Fetal to Neonatal Transition

Adjusting to Extra-Uterine Life

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

Endocrine System• Decapitated fetal pigs and lambs grow

normally in utero due to fetal (IGF-I and IGF-II from all tissues) and placental hormones and growth factors

• Maternal hormones not transported across the placenta except for some steroids

• Fetal-Placental Hormones Do Affect Maternal System

Endocrine System• Fetal-Placental Hormones Do Affect Maternal

System– Quieting effect on nervous system

• Progesterone• Opiods – endorphins, enkephalins, dynorphins

– Increase in cardiac output– Peripheral vasodilation– Increase renal clearance– Altered glucose, fat, protein and mineral

metabolism to accommodate needs of fetal-placental tissue growth

MATERNAL METABOLISM

– Nutritional Priorities of Fetus and Mother• Maternal

– Nervous System

– Bone– Muscle– Fat

Fetal DemandsNervous SystemBone

MuscleFat

Complete Inanition in Sows

• Water only: Days 0-40, 30 to 70 or 70 to 110– No effect on fetal weight at birth– Rapid realimentation of sows caused abortion– Model for nutrient partitioning– Animal welfare concerns– Study done by Lloyd Anderson, Iowa State University 9 Am J

Physiol. 1979 Sep;237(3):E273-8. – PMID: 474753 [PubMed - indexed for MEDLINE] – 4: Anderson LL, Hard DL, Kertiles LP. Related Articles,

Links – Progesterone secretion and fetal development during

prolonged starvation in the pig. Am J Physiol. 1979 237(3):E273-8; Am J Physiol. 1979 236(4):E335-41; Am J Physiol. 1978 234(2):E190-6.

Thyroid Function

• Thyroxin (T4) and triiodothyronine (T3) required for normal development of brain, bones, hair/wool

Pancrease

• Insulin regulates glucose metabolism by fetus

• Diabetic mother – leads to more glucose transport to fetal-placental tissue and increased (insulin dependent) storage of energy as glycogen and/or fat

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

Factors Affecting Reproductive Efficiency

OVULATION RATE

FERTILIZATION RATE

EMBRYONIC SURVIVAL

UTERINE CAPACITY

OVULATION RATE

FERTILIZATION RATE

EMBRYONIC DEATHS

UTERINE CAPACITY

FACTORS AFFECTING REPRODUCTIVE PERFORMANCE

OVULATION RATE• HORMONAL REGULATION

– eCG– FSH

• NUTRITION– Ad Libitum Feeding

• Swine – 14 days prior to estrus increases ovulation rate about 30%

• Sheep – Improved pasture or feed prior to onset of breeding season

OVULATION RATE (continued)• GENETIC SELECTION

– Boorola Merino• Single gene mutation to decrease inhibin• Ovulation rates – 3 to 5 or more• Finish Landrace and Romanov – 4 or more ovulations• Assaf ewes by introgression the FecB (Booroola) gene

(Gootwine et al., 2001).

• NUTRITION– Ad Libitum Feeding

• Swine – 14 days prior to estrus increases ovulation rate about 30%

• Sheep – Improved pasture or feed prior to onset of breeding season

OVULATION RATE (continued)• GENETIC SELECTION

– Nebraska Swine Herd• Ovulation rates increased by 5 in eight generations and 7

ovulations in 10 generations

– France – Hyperprolific Large White – 23 ovulations vs 17 for control line

• NUTRITION– Ad Libitum Feeding

• Swine – 14 days prior to estrus increases ovulation rate about 30%

• Sheep – Improved pasture or feed prior to onset of breeding season

Fertilization Rate• Swine – 95% - Breed at 12 and 24 h after onset

of estrus

• Sheep – 85-95% - Breed at 12 and 24 h after onset of estrus

• Cattle – 80-90% - Breed 12 h after onset of estrus

• Mare – 70 to 95% - Breed every other day with expectation of ovulation 48h before end of estrus or palpate to predict time of ovulation and breed accordingly

Breeding Soundness for Males• Quality of Semen

– Color – White to Cream colored – no blood etc– Sperm Motility – Greater than 50% minimum

• Circular Movement• Forward Motility Desirable

– Abnormal sperm• Broken Tails• Cytoplasmic Droplets• Crooked Tails• Abnormal Acrosome

– Sperm concentration– Total sperm

• Summer Sterility

Minimum Age for Males for Breeding

• Bulls – 9 months

• Stallion – 18 months

• Rams – 8 months

• Boars – 8 months

Breeding Soundness Evaluation Very Important

Embryonic Death Losses• Uterine Environment – Why don’t all embryos

die?

