Taber-CHDMultiple-Ge..

Congenital Heart Disease with
Multiple Gestation, Infertility and Its
Treatment
Evan Beth Taber MD
Maternal Fetal Medicine
DISCLOSURE
I have no financial relationship with any
manufacturer of any commercial product
and/or provider of commercial services
discussed in the CME activity
 I do not intend to discuss an
unapproved/investigative use of a
commercial product or device in my
presentation
 I affirm that my presentation complies with
the HIPPA privacy and security standards

Some Abbreviations
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ART – Artificial Reproductive Technology
ASRM- American Society for Reproductive Medicine
CHD – Congenital Heart Disease
IVF – In Vitro Fertilization 1978
ICSI Intracytoplasmic Sperm Injection – 1992
MZ – monozygotic twin
DZ -Dizygotic twin
MA = Monoamniotic
MC = Monochorionic
OI – Ovulation Induction- used oligoovulatory or anovulatory
SO – Superovulation- used ovulatory women with unexplained
or age-related subfertility
Scope :Points to Cover
 #1
Multiple gestations are increasing
 #2 CHD is increased in multiple
gestation
 #3 CHD is increased in infertility
patients and their treatment
 #4 Future areas for improvement?
Multiple gestations increase:
Why ?
 Parity
 Advanced
maternal age (AMA)
 Infertility treatments
Role of Parity with Multiples
Decreasing parity in Developing Countries
Maternal Age over Time :
CDC data 2004
Age Group
Rate Change
15 – 19 yo
1 % Down
20 – 24 yo
1 % Down
25 – 29 yo
2 % Increase
30 – 34 yo
4% Increase
35- 39
6 % Increase
40-44
5 % Increase
45-54
Unchanged
Dizygotic Twins
Increased with :
 Parity – this is down
 Age – but this is up
 Family History
 African / African-American ethnicity
Dizygotic Twins Incidence by
Ethnicity
8 per 1000 Caucasian
1.4 per 1000 Japan
49 per 1000 Nigeria
Monozygotic Twins Incidence
Natural MZ twins :
Constant about 4 per
1000 live births
 Constant with age,
race , and parity
 Some genetic
predisposition to MZ
but largely unrelated
to family history
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Percentage of Multiple Gestation
in US live births is increasing
Year
Twin %
Higher Order %
1998
2.8
0.193
2008
3.41
0.148
Source ASRM
Multiples:
Natural vs. Fertility Related -Twins
60 %
21 – 32 %
6- 16 %
Natural
OI/ SO
ART
OI/SO/ART increases
twins in general > 20 X
Most DZ
 ART also increases MZ
twins 6 – 10 X
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-Source ASRM
Natural vs. Fertility- Related
-Higher Order Multiples
Higher Order Multiples
20 %
Natural
80 %
Infertility Rx
39 % - 67 % OI/SO
13 – 44 % ART
 SO to ART carries
100 X incidence of
higher order multiples
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Durst Quads – Spont MZ
-Source ASRM
Grosselin SO Sextuplets
Natural vs. Fertility- Related-Higher
Order
SO to ART carries
100 X incidence of
higher order multiples
Nadya Suleman
“OCTAMOM”
Monozygosity and Infertility Treatment
©2010 Catholic Healthcare West
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Risk of Monozygotic Twins and
Infertility Rx :
Overall MZ twins 6 – 10 X
OI 2-3 X
Conventional IVF 2 X
ICSI up to 24 X
Monozygotic Twins and Infertility
Rx
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Assisted Zona Hatching
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Cochrane Review OR 3.26 ( 0.14 – 77.84)
? +/- culture medium composition
? Increased by extending the blastocyst stage
Infertility Treatment and Multiple
Gestation
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Both Dizygotic and Monozygotic multiples
increased
What are the implications of this for CHD ?
