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.
ADULT
RIGHT HEART ► LUNGS ► LEFT HEART
↑
↑
LIVER
↓ AORTA
←
←
←
BODY
FETUS
Liver
Ductus
Venosus
Lung
RIGHT HEART ► FORAMEN OVALE ► LEFT HEART
↑
↑
AORTA
PLACENTA
DUCTUS ARTERIOSIS
BODY OF FETUS
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 fetalplacental tissue growth
MATERNAL METABOLISM
– Nutritional Priorities of Fetus and Mother
• Maternal
– Nervous System
Fetal Demands
Nervous System
Bone
Muscle
Fat
– Bone
– Muscle
– Fat
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 lobuloalveolar 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
FACTORS AFFECTING REPRODUCTIVE
PERFORMANCE
UTERINE CAPACITY
EMBRYONIC DEATHS
FERTILIZATION RATE
OVULATION RATE
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 - Swine
High Ovulation
Rate
Control
Superovulated
18.4 CL
15.0 CL
20.2 CL
68 % Ova
Recovered
14% Meiotically
Immature (MI)
27%
Chromosomally
Abnormal
(CA)(41.5% total
abnormal)
81% Ova
Recovered
9% MI
68% Ova
Recovered
16% MI
24% CA (32.5%
total abnormal)
27% CA (43%
total abnormal
Western U.S. A. Ewes
• USDA Idaho
1CL – 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 18
Control
12
26 + 7
FLW
Hyperprolific
Meishan
23
13
41 + 7
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
Peri-Implantation Events
Conceptus Conceptus
Development position
Shedding of
zona pellucida
oIFN production
by trophoblast
Fimbria
Utero-tubal
junction
Embryo Implantation
migration
425µ
150µ
170µ
205µ
190 mm
30
mm
340µ
Estradiol
(pg/ml)
10
5
0
4
8
12
Days after mating
Progesterone
6
Estradiol
3
16
20
Progesterone
(ng/ml)
Oviduct
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 Areolae
Day 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 Advantage
Ewes
(%)
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
30
Ipsilateral
Contralater Bilateral
Transfer: 2 al Transfer: Transfer: 2
Blastocysts 2
blastocysts
Blastocysts
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