MATERNAL RESPONSE TO PREGNANCY, PARTURITION AND NEONTATAL TRANSITION TO EXTRA-UTERINE LIFE

1. MATERNAL RESPONSE TO PREGNANCY, PARTURITION AND NEONTATAL TRANSITION TO EXTRA-UTERINE LIFE ANSC 631 BAZER

2. MATERNAL RESPONSE TO PREGNANCY: GENERAL TIRED SLEEPY CARDIOVASCULAR ISSUES APPETITE MAMMARY DEVELOPMENT CHANGE IN LIBIDO

3. NAUSEAU AND VOMITING • 4 to 6 weeks to 14-16 weeks of pregnancy • Hyperemesis gravidarum severe nausea, vomiting, weight loss, and sometimes electrolyte disturbance, may require hospitalization for intravenous fluid and nutrition. • Why • Ho: adding spices to food inhibits growth of microorganisms and protects from diseases • expelling or avoiding foods during early months of pregnancy protects mother and embryo from foodborne illnesses and toxins, especially when the fetal development is most sensitive to disruption.

5. REVIEW OF DIGESTION • STOMACH – HCl, PEPSIN, RENIN AND GASTRIC LIPASE START PROCESS • SMALL INTESTINE • ENZYMES TRYPSIN, CHYMOTRIPSIN, ETC DIGEST PROTEINS • PROTEIN SOLUBILITY AND DIGESTIBILITY • AMINO ACIDS ABSORBED • CHYLE TO LACTEALS (LYMPH VESSELS) FOR SURVEILLANCE • LARGE INTESTINE • ABSORPS WATER AND SALTS

6. Maternal nutrition and fetal development. J Nutr. 2004 134:2169-2172 Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. Nutrition: intrauterine environmental factor altering expression of fetal genome with lifelong consequences ("fetal programming”) and "fetal origins of adult disease." 1) change structure, physiology, and metabolism of offspring predisposing individuals to metabolic, endocrine, and cardiovascular diseases as adults; 2) maternal undernutrition and overnutrition reduce placental-fetal blood flows and stunt fetal growth. 3) impaired placental NO (vasodilator/angiogenesis) and polyamines (DNA and protein synthesis) result in intrauterine growth retardation; 4) nutritional status alters epigenetic state through DNA methylation and histone modifications of fetal genome thereby impacting fetal programming and genomic imprinting.

8. MATERNAL CARDIOVASCULAR SYSTEM • 10-15% decrease in systemic arterial blood pressure • Decreased vascular tone: systemic vascular resistance = mean arterial pressure cardiac output PGE2, NO, PGI2 and decrease in alpha adrenergic receptor leads to vasodilation and decrease in mean arterial pressure

9. MATERNAL CARDIOVASCULAR SYSTEM • 25 to 60% increase in cardiac output • Increase mostly after mid-gestation • Cardiac output = heart rate X stroke volume • Heart rate increase by 20 to 30% • Stroke volume increase by 30-35% • Increases in: • Left Ventricle Mass • Left Atrial Size • End-Diastolic Dimensions • Blood Volume Increase by 10 to 50% • Highest percentages with multiple fetal-placental units

10. MATERNAL CARDIOVASCULAR SYSTEM • Red Blood Cell Mass (Hematocrit) • Increases less than blood volume • Increase in erythropoietin and erythropoiesis • Physiologic Anemia of Pregnancy • Blood Volume – Plasma Volume = Red Blood Cell Mass • Vascular Reactivity Decreases • Increased metabolic clearance of vasoactive agents such as norepinephrine and angiotensin II • Decrease in alpha adrenergic receptors • Increase in vasodilators – PGE2, PGI2, NO

11. MATERNAL CARDIOVASCULAR SYSTEM • Distribution of Cardiac Output • Sheep – 3 to 4 Liters/min • Uterus – 0.8 to 1.2 L/min • Uteroplacental Blood Flow (Percent of Cardiac Output • Ewe: 8% at mid-gestation; 16% in late gestation; and 0.06% for nonpregnant uterus. • Women: 17% at term • Mammary Blood Flow: Increases from 0.2% in first trimester to 2% at term • Skin Blood Flow – 100% increase over course of gestation

12. MATERNAL PULMONARY SYSTEM • Increased respiratory rate • Increase in tidal volume • Decrease in arterial pCO2 • Increase in chest circumferance – 5-7 cm in women • Decrease in bronchial/alveolar resistance