©2010 Catholic Healthcare West
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CHD and Multiple Gestation
©2010 Catholic Healthcare West
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CHD is increased in multiple
gestation
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The incidence varies by
 Zygosity and Chorionicity
Chorionicity appears to be a major factor
Among MZ, increased in Monochorionic
complicated twins- upcoming talks
 Conjoined
 TTTS
 Acardiac / Trap
Twin factors in CHD : Studies
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Early studies used discordant sex as surrogate
for dizygosity
Following study by Mastroiacovo 1999
one of landmark early studies
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Twins and CHD
Mastroiacovo 1999
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12,093,128 births 260,865 twins in 9 international registries
Increased CV,CNS,GI malformations twins
CHD Defect
RR
95 % CI
Single Ventricle
3.41
1.84 – 6.33
VSD
1.39
1.22 – 1.59
ASD
1.98
1.58-2.48
Truncus/TOF
1.48
1.01-2.15
Unspecified
1.46
1.26-1.70
Pulmonary
anomaly
2.24
1.67-3.00
Twin factors in CHD
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The Mastroiacovo study was a start but did not
have data on
gender
 chorionicity
 ART data
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Twin factors in CHD
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We need to look at chorionicity
DZ are DC/DA
 MZ twins can be DC/DA, MC/DA or MA/MA
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Monozygotic Twin Gestation and
Chorionicity
Timing of Split Chorionicity of % of MZ Twins
Egg
the MZ egg
< 3d
DC/DA
30 %
4–8d
MC/DA
65 %
9-12 d
MC/MA
<5%
Chorionicity determined by
Ultrasound
CHD risk in Multiples by
Chorionicity
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CHD risk in Twins by Zygosity/
Chorionicity
Hajdu 2006
 Hungary 1996 – 2003
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Classification used :
MC= MZ
 discordant sexes = DZ
 DC same sex = unknown zygosity
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Hajdu 2006 DZ cases
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DZ increased Epstein’s 25 % of total CHD
cases
Otherwise rate of CHD equal to that of
singletons per newborn
Hajdu 2006
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MC twins CHD rate 3-4 x singletons
Of the CHD cases :
36 % were Pulmonary Stenosis p < 0.05
45 % were Endocardial Fibroelastosis p < 0.05
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Role of TTTS not assessed
CHD and MC Twins
Manning and Archer 2006 UK
 165 Twin sets
 Acquired defects as part of TTTS excluded
 Chorionicity determined by ultrasound
MC/DA 7 % incidence CHD
MC/MA 57 % incidence CHD
 MC -Risk co twin 27 % with 75 % concordant
lesions
CHD twins
Manning UK Followup data 2008 DC/DA CHD
rate not increased except for IVF over singleton
pregnancy but 2X risk of at least one twin CHD
 MC/DA at least 1 with CHD 7 %
1 affected twin , risk 25 % co-twin affected
 All CHD subtypes represented but VSD most
common
CHD twins Manning 2008
MA/MA
 Increased over MC/DA esp laterality
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Heterotaxy OR 4.8 compared to singletons
CHD twins Manning 2008
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Conjoined Twins
Thoracopagus 90 % share pericardium > 75 % major
structural defects
Both thoracopagus and parapagus increase laterality
defects
CHD in MC twins
Bahtiyar Review 2007 JUM IVF
Reviewed literature to date
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Compared it to two background populations
Study group MC/DA +/- TTTS
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MC/DA CHD risk 6-10 X over background
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Increased with ART
TTTS risk 13 – 14 X over background
TTTS vs. non TTTS 2.78 x
Bahtiyar 2007
Bahtiyar 2007
Bahtiyar Review 2007 JUM
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VSDs most common CHD
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Pulmonary stenosis and Aortic stenosis with
TTTS lesions recipient twin
MC twins and CHD General
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Relative risk 3-7 X most series
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Both fetuses affected varies 3 – 27 %
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MC Concordance of lesions rates 75- 91 %
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DZ twin Concordance rates 14 %
Pathogenesis of CHD MC twins ?
