maternal nutrition and fetal...

MATERNAL NUTRITION AND

FETAL PROGRAMMING

Kimberly A Vonnahme, PhD Associate Professor Reproductive Physiologist Department of Animal Sciences

North Dakota State UniversityCollege of Agriculture, Food Systems,

and Natural ResourcesFargo, ND 58105-5727

“Healthy Offspring through Optimal Nutrition”

IF MAMA AIN’T

HAPPY,

AIN’T NOBODY

HAPPY

Kimberly A Vonnahme, PhD Associate Professor Reproductive Physiologist Department of Animal Sciences

North Dakota State UniversityCollege of Agriculture, Food Systems,

and Natural ResourcesFargo, ND 58105-5727

“Healthy Offspring through Optimal Nutrition”

ACKNOWLEDGEMENTS

Collaborators at NDSU Joel Caton Christopher Schauer Steve O’Rourke Larry Reynolds Dale Redmer Anna Grazul-Bilska Justin Luther Carrie Hammer Greg Lardy Kasey Carlin Eric Berg

Other collaborators Rick Funston—UNL Bret Taylor—USDA-ARS

SES

Students and Staff Leslie Lekatz Leticia Camacho Erin Harris Allison Meyer Tammi Neville Jim Kirsch Jake Reed

NDSU Animal Nutrition and Physiology Center

OUTLINE

What is Developmental Programming?

What is happening at NDSU?

Nutrient delivery to the fetus

PHENOTYPE

Phenotype = Genotype + Environment

Eg. Milk production = Holstein genetics + Mastitis

Classic Animal Breeding Example

PHENOTYPE

Future Animal Breeding Example

Phenotype = Genotype + Environment Eg. Yield grade = Angus genetics + Uterine environment

PROGRAMMING

The process through which a stimulus or

insult establishes a permanent response

Developmental programming hypothesis

Exposure during a critical period in

development may influence later metabolic

or physiological functions in adult life

“Farmers, ranchers and animal scientists know more about how nutrition affects fertility in cows, pigs and other commercially important animals than fertility experts know about how it affects reproduction in humans. There are small hints scattered across medical journals, but few systematic studies of this crucial connection in people”

DEVELOPMENTAL (FETAL)

PROGRAMMING

Also known as the “Barker Hypothesis”

Dr. David Barker

Clinical

Research

Animal

Research

Epidemiological

Information

THE DUTCH HUNGER WINTER

SEPTEMBER 1944 - MAY 1945

VONNAHME, MARCH 2008

% of babies

who become

obese as adults

0

1

2

3

None1 Last third First two thirds None2

INCIDENCE OF ADULT OBESITY IN

THE CHILDREN OF THE DUTCH

HUNGER WINTER

VONNAHME, MARCH 2008

DEVELOPMENTAL (FETAL)

PROGRAMMING

Also known as the “Barker Hypothesis”

Dr. David Barker

Clinical

Research

Animal

Research

Epidemiological

Information

10 PRINCIPLES OF

DEVELOPMENTAL

PROGRAMMING

1) During development in the womb, there are critical periods of vulnerability to suboptimal conditions.

Vulnerable periods occur at different times for different tissues.

Figure 1. Timeline of bovine fetal development.

The portion in red is the time point of feed

restriction in the current study.

“TIMING IS EVERYTHING”

10 PRINCIPLES OF

DEVELOPMENTAL

PROGRAMMING

5) The placenta plays a key role in programming.

