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

MATERNAL RESPONSE TO PREGNANCY, PARTURITION

AND NEONTATAL TRANSITION TO EXTRA-UTERINE LIFE

ANSC 631

BAZER

MATERNAL RESPONSE TO PREGNANCY: GENERAL

TIRED

SLEEPY

CARDIOVASCULAR ISSUES

APPETITE

MAMMARY DEVELOPMENT

CHANGE IN LIBIDO

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.

http://www.americanpregnancy.org/pregnancycomplications/hyperemesisgravidarum.html

American Scientist89 (2):142

Protecting Ourselves from Food: Spices and morning sickness may shield us from toxins and microorganisms in the diet. Paul W. Sherman, Samuel M. Flaxman

SPECULATION

•Progesterone is analgesic with LD50 that may cause nausea by acting on nervous system like an anesthetic

•Changes in gut immune system response to food allergens, e.g., like some people respond to peanuts or shell fish

http://www.americanscientist.org/template/AuthorDetail/authorid/207

http://www.americanscientist.org/template/AuthorDetail/authorid/208

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

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.

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


• 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


• 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


• 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

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

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

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

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

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.

MATERNAL METABOLISM

– Nutritional Priorities of Fetus and Mother• Maternal

– Nervous System

– Bone– Muscle– Fat

Fetal DemandsNervous SystemBone

MuscleFat

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.

MATERNAL METABOLISM

– Physical Activity Decreases• Progesterone

– Increase in sleep– Decrease in Anxiety

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

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 ReflexSuckling 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

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)

Fig. 14-14

Fig. 14-13

Fig. 14-15

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

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

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


• 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


• 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


• RelaxinMolecular Weight – 6,300 (6,000 to 10,000)Pig – From CLOther species – cow (CL, placenta), sheep (?), mare (placenta)Cervical Relaxation

Acts with other hormones:EstrogensPGF and PGEOxytocin


• 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?

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


• 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

EP1

Ca2+/IP3

EP2

cAMP

EP3a

cAMP

EP3b

cAMP

EP3c

cAMP

EP3d

cAMP/

EP4

cAMP

DP receptor

cAMP

IP receptor

cAMP

FPA,B receptor

Ca2+ + IP3

TP receptor

Ca2+ + IP3

Relaxant Receptors Constrictor Receptors

Ca2+ / IP3 or cAMP

Nuclear receptor

PPARPPARPPAR

IP3

cAMP

COOH

COOH

COOH

OH

PGI2

PGD2 PGE2 PGF2

PGH2 TxA2

PGG2

PGI Synthase TX Synthase

PGD Synthase PGE Synthase PGF Synthase

COOH

Arachidonic Acid(5, 8, 11, 14-eicosatetraenoic acid)

COOHO

O

Cox-1 Cox-2

9-keto-PGEreductase

OH

O

OOH

OHOH

OH

COOH

OHOH

O

COOH

OHO

OH

O

O

COOHO

O

OH

20

1917131211

1415 16 1810

9 87 4 2

356

Cox-1 Cox-2

PhospholipidscPLA2

PGDHPGFMPGEM

PGDH

Inhibited at ParturitionInhibited at Parturition

11β hydroxylase for corticosterone and cortisol

11β hydroxylase

OvineHuman

Fetal Hypothalamic Pituitary Adrenal Axis

↓

Fetal Glucocorticoid ProductionCorticosterone and Cortisol

→ Placental CRH←Placental Estrogens

↓↓

↓

IntrauterineProduction of Prostaglandins

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal Signals and Parturition

CRH is Produced by Human Chorion in response to cortisol from fetal adrenal

CRH stimulates Dehydroepianrosterone Sulfate (DHAS) from fetal adrenal that is converted to estrogens by chorion

Glucocorticoids and estrogens stimulate increased expression of prostaglandins E and F and decreases PGDF-15 that OTHERWISE inactivates PGs


Central Characteristics of Human ParturitionIncrease in CRH and PGHS2 in chorionDecrease in PGDH15Increase in FP and EP prostaglandin

receptorsDecreased sensitivity of uterus to

progesteroneIncrease in production of estrogens from

DHAS by chorionIncrease in myometrial contractions


Conversion of Progesterone to Estradiol and Loss of Progesterone Influence

Increased Contraction Associated ProteinsOxytocin ReceptorPGF ReceptorConnexion-43 Gap Junction Protein

Recent Suggestion that Increase in Progesterone Receptor C Isoform Results in Loss of Progesterone Responsiveness via PR Isoforms A and B in Human Myometrium (Condon et al. 2006 Mol Endocrinol 20:764-775