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Unequal distribution of inner cell mass
Splitting after laterality gradients determined , Lt
determining laterality so Rt side could lose reference pt
and interfere with looping -Heterotaxy
Heterokaryotypic monozygotism, with chromosome
abnormality post zygotic, during early cleavage,
differential methylation
Susceptibility to another insult ie 2nd hit theory
Acquired hemodynamic alterations eg TTTS for
recipient
Onward from Multiples to Infertility
and Its Treatments
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1 in 10 couples in US are infertile
5 % of US mothers use IVF to conceive
Multiple causes of infertility including advancing
maternal age
Infertility and Its Treatments
IVF
Ovulation
Induction
©2010 Catholic Healthcare West
GIVE
HOPE FOR
A CHILD
42
IVF Louise Brown 1st “ Test Tube”
Baby in 1978
IVF
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The number and proportions of children born
after IVF is increasing worldwide
The development of ART has been of great
benefit to millions of couples worldwide.
Since Louise Brown’s birth with “ standard
IVF” , there are a diverse range of techniques
used including GIFT, oocyte donation, embryo
cryopreservation, ICSI ,preimplantation genetics,
extended embryo (Blastocyst) culture
IVF
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Most IVF conceived children > 95 % are
healthy
However, concerns began to appear as early as
the late 1980s regarding safety
IVF Initial Report of Birth Defects
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Letter to the Editor Lancet Dr Lancaster 1987
Letter to the Lancet Editor
Dr Lancaster 1987
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1979 – 86 Reported on 16 IVF units in
Australia and New Zealand
Compared BD statistics to national data for
expected rates of malformations
5 x increase in spina bifida
6x increase in TGV
Note : 50% of cases were twins no chorionicity
data available
Further Studies of IVF and Birth
defects
Studies in the 1990s to early 2000s had
methodological problems:
 small sample size
 Varying classification of BD in registries, case
reports
 Unclear surveillance periods some studies
 Surveillance bias
 Plethora of technical variables in ART
 Heterogeneity of patient population
IVF and Birth Defects
Most of these studies fell under the radar until
two articles were published in the same issue of
the NEJM in 2002
The news hit the pages of Time Magazine
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Time Magazine
March 18 2002
NEJM 2002 Dual Articles
1st Article CDC reported 2.6 x risk of LBW or
VLBW neonates
 2nd Article by Michele Nelson UK - risk of
major BD
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 ICSI
8.6 % Conventional IVF 9 % vs Natural 4.2 %
AOR 2.0
 CHD in ICSI 1.3 % IVF 1.6 % vs 0.6 % controls
AOR 2.6
Nelson NEJM Article 2002
Risk of major BD with IVF and ICSI
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Odds ratio 2.0 BD for both IVF and ICSI
compared to Spontaneous Conception
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Results similar with singletons and term
IVF and Birth Defects
Multiple studies ensued and by 2005 at least 25
publications some with conflicting results, both
negative and positive increased risk CHD with
IVF and ICSI
Hansen Review IVF and BD 2005
STUDY DESIGN
Hansen 2005 did a review of the literature with 7
independent epidemiologists
 Found 51 papers worldwide
 Examined 25 final papers with no data overlap
1989 – 2003
 28,638 ART children from Europe,Australia,
Middle East and USA
Hansen Review IVF and BD 2005
RESULTS
 Results : 2/3 studies showed > 25 % increased
risk of birth defects
 Of the 25 papers 7 studies qualified for metaanalysis
 Meta analysis showed 30 – 40 % increased risk
 Pooled odds ratio studies 1.4 ( 1.28 – 1.53)
Hansen Review 2005
NNTH – Number needed to harm :
Number of children conceived by ART for 1 additional
child to have a birth defect ( BD)
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Baseline prevalence BD
