Intrauterine Effects of Multiple Births

1
Intrauterine Effects of Multiple Births

• Shannon McCarter
• Megan Shoemaker
• 11/15/2006
• BS 640

http//www.liquidself.com/twins/u312c.jpg
2
Some Statistics

• Just over 4 million births in the U.S. in 2000
• 3 (1 in 33) of babies were born as a twin or
  higher order multiple to mothers of age 25-29
• Increases to 4 at 30-34 years and almost 5 at
  35-39 years
• The incidence of multiple births has increased
  over the past 15 years with triplet births being
  the fastest growing portion.
• A recent study showed that higher-order births
  have doubled since 1990 and quadrupled since
  1980.

http//www.keepkidshealthy.com/twins/twin_statisti
cs.html
http//www.focusonyourchild.com/relation/art1/A000
0458.html
3
Some Statistics

• 'natural' fraternal twins 1.7
• identical twins 0.4
• conjoined twins 1 in 50-80,000
• 'natural' triplets 1 in 8,100
• twins with the use of fertility treatments 20-25

http//www.portlandtn.net/brphotos/triplets.jpg
http//www.keepkidshealthy.com/twins/twin_statisti
cs.html
4
Some Statistics

• Slightly more than half of all twins are males.
• Approximately one-fourth of identical twins are
  mirror-image twins (right side of one will match
  left side of the co-twin).
• In the United States, approximately one-third of
  twins are identical, one-third are same-sex
  fraternal and one-third are boy/girl.

http//www.focusonyourchild.com/relation/art1/A000
0458.html
5
Factors in increased multiple births

• Maternal family history of multiple births
• Race
• How many times you have been pregnant
• Whether or not you have had twins already
• Fertility Treatments

http//www.keepkidshealthy.com/twins/twin_statisti
cs.html
6
Overview

• Positional Effects
• Vasculature Design
• Death of a Fetus
• Hormone and Pathogen Movement

7
Positional Influences (IUP)

• Individual variability in sex-related traits may
  be influenced by inconsistency in hormonal
  exposure during fetal development due to the sex
  of neighboring fetuses.

http//www.colorado.edu/kines/Class/IPHY3730/image
/intrauterine.jpg
B. Ryan et al., 2002
8
Positional Influences

• Male fetuses produce testosterone in higher
  amounts and earlier than females
• Female fetuses produce estradiol in higher
  amounts later in gestation

B. Ryan et al., 2002
http//www.mendocinobeagle.com/litter10.group.newb
orn1.jpg
9
Positional Influences

• Hormone transfer
• diffuse through amniotic fluid
• travel through bloodstream of mother
• Caudal male hypothesis
• ex. rats
• Contiguous male hypothesis
• ex. mice and gerbils

B. Ryan et al., 2002
10
B. Ryan et al., 2002
11
B. Ryan et al., 2002
12
SDN-POA IUP

• Sex differences found in the hypothalamus
• The sexually dimorphic nucleus of the preoptic
  area (SDN-POA) is important in the regulation of
  sexual behavior
• There is a critical prenatal period in which the
  neuron shaping of the SDN-POA is most sensitive T
  and E