13. MATERNAL BLOOD COAGULATION INCREASES FROM 3 MONTHS TO TERM • Increased fibrinolytic cascade • Venous stasis – thromboemolic events • Increase in platelet aggregation and formation of stable fibrin clots • Intrinsic from Cell Injury and Collagen damage– increase in events beginning with Clotting Factor XII to platelet phospholipids and Ca++ to Fibrinogen and Clotting • Extrinsic (Rapid from Tissue [placenta] thromboplastin to go from Clotting Factor VII to Fibrinogen • Clotting mechanism increase rapidly at term

14. MATERNAL METABOLISM • Cost = 77,000 to 81,000 kilocalories • 24 year old woman – 56 kg • Gain 12.5 kg in pregnancy • 925 g protein • 3.83 kg fat • Fetus at term • 3.44 kg • 444 g fat • 543 g protein

15. MATERNAL METABOLISM • Pulmonary Ventilation – increases 3 L/min • 20% increase in maternal O2 absorption into blood • Pregnant Uterus – 25 ml O2/min • Pulmonary Muscles – 10 ml O2/min • Heart – 9 ml O2/min • Kidneys – 5 ml O2/min • Mammary Glands – 2 ml O2/min • Increasing Energy Intake Increases Appetite • Increase of 50 kcal/day first 34 weeks to 300 kcal/day during last 30 days [basal diet is 2,100 kcal/day] • Progesterone increases appetite • Increase in fat increases leptin

16. MATERNAL METABOLISM • Poor Nutrition • Smaller placentae by 20 to 30% and smaller babies by 200 to 300 g in first trimester • Increase in Nutrient Absorption by 0 to 3% • Increased pancreatic/biliary secretions • Increased intestinal blood flow • Decrease in gut motility • Hypertrophy of gut epithelial lining • Increase in villous height • Increase in intestinal dilation • Increase in epthelial hyperplasia • Increase in Vitamin D and Ca++ aborption • Increase in iron aborption • Lactogenic hormones increase absorption of Vitamin D, Ca++ and H2O.

17. MATERNAL METABOLISM • Nutritional Priorities of Fetus and Mother • Maternal • Nervous System • Bone • Muscle • Fat Fetal Demands Nervous System Bone Muscle Fat

18. MATERNAL METABOLISM • Poor Nutrition • Smaller placentae by 20 to 30% and smaller babies by 200 to 300 g in first trimester • Increase in Nutrient Absorption by 0 to 3% • Increased pancreatic/biliary secretions • Increased intestinal blood flow • Decrease in gut motility • Hypertrophy of gut epithelial lining • Increase in villous height • Increase in intestinal dilation • Increase in epthelial hyperplasia • Increase in Vitamin D and Ca++ aborption • Increase in iron aborption • Lactogenic hormones increase absorption of Vitamin D, Ca++ and H2O.

19. MATERNAL METABOLISM • Physical Activity Decreases • Progesterone • Increase in sleep • Decrease in Anxiety

23. Mammogenesis and Lactogenesis • Mammogenesis – Growth of Mammary Gland • Lactogenesis • Stage I – Milk Protein Synthesis • Stage II – Milk Protein Synthesis and Secretion • Galactopoiesis – sustained milk production

24. MAMMOGENESIS AND LACTOGENESIS Mammogenesis: Sex Steroid Hormones Estrogen --Involved in lengthening and branching of ducts Progesterone --Duct and ductule cell multiplication --Enlargement and/or widening -- Actually inhibits mammary growth at high levels Progesterone + Estrogen -- Causes lobuloalveolar development Initiation of Lactation (Lactogenesis) Ovarian and/or placental steroids decrease (Progesterone inhibits) Placental Lactogen disappears Lactogenic Complex Prolactin, Glucocorticoids. Insulin or IGF-I Milk-Ejection Reflex Oxytocin/Neuroendocrine Reflex Suckling or other teat/udder stimulation causes release of oxytocin from neurohypophysis Maintenance of Lactation (Galactopoesis) Galactopoetic Complex Prolactin (Not Cattle), GH, Insulin, Thyroid Hormone, Glucocorticoids

25. EVENTS PRECEDING PARTURITION • Final Maturation of Fetus and its Hypothalamic-Pituitary-Adrenal Axis • Initiation of Milk (Colostrum) Secretion • Expansion of Birth Canal • Nest Building (Prolactin) • Aggression (Prolactin) • Restlessness (Prolactin and Estrogen) • Initiation of Uterine Contractions • Parturition and Termination of Pregnancy • Bonding Between Dam and Offspring (Prolactin and Oxytocin)