SHEEP AND COW

PLACENTAS

Maternal (caruncular) perfusion

Fetal (cotyledonary) perfusion

COW CAPILLARY DENSITY

C

apill

ary

num

ber d

ensi

ty

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Con CotNR CotCon CarNR Car

Day 125 Day 250

a,bMeans +/- SEM within a day and tissue differ; P<0.01

ab

a,bMeans +/- SEM differ; P<0.01; Vonnahme et al., 2007

VASCULAR FUNCTION

Caruncular Bed, day 125

Epinephrine

1e-9

1e-8

1e-7

1e-6

1e-5

1e-4

1e-3

Cha

nge

from

bas

elin

e, %

-20

0

20

40

60

80

100

120

140

160

180ControlNutrient Restricted

Trt: P = 0.07Dose: P < 0.01T x D: P = 0.92

Vonnahme et al., unpublished data

VASCULAR FUNCTION

Caruncular Bed, day 125

Epinephrine

1e-9

1e-8

1e-7

1e-6

1e-5

1e-4

1e-3

Cha

nge

from

bas

elin

e, %

-20

0

20

40

60

80

100

120

140

160

180ControlNutrient Restricted

Trt: P = 0.07Dose: P < 0.01T x D: P = 0.92

Caruncular Bed, day 250

Epinephrine

1e-9

1e-8

1e-7

1e-6

1e-5

1e-4

1e-3

Cha

nge

from

bas

elin

e, %

-20

0

20

40

60

80ControlNutrient Restricted

Trt: P < 0.01Dose: P < 0.01T x D: P = 0.58

Vonnahme et al., unpublished data

10 PRINCIPLES OF

DEVELOPMENTAL

PROGRAMMING

6) Compensation carries a price. In an unfavorable environment, the developing baby makes attempts to compensate for deficiencies. However, the compensatory effort often carries a price.

?

?

MECHANISMS OF

PROGRAMMING?

Nutritional Influence

Reorganisation of organ structure

Abnormal early cell-cell interactions?

Metabolic Differentiation

DNA Control? (altered cell specific gene regulation)

DNA Environment? (altered DNA binding proteins)

Altered DNA methylation?

Altered Cell Number or

intracellular organization

WHAT’S HAPPENING

AT NDSU?

North Dakota State UniversityCollege of Agriculture, Food Systems,

and Natural ResourcesFargo, ND 58105-5727

“Healthy Offspring through Optimal Nutrition”

NDSU SHEEP STUDIES

High Selenium

(n=42)

Breeding to 50dGA Parturition

(n=14) 100% NRC

(n=14) 60% NRC

(n=13) 100% NRC

(n=14) 60% NRC

Normal Selenium

(n=40)

(n=81) All lambs placed on identical

nutrition scheme until market weight 48 h after birth to weaning =

Bucket Teat Unit Weaning to Market (n=13) 140% NRC

(n=14) 140% NRC

Lamb birth weight

Maternal nutritional intakeRES CON HIGH

Birt

h w

eigh

t, kg

0

1

2

3

4

5 MalesFemales

ab

ac acc

ab

Nut*sex; P = 0.02

EFFECT OF MATERNAL NUTRITION

ON LAMB IgG CONCENTRATION

0

500

1000

1500

2000

2500S

eru

m I

gG

(m

g/d

l)

RES (60%) CON (100%) HIGH (140%)

A Se H Se

Hammer et al., 2011

Nutr. X Se; P < 0.05

EFFECT OF MATERNAL NUTRITION ON

LAMB MORTALITY FROM BIRTH TO

WEANING

0

1

2

3

4

5

6

7

8

9M

ort

ali

ty (

# o

f L

am

bs)

RES (60%) CON (100%) HIGH (140%)

No. of Lambs Hammer et al., 2011

P < 0.02

EFFECT OF MATERNAL NUTRITION ON

COLOSTRUM PRODUCTION IN EWE

LAMBS

0

100

200

300

400

500

600

g o

r m

L

RES (60%) CON (100%) HIGH (140%)

Colostrum Wt. (g) Colstrum Vol. (mL)

Swanson et al., 2008

CON vs. RES, CON vs. HIGH P < 0.01

EFFECT OF MATERNAL NUTRITION

ON TOTAL IgG PRODUCTION

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

Co

lost

ral

IgG

(g

/L)

RES (60%) CON (100%) HIGH (140%)

IgG (mg)

Swanson et al., 2008

CON vs. RES, P = 0.06 CON vs. HIGH; P = 0.06

THE MAMMARY GLAND

HIGH (140% NRC)

MOD (100 % NRC)

LOW (60% NRC)

