Health in Pregnancy Peter Ward Pathology North-Sydney Chemical Pathology, Royal North Shore Hospital Health in Pregnancy • Normal pregnancy is characterized by profound changes in almost every organ system in order to accommodate the demands of the fetoplacental unit. • Large amounts of oestrogens, progesterone 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 fetus • 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 • Placenta 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 hormones vital to the pregnancy • Placental hormone production generally increases in proportion to the increase in placental mass. • Exception is hCG (human chorionic gonadotropin) 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 pregnancies 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 peptide ↓ - 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 protein 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 Liver 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; fibrinogen increases in late pregnancy. Other changes • Lipase and LD double • Some transport proteins (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 cortisol, 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 • Somatostatin decreases with advancing gestation – Inhibits human placental lactogen (hPL), a hormone that causes insulin resistance. – Structure of hPL is 96% homologous with GH and 67% with prolactin – Potent growth and lactogenic properties • TRH unchanged Anterior Pituitary hormones • The anterior lobe enlarges up to 3× due to hyperplasia and hypertrophy of lactotrophs • Prolactin increases, peaking at delivery – Probably due to increasing estradiol during pregnancy – Preparation for lactation – 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 thyroid 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 renin-angiotensin-aldosterone 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 natriuretic peptide 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 testosterone increases – Free testosterone is unchanged, but increases in third trimester – Androstenedione 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 glucose 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 insulin resistance 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 human placental lactogen – Insulin levels are higher both in