NNTH
1%
250
4 %
62
IVF and birth defects
Another study by- Olson U of Iowa same year
2005 1,462 IVF conceptions
 OR Major defect all 1.3 ( 95 % CI 1.0 – 1.67)
 Singletons 1.44 ( 95 % CI 0.98 – 2.12)
IUI 1.19 ( 95 % CI 0.66 – 2.13)
 No difference ICSI or cryopreserved embryos,
ZIFT or prolonged culture media in singletons
some effect cryopreservation twins
 CHD seen TOF, VSD, ASD
IVF and the Fetal Heart
IVF and CHD specifically
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Bonduelle Series of Reports 1999- 2009 ICSI Belgium
8 yr followup
Higher GU anomalies in boys with ICSI but not of
other major BD
Kurinczuk and Bower 1999 did analysis of Bonduelle
study reclassifying the birth defects with new results
ICSI had major BD OR 2.03
 3.3 % CHD vs 0.67 % background ie 5 x increase risk
Excluding “trivial VSD” OR 3.99
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R-analysis soundly criticized by original authors
ICSI
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Intracytoplasmic Sperm Injection
Developed in 1992 for treatment male factor infertility
IVF and CHD: Koivuvova 2002
Finland
 304 IVF cases compared to controls , followed
to 3 yrs of age
 ALL CHD had OR 4.0 risk with IVF (CI 1.4 –
11.7)
 Singletons OR 3.0 ( CI 0.5 – 18.0)
 Types ASD/VSD/Coarctation
 Prevalence BD increased in males even with
exclusion of GU anomalies
IVF and BD Reefhuis 2008
USA National Birth Defects Prevention Study
( NBDPS) / CDC
 13,586 Cases and 5008 controls
 Found significant associations of ART with
CHD, cleft lip+/- palate, esophageal atresia,
anorectal atresia and hypospadias
 Syndrome association was VACTERL ,
oculoauriculovertebral spectrum
 No significant difference with twins
IVF and CHD Reefhuis 2008
Singleton data CHD
Defect
AOR
95% CI
Septal
2.1
1.1 – 4.0
Conotruncal 1.4
0.6 – 3.2
TOF
1.6
0.6 – 4.3
CL+/- CP
2.4
1.2 – 5.1
Esophageal
Atresia
4.5
1.9 – 10.5
Summary IVF-ICSI and CHD
Author
OR
95% CI
Kallen
2.6
2.2-3.1
Kurinczuk
and Bower
3.99
2.8-7.3
Koivuvova
3.0
0.5 – 18.0
Reefhuis
2.1
1.1 – 4.0
Comments
ASD,VSD,
TGA,
TOF,situs
inversus,
VSD
Singletons
Singletons
septal
CHD and Infertility Treatment :
Summary
Treatments from OI/SO to Infertility and
IVF/ICSI carry a modest increased risk of
CHD even for singletons
 Data on IVF / ICSI largely same
 OR CHD of 2 – 5 X
©2010 Catholic Healthcare West
65
CHD and ART: What about
Infertility itself ?
Many rebuttals of these positive studies between ART
and BD , raised control that the control groups were
spontaneous conceived fetuses
 Studying natural conceptions with infertility obviously
not an easy task…
 However, some studies have tried, and have shown that
the population of infertility couples have an increased risk
of fetal malformations over the background population
risk

Zhu 2006 Danish Birth Cohort
Infertility and BD
 1997-2003 Longitudinal study Time to
Conception and Infertility Rx
 Median time of follow-up 4 yrs
 52,380 Fertile couples ( Time < 12 mo)
 5910 Infertile (Time > 12 mo) No Rx
 5564 Infertile with Rx
Danish Cohort – Singletons Time to
Pregnancy and BD
Type
BD
ALL
Fertile
TTP < 12 mo
No
%
Infertile Spont Infertile with
TTP > 12 mo Treatment
no Rx
HR
CI
HR
CI
2564
5
1.20
1.071.35
1.39
1.231.57
1.2
1.25
0.971.61
1.21
0.911.62
Circ
494
System
-CV
Danish Cohort :Time to Pregnancy
and BD
Increased Time to Pregnancy high OR of birth
defects
 Using 0-2 mo as reference for Hazard Ratio
3-5 mo HR 1.16 ( 1.06-1.27)
6-12 mo HR 1.17 ( 1.06 – 1.30)
> 12 mo HR 1.29 ( 1.14 – 1.45)
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Danish Cohort Risk BD according
to Type of Infertility Rx
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Compared to Singletons of Fertile Couples,
children after all types of infertility Rx had
increased prevalence BD with HR 1.3 – 1.85
Only ICSI had higher overall prevalence of
specific BD with HR 1.57 , with increase in GU
and musculoskeletal but not CHD
Compared to twins of Fertile couples, twins
after infertility Rx had no higher prevalence BD
Infertility and Fetal Birth Defects:
Reasons ?