High Se n = 13 n = 13 n = 11

Adequate Se n = 13 n = 12 n = 14

Nutritional TreatmentsLOW MOD HIGH

Cap

illar

y A

rea

Den

sity

, %

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18ASeHSe

Se: P < 0.001Nut: P = 0.63Se*Nut: P = 0.51

CAPILLARY AREA DENSITY

VONNAHME, FEBRUARY 2009

Nutrition during

pregnancy impacts on

milk yield

Day postpartum0 2 4 6 8 10 12 14 16 18 20

Milk

yie

ld, g

500

600

700

800

900

1000

1100

60% NRC100% NRC140% NRC

P < 0.001

Selenium during

pregnancy effects on milk

yield

P < 0.001

Days postpartum0 2 4 6 8 10 12 14 16 18 20

Milk

yie

ld, g

500

600

700

800

900

1000

1100

ASeHSe

OTHER POSTNATAL

RESPONSES

Se has positive impacts on carcass traits

Se decreases digestibility

Se increases visceral adiposity

No effect of maternal diet on N retention

No effect of maternal diet on development of the reproductive system

Similar day to puberty

Similar CL proliferation rates

Blood distribution

during pregnancy

Uteroplacental blood flow increases dramatically to support the nutritional demands of the rapidly growing fetus

Increased maternal plasma volume

30 to 40% increase

Increased maternal cardiac output

35% increase in stroke volume

15% increase in heart rate

Fractional distribution of cardiac output to the uterus

% of Cardiac Output

0.5% non-pregnant

>16% late pregnant

Note: the % of cardiac output delivered to the other tissues falls, however, absolute values of blood flow are unchanged, further pointing to the need for an expanded blood volume

Rosenfeld, 1984

Nourishing the

uteroplacenta

Uterine blood flow is increased during pregnancy

Vasodilatation

Vascular remodeling

Caruncular

Cotyledonary

Day 50 Day 140

•Fetal (Cotyledonary) Vascularity: – Capillary area density (6.2X) – Capillary no. density (12.3X) – Cap. surface density (6.0X) – Area per capillary (1.9X)

•Maternal (Caruncular) Vascularity: – Capillary area density (3.3X) – Capillary no. density (1.5X) – Cap. surface density (1.7X) – Area per capillary (2.2X)

DOPPLER ULTRASONOGRAPHY

METHODS

Fetal heart rate

Pulsatility index (PI) = PSV – EDV Mean Velocity

Resistance index (RI) = PSV – EDV PSV

Angle of insonation

Diameter of vessel

90

45

PATIENCE AND TIME

REALIMENTATION WILL INCREASE

UTERINE BLOOD FLOW

100%

(n=18)

100% (n=6)

60% (n=6)

60% (n=6)

100%

100%

60%

100%

d 0 d 30 d 85 d 140 d 260

Percentage NRC recommendations

5/22/2012

UTERINE ARTERIAL

RESISTANCE

Day of gestation

30 44 58 72 85 100

114

128

140

156

170

184

198

212

226

240

254

Resis

tan

ce in

dex

0.60

0.65

0.70

0.75

0.80

0.85CCCRCCRRC

SEMTrt, P < 0.001Day, P < 0.001Trt*day, P = 0.460.0

0.2

0.4

0.6

0.8 a a b

GLOBAL NUTRITION

Maternal intake and BW

changes

Day of gestation40 60 80 100 120 140 160

Wei

ght,

kg

45

50

55

60

65

70

75

8060% NRC100% NRC140% NRC

*Se – NS Diet – P<0.01,

(d90-145, all diets differ)

Lamb birth weight

Maternal nutritional intakeRES CON HIGH

Birt

h w

eigh

t, kg

0

1

2

3

4

5 MalesFemales

ab

ac acc

ab

Nut*sex; P = 0.02

Umbilical Blood Flow in

Pregnant Ewes

RES CON EXCC

han

ge i

n R

I, %

-20

-15

-10

-5

0

5

10

15P = 0.01a

b

ab

Lekatz et al., 2009

PROTEIN SUPPLEMENTATION

DURING LATE PREGNANCY

Impacts on female progeny reproductive success

3 yrs: Gudmundsen Sandhills (n=170 heifer calves)