Controlling Time of Parturition

• Efficient use of labor and facilities to reduce neonatal death losses

• Reduce length of gestation • Increase opportunities for cross-fostering

neonates in event of failure of dam to accept offspring, cannabilism or failure to lactate

• Convenience of producer• In swine, uniformity of post-weaning estrus

Controlling Time of Parturition (continued)

• Swine: Corticoids Ineffective– PGF-2 alpha – 200 ug cloprostenol or 10 mg Lutalyse at 7

AM and 7 PM with farrowing 24-26 h later. – Should not be used prior to Day 112 of pregnancy due to

decreased survival of neonate

• Cows; Corticoids, Estradiol and PGF are effective– 20 mg dexamethasone to dam most commonly used. For

maximal survival of calf, cows should be within 1 week of term. Some countries with wet and dry season induce parturition to coincide with rainy season, high nutrient availability and focus on milk production with calves having little economic value

• Retained placentae major issue


• Mare: Corticoids, PGF and Oxytocin– 2.5 mg PGF (Lutalyse) every 12 hours causes

birth/abortion in late gestation.– 200 dexamethasone/day for 4 days with foals being

born 72 to 96 h after end of treatment– 20 IU to 200 IU Oxytocin administered with estradiol

will cause cervical dilation and birth in some cases.

Post-Partum Period

• Cow– Days 0-12 – Sloughing and Discharge of

endometrial tissue and placenta– Days 25-30 – Uterine Involution completed– Days 40-45 – Uterus considered ready for

next pregnancy– Dairy – First estrus around Day 15 to 20 and

breeding from Day 60– Beef – First estrus between 60 and 100 days

and breed during desired dates (spring or fall)

Post-Partum Period• Sheep

– Uterus involuted by Days 25 to 30• Breed in fall

• Pig– Uterine involution completed by Days 21 to 28– Breed at post-weaning estrus (3-7 days)

• Mare

Foal Heat – 5-15 days postpartum

Breed if no complications

Human

Highly variable and related to many factors

Suckling intensity, body condition, nutrition etc

Fetal to Neonatal Transition

Adjusting to Extra-Uterine Life

Fig. 14-14

Fig. 14-13

Fig. 14-15

Cardiovascular Function• Ductus Arteriosis – Duct between Pulmonary

Artery and Aorta that allows most blood to be shunted past the Pulmonary Artery and into Aorta. With increase in pO2 at birth, the Ductus Arteriosis closes and blood is forced to go to the lungs for oxygenation.

• Foramen Ovale – Valve (flap-type) that closes when pressure in left side of heart increases upon closure of the Ductus Arteriosis.

ADULTRIGHT HEART ► LUNGS ► LEFT HEART

↑ ↓ AORTA ↑LIVER ← ← ← BODY

FETUS

RIGHT HEART ► FORAMEN OVALE ► LEFT HEART↑↑ AORTA

DUCTUS ARTERIOSIS

PLACENTA BODY OF FETUS

Lung

LiverDuctus

Venosus

Gut• Filled with Amniotic Fluid drunk at 500 ml/day• Contains meconium – fecal material• Absorbs amino acids, sugars and electrolytes• Digestion of proteins, aborption of amino acids and

incorporation into fetal tissues• Colostrum – fluid phase pinocytosis and gut closure

regarding absorption of immunoglobulins– Passive Immunity – required for piglets and beneficial for

offspring of all species– Gut maturation

• IGF-I and EGF in colostrum stimulate gut maturation

Renal System

• Normal fetus – 450 ml urine/day into amniotic sac with turnover of 300 to 600 ml/h of amnionic fluid

• Proteinuria in fetal life to closure of kidney tubules in neonate

• Absence or malfunction of kidneys leads to death or retarded development

Respiratory System

• Fetal breathing occurs in utero

• Allows development of intercostal muscles of chest and diaphragm associated with breathing

Fetal Adrenal Glands• Norepinephrine

– Release of surfactant from epithelial cells of lung lobulo-alveolar structures

– Absorption of liquid from lungs

• Glucocorticoids (Cortisol and Corticosterone)– Lung maturation– Lactogenesis– Thyroxin to Triiodothyronine– Glucose storage as glycogen– Insulin secretion in response to glucose– Transition from fetal hemoglobin to adult hemoglobin– Closure of Ductus Arteriosis– Parturition

Lung Maturation• Synthesis and secretion of surfactant by lung

alveolar epithelium– Glucocorticoids – Synthesis (Transcription and

Translation) of surfactant and storage in cells– Norepinephrine – Secretion of surfactant

• Surfactant essential for lung alveoli to maintain integrity and not collapse by providing high surface tension when stretched.