• Early Embryonic Deaths Predominate– Oocyte

• Meiotic Maturity• chromosome Abnormalities

– Nutrition – Overnutrition increases embryo deaths– Environment

• Heat Stress• Toxicant

– Endocrine Deficiencies

Embryonic Death Losses• Oocyte Quality (Nebraska Study, Koenig)

• Meiotic Maturity• Chromosomal Abnormalities• Higher Ovulation Rates and greater frequencies of

abnormal oocytes• Pubertal vs Mature Females

• Embryonic Lethals– Women (Boue 1975) – 10,000 women in France

• 90% of women abort before 14 days of pregnancy• 1500 spontaneous abortions• 62% abnormal karyotype

– 15% monosomy– 72% triploidy– 6% tetraploidy– 7% - Other?

Nebraska Study - SwineHigh Ovulation Rate

Control Superovulated

18.4 CL 15.0 CL 20.2 CL

68 % Ova Recovered

81% Ova Recovered

68% Ova Recovered

14% Meiotically Immature (MI)

9% MI 16% MI

27% Chromosomally Abnormal (CA)(41.5% total abnormal)

24% CA (32.5% total abnormal)

27% CA (43% total abnormal

Western U.S. A. Ewes

• USDA Idaho1CL – 90 lambs / 100 ewes

2 CL – 175 lambs / 100 ewes

3 CL – 190 lambs / 100 ewes

High Environmental Temperature

• Increase Ovarian and Uterine Temperature

• Decrease Uterine Blood Flow

• Increase in Heat Shock Proteins

• Direct vs Indirect Effects– Effect from onset of estrus to ovulation– Oocyte maturation?– Transriptional or translational events?

Abnormal Uterine Environment

• Environmental Estrogens– Aflotoxins from moldy corn – swine become

pseudopregnant due to loss of embryonic deaths around Day 15 of pregnancy – loss of extracellular matrix of uterus

• Postpartum Period – Inadequate uterine involution

French Large White, French Hyperprolific Large White and Chinese Meishan Reproductive Performance

Breed Ovulation Rate

Litter Size Embryo Mortality

French,LW Control

18 12 26 + 7

FLW Hyper-prolific

23 13 41 + 7

Meishan 17 16 16 + 9

Time of Embryonic Loss

• Pig – Days 9 to 12 (70%); 12 – 18 (25%) and 18 to term (5%)

• Sheep – Days 8-14 (70%)

• Cows – By Day 17 (85%)

• Mare – By Day 14-15 (85 to 90%)

Porcine Placentation

Peri-Implantation Events

Days after mating

Embryomigration

Fimbria

Oviduct Utero-tubaljunction

Implantation

Progesterone

Estradiol

150µ 170µ 205µ 340µ

190 mm30mm425µ

840

5

10

1612 20

3

6

Co

nce

ptu

sp

osi

tio

n

Co

nce

ptu

sD

evel

op

men

t E

stra

dio

l(p

g/m

l)

Pro

ges

tero

ne

(ng

/ml)

oIFN productionby trophoblast

Shedding ofzona pellucida

Peri-Implantation Events

Uterine Capacity• Biochemical and Physiological Limitations to

Establishment and Maintenance of Fetal-Placental Development to Term– Endometrial Surface Area– Uterine Secretory Activity– Uterine Vasculature

• Low Resistance• High Flow• Capillary Bed Density• Placentomes

• General Considerations– Size– Function– Accommodation

Pig Placental AreolaeDay 70

• Number areolae correlated with fetal growth and birthweight

- Knight et al. (J. Anim. Sci. 1977;

44:620)- van Rens & van der Lende.

(Theriogenology 2002; 57:1651)

Western Range Ewes in USA

CL Lambs/100 Ewes

Advantage (%)

1 97

2 170 +73%

3 192 +18%

Age and Frequency of Twins in Holstein and Beef Cows

• Heifers – 1.3%

• 4 years of age – 4.4%

• 10 yeaers of age – 7.1%

• Beef Cows – 0.2 to 0.6%

Pregnancy Following Ipsilateral vs Bilateral Embryo Transfer in Beef Cows

Day of Pregnancy

Ipsilateral Transfer: 2 Blastocysts

Contralateral Transfer: 2 Blastocysts

Bilateral Transfer: 2 blastocysts

30 11/15 5/15 10/15

110 10/15 2/15 4/15

Intrauterine Migration of Blastocysts

• Sheep – Yes, when there are multiple ovulations

• Cattle – Rare, less than 10% regardless of site of ovulation– Sreenan and Beehan (1976) indicated 75% to 81%

embryo survival in 52 dairy heifers following bilateral embryo transfer

Problems with Multiple Offspring in Cattle

• Freemartins

• Abortions at about 150 to 180 days

• Small calves with high mortality

• Cows abandon one calf

• Retained placenta from 6 – 11% for cows with single calf to 66% to 100% in cows giving birth to multiple calves

Characteristics of Prolific Breeds of Sheep and Pigs

• Moderate increase or no increase in ovulation rate

• Increased embryonic survival

• Smaller, but uniform placentae

• Smaller, but uniform birth weights of offspring

• Increase in mammary development – milk production or increase in number of glands

• Increase in uterine vascularity

• Models for functional genomic inquiries

COW