11/2/2015
Multiple pregnancies
Ana Bircher, MD
American Board Certified
Medical Geneticist
Multiple pregnancy
Twin boom in terms of life births, not only in USA
but also internationally
42% increase since 1990
70% increase since 1980
1980: 18 twins/1000 births
2006: 32 twins/1000 births
Multiple pregnancies
• Despite of this high and increasing incidence,
many women act very surprised during first
trimester ultrasound
• Few receive prenatal counseling regarding exact
chances of twins or multiples
• And the majority do not receive genetic
counseling after the diagnosis is made
Peters et al., 2006
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CT, NJ, RI, MA 40 twins/1000
UT, NM 20 twins/1000
Multiple pregnancy
• Most significant correlate is increase in
average maternal age (AMA) especially striking
in the Northeast of USA
• Poorly understood mechanism
• AMA accounts for 1/3 of this increase
• Assisted reproductive techniques (ART)
Types of twins
Two eggs – two sperm
Di-zygotic
FRATERNAL
One egg – one sperm
Mono-zygotic
IDENTICAL
Zygote: a cell formed by the union of one sperm and one egg
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Di-zygotic twins
Two eggs – two sperm
Two placentas
Two amniotic cavities
Two genetically different babies
Same or different sex
Mono-zygotic twins
One sperm – One egg
Number of placentas (chorions) and amnions
depend on the time of splitting
Dizygotic twins
Same father - Same cycle = Fraternal twins
Same father – Different cycle = Super-fetation
Not the same father = Super-fecundation
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Factors affecting dizygotic twinning
Advanced maternal age
Peak at 37 years old – Reasons: unknown
Increased body mass index and height
Likely due to raised gonadotrophin levels
Family history of twins (maternal)
Higher parity
Ethnicity
Dizygotic twins: geographic risk
Factors affecting dizygotic twinning
• Dietary factors (Nigerian diet
is high in yams that contain
high levels of estrogens
• Vegan women have 1/5 the
rate of women that include
milk products on diet. IGF has
been found to be elevated in
cows. Twin rates increases with
dairy-rich diets
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Factors affecting dizygotic twinning
Assisted artificial
reproductive technology
AART
Monozygotic twins
One zygote
Monozygotic twins
<4 days
18-36%
Morula
4-8 days
57-75%
>13 days
2.5%
>8 days
4%20
Blastula
Blastocyst
Diamniotic monochorionic
Diamniotic dichorionic
Monoamniotic Monochorionic
Conjoined
Courtesy Dr. Jeanty
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MZ factors
• Random and constant rate across populations:
0.4%
• Reason for zygote split: Not known, external
factors
• However, familial MZ twining is higher than
expected
• Certain syndromes have an increased twin
rate (Opitz syndrome (33%), BWS (8%
compared to 0.4% in general population)
Familial monozygotic twinning
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
Placentation
DiAmniotic
MonoChorionic
Single placenta
DiAmniotic
DiChorionic
Fused placentae
DiAmniotic
DiChorionic
Separate placentae
MonoAmniotic
MonoChorionic
Single placenta
Bernirschke K: Twinning: biology and placentation
in US and multifetal pregnancy. Parthenon 1998
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Mortality
DiAmniotic
MonoChorionic
Single placenta
DiAmniotic
DiChorionic
Fused placentae
32%
44%
11%
13%
MonoAmniotic
MonoChorionic
Single placenta
DiAmniotic
DiChorionic
Separate placentae
Bernirschke K: Twinning: biology and placentation
in US and multifetal pregnancy. Parthenon 1998
Twin A — Twin B
Left-Right —Superior-Inferior
Risks associated with twin pregnancy
• Maternal
- during pregnancy
- during delivery
- after delivery
• Fetal
• Neonatal
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Maternal complications during pregnancy
• Increased blood volume and cardiac output
• Increased demand for iron, folic acid, and other nutrients
• Gestational hypertension: More than twice as likely. It
often develops earlier and more severe than in singletons
– Increased chance for placental abruptio
• Anemia: more than twice as common
• Increased weight gain
• Respiratory difficulty
