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Intrauterine Effects of Multiple Births. Shannon McCarter Megan Shoemaker 11/15/2006 BS 640. http://www.liquidself.com/twins/u312c.jpg. Some Statistics. Just over 4 million births in the U.S. in 2000
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Intrauterine Effects of Multiple Births Shannon McCarter Megan Shoemaker 11/15/2006 BS 640 http://www.liquidself.com/twins/u312c.jpg
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_statistics.html http://www.focusonyourchild.com/relation/art1/A0000458.html
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_statistics.html
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/A0000458.html
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_statistics.html
Overview • Positional Effects • Vasculature Design • Death of a Fetus • Hormone and Pathogen Movement
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
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.newborn1.jpg
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
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
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 40–50 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
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 < 0.001). The number of animals in each group is listed at the bottom. M. Pei et al., 2006
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 < 0.01). The number of animals in each group is listed at the bottom. M. Pei et al., 2006
Estradiol Concentration Fig. 5. The mean concentration of 17β-estradiol in the diencephalic tissue during gestation using an enzyme immunoassay of 17β-estradiol. The concentrations of 17β-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 < 0.01). The number of animals in each group is listed at the bottom. M. Pei et al., 2006
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
Growth Restriction • Factors: • Genetic • Epigenetic • Environmental • Space in uterus • Nutrient Availability • Placental Efficiency/Capability • Maternal Size/Maturity Bazer, Wallace, and Spencer 2006.
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.
Human Twin Pregnancy Types http://www.mombaby.org/UserFiles/File/TTTS.html
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
TTTS • Anastomoses • Bi-directional arterial-arterial • Veno-veno • Unidirectional arteriovenous anastomes • TTTS occurs when bi-directional anastomoses don’t compensate for unidirectional ones Y. K. Lim et al., 2005
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/58947039-BCCC-47F9-A81A-B083674A0D6F/0/ttts.jpg U. Harkness et al., 2005 M. Sueters et al., 2006
Treatment/ Management • Amnioreduction • Septostomy or microseptostomy Y. K. Lim et al., 2005 U. Harkness et al., 2005
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
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
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
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
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
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
Prognosis for Surviving Twin Pharoah, 2000
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.
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.
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.
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.
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.
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, O’Rourke, Baszler. 2006
Scrapie • Fetal/Cotyledon Infection Depends on: 1. maternal genotype 2. fetal genotype 3. proximity to susceptible twins Alverson, O’Rourke, Baszler. 2006
ARQ/ARQ fetus Uterine Horn 1 ARQ/ARR fetus ARQ/ARR fetus Uterine Horn 2 Alverson, O’Rourke, Baszler. 2006
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
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!
Summary • Intrauterine Position • Growth Restictions • Vasculature • Death of Co-Twin • Hormone and Pathogen Transfer between fetuses
Implications • Better understanding of multifetal gestations • Better prenatal care • Improved treatment of abnormalities • Maximal livestock production