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Advanced maternal age
Advanced paternal age
Age infertility couples on average 5 yrs older than couples
with spontaneous conception
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Background genetic disorders
Imprinting disorders/epigenetics
 Male factor infertility
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ICSI
Male Infertility
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CF TR gene abnormalities
Y chromosome microdeletions
GU anomalies eg hypospadias
High rates of chromosome abnormalities
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2.2 – 14.3 %
Now evidence both male and female may have
chromosome abnormalities
Chromosomal Abnormalities ICSI
Couples Gekas 2001 France
Type
MEN
WOMEN
Overall
6.1 %
4.84 %
Reciprocal Trans
1.23
0.69
Robertsonian
Trans
Inversions
0.82
0.69
0.13
0.69
Sex Chromosomal 3.32
2.77
Other Structural
0%
0.59
Chromosomal Abnormalities ICSI
Couples Gekas 2001 France
Compared to newborns
 Higher 47 XXY in azoospermic men
 Higher Y chromosomal azoospermic men
 Sex chromosomal mosaicism esp in females
 Increased autosomal balanced structural
abnormalities
Summary of data :Multiple and
Infertility and BD/CHD
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OI/SO/ART increases twins > 20 X
ART increases MZ twins 6-10 X
SO/ART increases Higher order multiples 100X
DZ twins risk BD/CHD increased because two
babies, but not over background most studies
MC twins have a risk of CHD 3-7 X singletons
Summary of data :Multiple and
Infertility and BD/CHD

Infertility itself carries a mild risk of Birth
defects and CHD :
1.2 X risk BD
 1.25 X risk CHD
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IVF gives a 30 – 40 % risk of birth defects
compared to spontaneous conception OR 1.4
Summary of data :Multiple and
Infertility and BD/CHD over spont
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The BD risk of IVF modest 1.3 – 1.85
The Cardiovascular System is considerably
affected
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OR CHD 2 – 5 X
ICSI risk is about same as IVF with most studies
showing exception being the GU anomalies
which are also seen with male infertility
Dealing with BD Risk with Infertility
Strategies for the future
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REI METHODS : Reduce multiple gestation
Number embryo transfer guidelines - Enforce < 2 ?
 Special selection embryos?
 Pre-implantation genetics
 Change methodology for superovulation, egg
surveillance
 Consider single embryo transfer ( SET) – good
prognosis cases
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SET technique reduces multiple
rates without affecting success rates
New study quoted in the NY Times on Oct 31st
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Kresowik Article in Press Fert Steril 2011
U of Iowa
< 38 yo with fresh cycle autologous oocytes and
donor oocytes compared pre-May 2004 to post
2004 – 2009 mandated SET (mSET)
364mSET with LB rate 64.6 % vs to 51.1 %
and multiple rate 3.4 % vs 34.8 %
Dealing with BD/CHD Risk with
Infertility Strategies for the future
INTERNATAL
Multivitamin supplementation including folic acid
 Internatal or prenatal genetic counseling
 Change in screening parents eg karyotyping both
if male infertility
 ? Epigenetics information
Dealing with BD/CHD Risk with
Infertility Strategies for the future
PREGNANCY MANAGEMENT
 First trimester ultrasound including chorionicity
determination with multiples
Dealing with BD Risk with
Infertility:
Pregnancy Management

NT screening
Dealing with BD Risk with
Infertility:
Pregnancy Management
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
Early CV screening including transvaginal – Dr
Solomon’s Talk
Ductus Venosus Doppler
Dealing with BD Risk with
Infertility:
Pregnancy Management

Offer prenatal diagnosis eg CVS/ Amniocentesis

Note IVF couples less likely to avail of invasive testing than
non IVF couples
Future Strategies once pregnant
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
2nd trimester fetal ECHO
with high risk patients
esp MC twins
Early surveillance of MC
twins for TTTS
Future: Can we get more
information ?
 Include
details of the ART data on
birth certificates or link to birth
defects registries
 Standardize
birth defect classification /
multicenter/ international databases
The End
QUESTIONS ?