• Excessive fluid retention, edema
• Increased episodes of supine hypotension
More frequent check-ups, more emphasis in certain nutrients,
more precautions with activities
Heterotopic pregnancy
Maternal complications during labor
and delivery
• Risk for mal-presentation - Locked twins
C-sections
• Post-partum hemorrhage
• Cord prolapse
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Fetal complications
•
•
•
•
•
•
High perinatal mortality and morbidity
Miscarriage
Preterm labor
Polyhydramnios
Growth restriction
Congenital malformations
Fetal complications
Increased mortality rate
At least one fetal loss
< than 24 weeks
> than 24 weeks
Dichorionic
2.5%
2.8%
Monochorionic
12.7%
4.9%
Having only one placenta is a major risk factor for fetal loss
and other fetal complications. Mortality is 3-4 higher than in
dichorionic
Mortality is higher even in normal-appearing fetuses
Surviving fetus with vanishing twin have increased risk for being small
for gestational age and IUGR
Fetal complications
In monochorionic twins death of one fetus may
result in immediate complications in the
survivor (brain damage ,death,
neurodevelopment handicap)
Acute hypotensive episodes secondary to
placental vascular anastomosis between the
two fetuses result in hemodynamic volume
shifts from the live to the dead fetus.
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Fetal risks
Preterm infant
(before 37 weeks EGA)
SIX times more likely to be preterm than singletons
Over 60% of twins and almost all higher-multiple
Breathing, feeding, temperature regulation, fight infections
Preterm delivery (24-32 weeks)
Singletons
1.2%
Dichorionic
5.5%
Monochorionic
9.2%
Median age at delivery
-Monochorionic 36 weeks - Dichorionic: 37 weeks
Fetal risks
Intrauterine growth restriction
Risk for IUGR baby is 10 times greater than in singletons
One fetus
Both fetuses
Dichorionic
23%
1.7%
Monochorionic
34%
7.5%
Growth discrepancy
Weight discordance more than 20%
15-30% of multiple gestations
500 and 999gr in 18% of the twin sets and were
in excess of 1000gr in 3%.
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Growth discrepancy
Outcome
2.5 risk of perinatal mortality
6.5 risk of stillbirth
Small twin mortality: 20%
(6 times > than in concordant twins).
Fetal risks
Congenital anomalies
Anomalies are present in 10% of twins
• All types of anomalies
– Deformations due to constraint/crowding
(plagiocephaly, dislocated hips, club feet)
– Dysruptions (limb reduction defects, hemifacial
microsomia, bowel atresia)
– Malformations: heart defects
Incidence varies depending on chorionicity.
Complications of twins compared to
singletons
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Twin-to-twin transfusion syndrome
• One placenta
• Present in varying degrees in 76-98% of MZ
twins
• Vessels: threadlike 5 mm.
Twin-to-twin transfusion syndrome - TTTS
Recipient: hypervolemic, polycythemia
excessive urination, polyhydramnios,
hypertension, hydrops, cardiac failure
Intracranial hemorrhage, periventricular
leukomalacia
Donor: hypovolemic, anemic
IUGR, hypoxia, restricted urine, oligoamnios
Children’s Hospital of Philadelphia
TTTS treatment
Amnioreduction
Children’s Hospital of Philadelphia
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TTTS treatment
Microseptostomy
TTTS treatment
Laser surgery
TTTS treatment
Laser surgery
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TTTS
• Severe forms complicate 15% of MC
• If untreated, before 28 weeks it carries a
mortality rate of 80% for one or both
twins
• Intraventricular hemorrhage
• Periventricular leukomalacia
Twin embolization syndrome
Encephaloclastic lesions
Hemifacial microsomia
Cutis aplasia
Intestinal atresia
Gastroschisis
Limb reduction
Hypotension vs. thromboplastin passage
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Twin embolization syndrome: outcome
Arterio-arterial transfusion
Placental anastomosis by 18-21 days
Twin
Reverse
Arterial
Perfusion
Pump twin
Recipient twin
Recipient twin
Umbilical vein
Artery with
reversed flow
“Used”, deoxygenated blood
caudo-cranial perfusion gradient
upper body disruption
Pump twin
Umbilical vein
Artery
Increased cardiac load
High output failure
Polyhydramnios
Hydrops
Premature delivery