13
Fig. 1. Representative coronal sections through
sexually dimorphic nucleus of the preoptic area
(SDN-POA) with calbindin-D28k immunoreactivity in
adult rats. The stereographic SDN-POA region is
shown by overlapping of 4050 image planes. Scale
bar, 100 µm. 2F, rats gestated between two female
fetuses 2M, rats gestated between two male
fetuses.
M. Pei et al., 2006
14
SDN-POA Volume
Fig. 3. The volume of the sexually dimorphic
nucleus of the preoptic area (SDN-POA) analysed
using a confocal laser scanning microscope. Means
SEM are indicated by the vertical bars.
(A) Comparison of males and females.
(B) Comparison of male rats gestated between two
male fetuses (2M), male rats gestated between two
female fetuses (2F), 2M females and 2F females.
Significant differences (P lt 0.001). The number
of animals in each group is listed at the bottom.
M. Pei et al., 2006
15
Testosterone Concentration
Fig. 4. The mean concentration of testosterone in
the diencephalic tissue during gestation using an
enzyme immunoassay of testosterone.
Concentrations of testosterone (mean SEM) in
male rats gestated between two male fetuses (2M),
male rats gestated between two female fetuses
(2F), 2M female and 2F female fetuses were
measured. (A) Concentration on day 18 of
gestation (B) concentration on day 21 of
gestation. Significant differences between the
2M males and 2F males (P lt 0.01). The number of
animals in each group is listed at the bottom.
M. Pei et al., 2006
16
Estradiol Concentration
Fig. 5. The mean concentration of 17ß-estradiol
in the diencephalic tissue during gestation using
an enzyme immunoassay of 17ß-estradiol. The
concentrations of 17ß-estradiol (mean SEM) in
male rats gestated between two male fetuses (2M),
male rats gestated between two female fetuses
(2F), 2M female and 2F female fetuses were
measured. (A) Concentration on day 18 of
gestation (B) concentration on day 21 of
gestation. Significant differences between the
2M males and 2F males (P lt 0.01). The number of
animals in each group is listed at the bottom.
M. Pei et al., 2006
17
Some evidence in humans

• Some minor hormonal influences may be present but
  do not appear to cause the same level on
  modifications as litter bearing animals.
• Sensation seeking
• Spontaneous otoacoustic emissions

B. Ryan et al., 2002
18
Growth Restriction

• Factors
• Genetic
• Epigenetic
• Environmental
• Space in uterus
• Nutrient Availability
• Placental Efficiency/Capability
• Maternal Size/Maturity

Bazer, Wallace, and Spencer 2006.
19
Growth Restriction

• Increased Number of Fetuses
• Placental insufficiency
• Decreased placental mass per fetus
• (vs. single births)
• Low birth weights
• Lambs twin 78 of a singleton
• triplet 62 of a singleton
• Pigs birth weight is directly affected by the
  number of littermates

Bazer, Wallace, and Spencer 2006.
20
Human Twin Pregnancy Types
http//www.mombaby.org/UserFiles/File/TTTS.html
21
Twin-Twin Transfusion Syndrome

• 1/3 of twins are monozygous
• 70 of these are monochorionic
• TTTS affects up to 15 of all MC pregnancies
• If left untreated, there is about an 80
  mortality rate

Y. K. Lim et al., 2005
22
TTTS

• Anastomoses
• Bi-directional arterial-arterial
• Veno-veno
• Unidirectional arteriovenous anastomes
• TTTS occurs when bi-directional anastomoses dont
  compensate for unidirectional ones

Y. K. Lim et al., 2005
23
TTTS

• One twin (recipient) receives more blood and
  produces more urine than the other (donor)
• Early diagnosis by ultrasound is essential for
  treatment
• Quintero defined stages based on ultrasound
• Stages I-V

http//www.fetalcarecenter.org/NR/rdonlyres/589470
39-BCCC-47F9-A81A-B083674A0D6F/0/ttts.jpg
U. Harkness et al., 2005 M. Sueters et al., 2006
24
Treatment/ Management

• Amnioreduction
• Septostomy or microseptostomy

Y. K. Lim et al., 2005 U. Harkness et al., 2005
25
Treatment/ Management

• Selective laser ablation of the placental
  anastomotic vessels (fetoscope)
• Selective cord coagulation

Y. K. Lim et al., 2005 U. Harkness et al., 2005
26
Death of a Fetus

• Litter bearing species
• Fetal death common
• Resorption
• Minimal effect on survivors
• Rats increased in fetal weight
• Due to increase in uterine space

Barr, Jensh, and Brent. 1970
27
Death of a Fetus

• Humans
• Risk Factors for Damage to Survivor
• Probability of death of second twin inversely
  related to time of first death
• Death in early gestation has minimal effects
• Monochorionic monozygotic twins/triplets
• Same Sex 2-3x more susceptible

Pharoah, 2000 Johnson and Zhang, 2006
28
Vanishing Twin Syndrome

• 25 of multifetal pregnancies result in a loss in
  first trimester
• minimal effects on remaining fetuses
• more common in monozygotic twins with
  monochorionic placenta
• Potential cause of cerebral palsy in singleton
  children?