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31. Parturition in Mammals • Controlled by fetus • Congenital absence of Hypothalamic-Pituitary-Adrenal Axis • Ewe consumption of Veratrum californicum on Days 14-15 • Delayed Parturition • Lambs up to Day 175 and 20 pounds or more; some cases ewes died • Piglets taken at Day 125 • Similar reports for calves taken by C-Section at very heavy weights, e.g., 200 lb

32. Parturition – Sheep Model • Fetus • Hypothalamus • CRH • Anterior Pituitary • ACTH • Prolactin • Adrenal Gland • Cortisol and Corticosterone • Placenta • Progesterone decreasing, estrogen increasing due to C-21 Steroid 17 alpha hydroxylase enzyme • Maternal • Corpus Luteum • Progesterone and Relaxin (some species) • Anterior Pituitary • Prolactin and Growth Hormone • Posterior Pituitary • Oxytocin • Uterus • PGF2-alpha increasing

33. Hormonal Factors Associate with Parturition • Fetal Hypothalamic-Pituitary-Adrenal Axis • A. CRH – Day 100 Fetal Life • B. ACTH – Day 125 Fetal Life • C. Cortisol Production – Dependent on Critical Mass of Adrenal Tissue • D. Cortisol – Increases most rapidly 2 to 3 days before onset of labor and parturition • In pigs, adrenal weight increases along with circulating levels of cortisol most rapidly after Day 100 of the 114 day period of gestation

34. Hormonal Factors Associate with Parturition • Fetal Hypothalamic-Pituitary-Adrenal Axis • E. Cortisol • Stimulates rapid increase in C21 Steroid 17-alpha hydroylase enzyme for conversion of Progesterone to 17-alpha hydroxy Progesterone when then is metabolized to androgens and estrogens • P4 DECREASES RAPIDLY DUE TO CONVERSION OF PROGESTERONE TO ESTROGENS • Decrease sulfotransferase in endometrium so MORE UNCONJUGATED ESTROGENS • Stimulate PGF secretion

36. Hormonal Factors Associate with Parturition • Oxytocin • Released in response to PGF and due to Ferguson Reflex of fetal pressure on cervix • Stimulates uterine contractions • Stimulates bonding between mother and offspring

37. Hormonal Factors Associate with Parturition • Relaxin Molecular Weight – 6,300 (6,000 to 10,000) Pig – From CL Other species – cow (CL, placenta), sheep (?), mare (placenta) Cervical Relaxation Acts with other hormones: Estrogens PGF and PGE Oxytocin

38. Hormonal Factors Associate with Parturition • Relaxin (continued) • Increases Keratin SO4 in cervical collagen • Decreases Dermatin SO4 in cervical collagen • With loss of Dermatin SO4 there is a decrease in cross-linking among collagen fibers and greater elasticity of connective tissue of cervix and pelvic ligaments to increase distinsibility of pelvic canal for birth of fetus • Role in lactation by stimulating growth and development of teat and possibly lactation • Ovariectomized pigs give birth, but don’t lactate normally, so is relaxin critical to parturition?

40. Hormonal Factors Associated with Parturition • Uterine Myometrial Contractions • Coordinated and Rhythmic Contractions of Myometrium • Involuntary Contractions of Abdominal Muscles • Dilation and Softening/Distensibility of Cervix • Myometrial Contractions • Increased synthesis of gap junctions (e.g., Connexin 43) due to decreasing progesterone and increasing estradiol Essential for strong coordinated contractions • Increase in cAMP associated with increase numbers of gap junctions • Increase in free Ca++ and its binding to calmodulin which activates myosin kinase: • Myosin kinase → Myosin-PO4 • Myosin-PO4 + Actin = Contractions

41. Hormonal Factors Associate with Parturition • Uterine Myometrial Contractions (continued) • Increase in free Ca++ and its binding to calmodulin which activates myosin kinase: • Myosin kinase → Myosin-PO4 • Myosin-PO4 + Actin = Contractions • Oxytocin lowers threshhold potential for action potential of myometrium and increases rate of Ca++ influx to stimulate contractions • PGF increases intracellular free Ca++ and frequency of contractions

44. Inhibited at Parturition Inhibited at Parturition