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TRAP
The acephalus-acardiac twin
Lebel The Fetus.net
Acardiac amorphous
Beth Gross: The Fetus.net
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Cord entanglement
Malformations in multiple pregnancies
• Prevalence in dizygotic twins is the same as in
singletons
• In monozygotic prevalence is 2-3 times higher
• True malformations – genetic syndromes
• Disruptions
• Deformations
• Conjoint twins
Midline defects
Neural tube defects
Sirenomelia
Coacal exstrophy
Caudal duplication
Esophageal atresia
Limb-body-wall
complex
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Genetic syndrome
Achondroplasia
Congenital heart disease
•
•
•
•
•
CHD in general population: 0.8 in 100
CHD in monochorionic twins: 9.1%
9-fold increase
If complicated with TTTS: 13-14 Fold increase
Most common: VSD and pulmonary stenosis
Conjoint twins
More than 8 days
after conception
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70-95% are girls
40% stillbirth
30% neonatal death
The Cheng twins: the original
siamese twins
The Hilton sisters
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Ectoparasitic twin
Split more than
13 days after conception
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Fetus-in-fetu
• Size: up to 30 cm
• Usually symptomatic during first
year of life
• May be discovered in adults
• Spine or spinal cord (one of the
earliest structure to form)
“IDENTICAL” twins
• MZ twins are RARELY absolutely identical
• Some differences occur soon after the zygote
divides
• Other epigenetic/genetic changes accumulate
more slowly over the lifetime
• Mistakenly confused as dizygotic (“fraternal”)
• Benefits to accurately assess zygosity:
– Solid organ transplantation matching
– Preventive management of disorders
– Better counseling of parents of uniqueness
MZ twins are NOT identical
Discordant MZ twins have been increasingly reported
• Chromosome mosaicism
• Point mutations
• Mitochondrial disorders
• Epigenetic changes (X-inactivation, methylation)
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“Identical” twins different sex
Normal boy
Girl with Turner syndrome
Heterokaryotic monozygotes
Down syndrome baby
47,XX+21
46,XX
47,XX+21
Down syndrome baby
Normal baby
Down syndrome baby
Imprinting defect
CKNQ1OT1
Beckwidt-Wiedeman
Twinning
Monozygotic twins - ART
ART predisposes to
imprinting errors AND to
MZ twinning
MZ more than 2-fold in ART
Twinning gene?
Smith’s Recognizable patterns of Human Malformation
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Mirror image monozygotic twins
Reverse laterality
Up to 25% for small findings such as:
– Fingerprint patterns
– Hair patterns
– Face
– Brain laterality
• More common in
conjoined twins
Intermediate forms – Chimerism
• Greek mythology: monster with body of a
lioness the head of a goat and the tail of a
snake
• Two or more different populations of cells
• More common than
previously thought
Chimerism
• Chimerism exists in
animals and humans
• We just started
understanding causes
• IVF is a risk factor
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Intermediate twins
Semi-monozygotic twins
ART is a risk factor
Identical Non-identical
• 17 months MZ
• Severely malnourished
size 8 months old
• Global developmental delay
• Extensive medical issues
• Smaller HBP – Bigger LBP
• Different personalities
Why two children that share SAME genetics, SAME environment
and even SAME head be so different??
When facing
facing this
this ominous
ominous spectrum
spectrum
When
with
with escalating
escalating strate
strate of
of societal,
societal,
financial,
financial,and
and familial
familial burdens
burdens
ItIt isis easy
easy to
to miss
miss the
the more
more positive
positive
contribution:
contribution:twins
twins often
often bring
bring
unbridled
unbridled joy
joy and
and unique
unique insights
insights
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
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• Article to read:
Two Miracles, One Year Later
Author: Robert Marion
American Journal of Medical Genetics Part
C (Seminars in Medical Genetics)
151C:167-172 (2009).
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