Pharoah, 2000 Johnson and Zhang, 2006
29
Loss after First Trimester

• Less common .5-6.8
• Possible Causes
• cord entanglement
• TTTS
• chronic placental insufficiency
• congenital anomalies
• Greater Risk of Adverse Effects on the Surviving
  Twin

Pharoah, 2000 Johnson and Zhang, 2006
30
Prognosis for Surviving Twin

• Premature Birth
• Increased risk of neonatal death
• Neurological Effects
• Cerebral Palsy
• England/Wales 1993-95 20 risk
• Encephalitis
• Learning Disorders
• Mental Retardation

Pharoah, 2000 Johnson and Zhang, 2006
31
Prognosis for Surviving Twin
Pharoah, 2000
32
Freemartins

• sterile bovine
• Incorrect Female Sex Determination in a
  heterosexual twin pregnancy
• Male develops normally
• Female partial sex reversal
• Incidence
• Cattle 90
• Sheep 1-7

Padula, 2004. Short, 1970. Smith et. al. 2000.
33
Freemartin Biology

• Vascular connections develop between heterosexual
  twins
• Day 39 fusion of extraembryonic membranes
• Formation of a common chorion
• Sharing of cotyledons
• Common blood supply
• Day 40 testes form in male fetus
• Female exposed to male hormone production

Senger, 2003.
34
Freemartin Biology

• Default female differentiation pathway is
  interrupted
• Female is exposed to
• 1. AMH
• 2. Testosterone
• Paramesonephric ducts partially form
• Ovaries do not functionally develop
• May produce E2 and testosterone

Senger, 2003. Padula, 2005.
35
Freemartin Phenotype

• Short vagina
• Small, atrophic gonads
• Possible enlarged clitoris
• Lack of a defined cervix
• Increased ano-vulval distance
• Lack of estrous behavior
• Possible male behaviors (bullish)

Padula, 2004. Short, 1970. Smith et. al. 2000.
36
Bell, Hunter 1779.
37
Maternal Infection

• Maternal Fever during delivery
• Risk of neonatal encephalopathy
• Maternal Infection
• Damage to fetus
• Pathogen itself
• Immune molecules (e.g. cytokines)
• Risk of Cerebral Palsy

Karin, 2002.
38
Scrapie

• Prion Disease affecting Sheep
• Infection spreads horizontally
• Susceptible Genotypes
• VRQ/VRQ, ARQ/VRQ, ARQ/ARQ
• Nonsusceptible Genotypes
• ARR/ARR, ARQ/ARR, ARQ/VRR
• PrPsc known to accumulate in placenta

Alverson, ORourke, Baszler. 2006
39
Scrapie

• Fetal/Cotyledon Infection Depends on
• 1. maternal genotype
• 2. fetal genotype
• 3. proximity to susceptible twins

Alverson, ORourke, Baszler. 2006
40
ARQ/ARQ fetus
Uterine Horn 1
ARQ/ARR fetus
ARQ/ARR fetus
Uterine Horn 2
Alverson, ORourke, Baszler. 2006
41
Cytomegalovirus

• .2-2.5 human pregnancies
• Most common viral congenital infection
• 80-90 asymptomatic at birth
• but 5-17 show later effects
• hearing loss
• mental retardation
• 15 symptomatic at birth
• Splenomegaly, jaundice, hepatomegaly,
  chorioretinitis, periventricular calcifications,
  hearing loss

42
Cytomegalovirus

• 40 chance of fetal infection
• Influenced by
• 1. Viral load of maternal infection
• Short acute phase
• 2. Connectivity of Fetuses
• Dichorionic Placentation only one twin may be
  infected
• Monochorionic Placentation or Fused Dichorionic
  both twins usually infected
• 3. Resistance of Placenta/extraembryonic
  membranes
• common for only one twin to be infected!

43
Summary

• Intrauterine Position
• Growth Restictions
• Vasculature
• Death of Co-Twin
• Hormone and Pathogen Transfer between fetuses

44
Implications

• Better understanding of multifetal gestations
• Better prenatal care
• Improved treatment of abnormalities
• Maximal livestock production

45
Questions?
46
Short, 1970.