• Fetuses deficient in surfactant develop Hyalin Membrane Disease and often die

• Now Pediatricians have artificial surfactant to decrease risk of Hyalin Membrane Disease

Respiration• Umbilical Circulation

– pO2• Artery – 15• Vein - 25

– pCO2• Artery – 55• Vein – 40

• Maternal Uterine Circulation– pO2

• Artery – 95• Vein – 35

– pCO2• Artery – 35• Vein - 45

ADULTRIGHT HEART ► LUNGS ► LEFT HEART

↑ ↓ AORTA ↑LIVER ← ← ← BODY

FETUS

RIGHT HEART ► FORAMEN OVALE ► LEFT HEART↑↑ AORTA

DUCTUS ARTERIOSIS

PLACENTA BODY OF FETUS

Lung

LiverDuctus

Venosus

Postpartum Uterus

Uterine Involution and Repair

).

11β hydroxylase for corticosterone and cortisol

11β hydroxylase

OvineHuman

Fetal Hypothalamic Pituitary Adrenal Axis

↓

Fetal Glucocorticoid ProductionCorticosterone and Cortisol

→ Placental CRH←Placental Estrogens

↓↓

↓

IntrauterineProduction of Prostaglandins


CRH is Produced by Human Chorion in response to cortisol from fetal adrenal

CRH stimulates Dehydroepianrosterone Sulfate (DHAS) from fetal adrenal that is converted to estrogens by chorion

Glucocorticoids and estrogens stimulate increased expression of prostaglandins E and F and decreases PGDF-15 that inactivates PGs


Central Characteristics of Human ParturitionIncrease in CRH and PGHS-2 in chorionDecrease in PGDH-15Increase in FP and EP prostaglandin

receptorsDecreased sensitivity of uterus to

progesteroneIncrease in production of estrogens from

DHAS by chorionIncrease in myometrial contractions


Conversion of Progesterone to Estradiol and Loss of Progesterone Influence

Increased Contraction Associated ProteinsOxytocin ReceptorPGF ReceptorConnexion-43 Gap Junction Protein

Recent Suggestion that Increase in Progesterone Receptor C Isoform Results in Loss of Progesterone Responsiveness via PR Isoforms A and B in Human Myometrium (Condon et al. 2006 Mol Endocrinol 20:764-775

Controlling Time of Parturition

• Efficient use of labor and facilities to reduce neonatal death losses

• Reduce length of gestation • Increase opportunities for cross-fostering

neonates in event of failure of dam to accept offspring, cannabilism or failure to lactate

• Convenience of producer• In swine, uniformity of post-weaning estrus


• Swine: Corticoids Ineffective– PGF-2 alpha – 200 ug cloprostenol or 10 mg Lutalyse at 7

AM and 7 PM with farrowing 24-26 h later. – Should not be used prior to Day 112 of pregnancy due to

decreased survival of neonate

• Cows; Corticoids, Estradiol and PGF are effective– 20 mg dexamethasone to dam most commonly used. For

maximal survival of calf, cows should be within 1 week of term. Some countries with wet and dry season induce parturition to coincide with rainy season, high nutrient availability and focus on milk production with calves having little economic value

• Retained placentae major issue


• Mare: Corticoids, PGF and Oxytocin– 2.5 mg PGF (Lutalyse) every 12 hours causes

birth/abortion in late gestation.– 200 dexamethasone/day for 4 days with foals being

born 72 to 96 h after end of treatment– 20 IU to 200 IU Oxytocin administered with estradiol

will cause cervical dilation and birth in some cases.

Post-Partum Period

• Cow– Days 0-12 – Sloughing and Discharge of

endometrial tissue and placenta– Days 25-30 – Uterine Involution completed– Days 40-45 – Uterus considered ready for

next pregnancy– Dairy – First estrus around Day 15 to 20 and

breeding from Day 60– Beef – First estrus between 60 and 100 days

and breed during desired dates (spring or fall)

Post-Partum Period• Sheep

– Uterus involuted by Days 25 to 30• Breed in fall

• Pig– Uterine involution completed by Days 21 to 28– Breed at post-weaning estrus (3-7 days)

• Mare

Foal Heat – 5-15 days postpartum

Breed if no complications

Human

Highly variable and related to many factors

Suckling intensity, body condition, nutrition etc

Documents

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