25- di(OH)2Vit D or increased intestinal calcium absorption Thyroid function • Normal pregnancy is a euthyroid state • Thyroxine binding globulin (TBG) increases 2× due to oestrogen – Total T4 and T3 concentrations rise during the first half of pregnancy, plateauing at approximately 20/40

• hCG has weak thyroid-stimulating activity – high levels of hCG in first trimester lead to suppression of TSH resulting in a corresponding slight increase in free T4 and Free T3. • As hCG declines, TSH rises slightly and free T4 and T3 decline • Need to have method specific Free Thyroid Hormone Ref Int Adrenal • Stimulation of the -angiotensin- system – Due to reductions in vascular resistance and blood pressure

• Aldosterone increases markedly during first trimester and continues to increase to 4 – 6× URL – Progesterone competes with aldosterone for binding to the mineralocorticoid receptor – Subsequent natriuretic effect

• Atrial decreases as renin and aldosterone increase – Consistent with a state of effective hypovolemia

• Cortisol increases due to placental CRH – CBG also increases 2–3×, so that total cortisol is increased to a greater degree than free cortisol

• SHBG increases 6× – Total increases – Free testosterone is unchanged, but increases in third trimester – also increases in the third trimester – DHEAS decreases due to increased metabolic clearance

aldosterone progesterone Metabolic Adaption

• Late in gestation, maternal physiology is primarily influenced by placental hormones • Effect on both and lipid metabolism to ensure that the fetus has an adequate supply of fuel and nutrients at all times. • Late pregnancy →↑fetal growth and demand for nutrients. • Maternal response is to switch from CHO to fat utilization – Facilitated by both and ↑ lipolytic hormones – Glucose is reserved for the fetus – Alternative fuels made available for the mother Glucose metabolism • Changes in maternal carbohydrate and fat metabolism ensure a supply of fuel for the fetus • Hyperplasia of pancreatic β cells with increased insulin secretion – Due to – Insulin levels are higher both in the fasting and postprandial states – Progressive insulin resistance (begins 2nd trimester, peaks 3rd ) – Due to↑placental secretion of diabetogenic hormones hPL, GH, Cortisol • Fasting glucose decreases by 10-20% – Increased glycogenesis, decreased – Also due to fetal consumption (especially in late pregnancy) • Insulin resistance and relative of pregnant women results in ↑ and allows mother to preferentially use fat. • Placenta readily transfers glucose, amino acids and bodies to the fetus but is impermeable to large lipids –control of passage • GDM occurs when pancreatic function is insufficient to overcome insulin resistance

Lipid Metabolism • Total cholesterol increases – Thought to assist placental steroidogenesis

• Triglycerides increase markedly (x3) – Due to: • increased hepatic lipase activity, ie, increased hepatic triglyceride synthesis • reduced lipoprotein lipase activity, ie, decreased catabolism of – Provide maternal fuel while sparing glucose for the fetus

• HDL-C initially increases and then fall in the third trimester

• Apolipoproteins A-I, A-II, and B increase

• Changes in Lipid metabolism are adaptive to fetal-maternal needs – Fat accumulation characterises the 2nd trimester – Maternal consumption of the stored fat characterises the 3rd trimester