Cows bred

No supplement (NoProt)

Protein (Prot) 0.45 kg/d 42% CP

12/1 – 2/28 LG

3 yrs: Gudmundsen Sandhills (n=170 heifer calves)

Cows bred

No supplement (NoProt)

Protein (Prot) 0.45 kg/d 42% CP

12/1 – 2/28 LG Ave calving date =March 27

REPRODUCTIVE PERFORMANCE

Treatment

Item Prot NoProt SEM P-value

Age at Puberty, d 339 334 10 0.70

Cycling at beginning of breeding

season, % 61 67 - 0.45

Calved in first 21 d, % 77 49 - 0.005

Overall pregnancy rate, % 93 80 - 0.05

Calving date, Julian d 71 75 3 0.15

Calf birth wt, kg 33 33 1 0.94

Unassisted births, % 78 64 - 0.24

REPRODUCTIVE PERFORMANCE

Treatment

Item Prot NoProt SEM P-value

Age at Puberty, d 339 334 10 0.70

Cycling at beginning of breeding

season, % 61 67 - 0.45

Calved in first 21 d, % 77 49 - 0.005

Overall pregnancy rate, % 93 80 - 0.05

Calving date, Julian d 71 75 3 0.15

Calf birth wt, kg 33 33 1 0.94

Unassisted births, % 78 64 - 0.24

REPRODUCTIVE PERFORMANCE

Treatment

Item Prot NoProt SEM P-value

Age at Puberty, d 339 334 10 0.70

Cycling at beginning of breeding

season, % 61 67 - 0.45

Calved in first 21 d, % 77 49 - 0.005

Overall pregnancy rate, % 93 80 - 0.05

Calving date, Julian d 71 75 3 0.15

Calf birth wt, kg 33 33 1 0.94

Unassisted births, % 78 64 - 0.24

CONTROL DIET (n = 10)

CONTROL DIET (n = 5)

CONTROL DIET +

SUPPLEMENT (n = 5)

d 180 US Begins

CAN MELATONIN SPARE

FETAL WEIGHT LOSS?

CAN MELATONIN SPARE

FETAL WEIGHT LOSS?

LEMLEY ET AL., 2011

Day 130

ADQ (n = 31) CON-RES (n = 8)

Day 0 Day 50

CON-ADQ (n = 7)

MEL-ADQ (n = 8)

MEL-RES (n = 8)

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500CON-RES (n = 8)CON-ADQ (n = 7)MEL-RES (n = 8)MEL-ADQ (n = 8)

Trt*Nut*Day; P = 0.15

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500CON (n = 15)MEL (n = 16)

Trt*Day; P < 0.001

*

*

*

*

**

Gestation, d

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500ADQ (n = 15)RES (n = 16)

Nut*Day; P < 0.0001

*

*

*

*

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500CON-RES (n = 8)CON-ADQ (n = 7)MEL-RES (n = 8)MEL-ADQ (n = 8)

Trt*Nut*Day; P = 0.15

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500CON (n = 15)MEL (n = 16)

Trt*Day; P < 0.001

*

*

*

*

**

Gestation, d

40 50 60 70 80 90 100 110

Um

bil

ical

BF

, m

L/m

in

0

100

200

300

400

500ADQ (n = 15)RES (n = 16)

Nut*Day; P < 0.0001

*

*

*

*

DON’T JUST BLAME YOUR MOM!

Research studies performed in rodents

Drugs

Carcinogens

Environmental estrogens (BPA)

Conclusions: Dad can impact fetal development

Work in livestock is largely lacking

FUTURE DIRECTIONS

Time period of supplementation

Specific nutrients that are important

Maternal efficiencies

Factors that impact uterine and placental blood flow

Developmental

Programming

IMPORTANT TO ANIMAL HEALTH AND PRODUCTIVITY:

Growth and nutrient transfer

Reproductive capacity

Aging and lifetime productivity

GOAL: HEALTHY OFFSPRING!!!

VONNAHME, MARCH 2008

ACKNOWLEDGEMENTS

NDSU Animal Nutrition and Physiology Center