Fetal Echo- New Indications

Which Pregnancies Are At Greatest
Risk for Fetal Congenital Heart
Disease?
New and Interesting Concepts
Julia E. Solomon MD
Director, Fetal Diagnostic Center
Chandler Regional Medical Center
St Joseph’s Hospital & Medical Center
Phoenix, AZ
DISCLOSURE INFORMATION
-I provide educational material to GE Healthcare as an
independent contractor 2-3 times/year
-I have no other financial relationship with any manufacturer of any
commercial product and/or provider of commercial services
discussed in the conference.
-I do not intend to discuss an unapproved/investigative use of a
commercial product or device in my presentation.
Rationale for Fetal Echocardiography:
- variety of maternal or fetal indications may result in an
increased risk of CHD
- select those at greater risk for a more detailed evaluation
of the cardiovascular system than is typical of routine
obstetric ultrasound
Inherited
Teratogen
Dx
Maternal
FHx
Diabetes
Anti-SSa
CHD
Exposure
Marfan’s
Extracardiac
Abnormal
Arrhythmia
Aneuploidy
Hydrops
Fetal US
Abnormality
Diabetes
Anti-SSa
Abnormal US
Hydrops
Aneuploidy
Inherited Dx
Marfan’s
FHx CHD
Arrhythmia
Teratogen
Exposure
Extracardiac
Abnormality
Nuchal Translucency
•
•
Transient finding in the first trimester
collection between skin and muscles in nuchal area
Fluid balanced taxed in 11-14 wk fetus
•
Nuchal Translucency
• Strong association with fetal aneuploidy
when increased
• Regresses beyond 14 weeks
• Part of 1st trimester screening for
aneuploidy when combined with maternal
age, serum PAPP-A and free βhCG
• 95th percentile measurement varies with
GA but is approx. 2.5 mm
• 99th percentile- 3.5 mm
1.9 mm
Normal nuchal translucency
Abnormally increased NT
Reasons for Increased NT
• Cardiac dysfunction **
• Venous congestion of head and neck
composition of extracellular
• Altered
matrix
• Impaired lymphatic drainage
• Fetal anemia
• Fetal hypoproteinemia
• Fetal infection
In addition to association with aneuploidy:
-Partial list of conditions that have been associated with an
increased nuchal translucency
NT and the risk of CHD
• Hyett et al, BJOG,
1999
95th%
99th%
• 29,154 euploid
Sensitivity
56.0
40.0
• Of 50 cases with
Specificity
93.8
99.0
PPV
1.5
6.3
NPV
99.9
99.9
fetuses, 10-14 wks
major CHD, 56%
had an increased
nuchal translucency
(>95th %)
• Initially suggestive of
left>right lesions
-34,000+ fetuses
- reported only 15% sensitivity using 3.5 mm (99%)
*but* excluded fetuses with cystic hygromas
- when included, sensitivity returns to 35.3%
- distinction is effectively meaningless and introduces
ascertainment bias
Large Studies of NT and Prenatal Screening for CHD
Author/year
n
Incidence
major CHD
NT threshold
(%)
Sensitivity (%)
PPV (%)
Hyett 1999
29154
1.7/1000
99th
40
6.3
Michailidis
2001
6606
1.7/1000
99th
95th
36.3
27
4.1
1.7
Hafner 2003
12978
2.1/1000
95th
25.9
1.1
Bahado-Singh
2005
8167
2.1/1000
95th
29.4
0.8
Simpson 2007 34266
1.5/1000
99th
13.5*
3.3
Sananes 2010 12910
3.4/1000
95th
54.5
8.4
Increased NT and the risk of CHD
•
•
Initial estimation somewhat optimistic
•
•
Studies differ in use of 95th vs 99th %
•
Makrydimas et al, AJOG, 2003, “Screening
performance of first trimester nuchal translucency
for major cardiac defects: A meta-analysis”
Sensitivity 31% (99th), 37% (95th)
•
for any given defect, 25-50% of fetuses exhibited
↑NT
Superior to traditional reasons for echo referral,
including abnormal 4CV (26%)
Risk of CHD as a function of NT measurement
Prevalence of CHD/1000 euploid fetuses vs NT measurement
Prevalence CHD/1000 euploid fetuses
700
643
600
500
400
300
150
200
100
0
3
15.5
33.5
1.0-2.5
2.5-3.5
3.5-4.4
190.5
74.8
4.5-5.4
NT meas (mm)
5.5-6.4
6.5-8.4
>8.5
Why is the NT increased in CHD?
1. ? overt cardiac failure
2. ? abnormal DV Doppler profile/reversed ‘a’
wave
3. ? transient cardiac dysfunction
4. ? tricuspid regurgitation
Bottom Line: No adequate explanation
Assessment for CHD in ↑NT fetuses
- NT >3.5- found in ~1% of pregnancies
- high risk for CHD
- should have echo ideally at time of NT scan and again later
in the second trimester
- NTs between 95 & 99th percentiles- found in ~4%
- overall risk of CHD roughly 2%
- similar to background risk in IDDM, FHx CHD
- “extent to which echo is offered depends on
accessibility” (ISUOG)
No evidence of TR
-short reverse spike = closure of valve cusp
-jet produced by pulmonary arterial flow
(<50cm/s)
Tricuspid Regurgitation
-regurgitation during 1/2 of systole with
velocity >80 cm/s
}
Normal ‘a’ wave
Reversed ‘a’ wave
So what does this mean for CHD?
↑NT population: risk further modified
Overall Risk
a-wave normal
a-wave reversed
Overall Risk
No TR
+ TR
50
70
60
40
Percentage
Percentage
50
30
20
40
30
20
10
0
10
3
4
5
NT in mm
>5.5
0
3
4
5
NT in mm
>5.5
Assisted Reproductive Technology
2010 CDC data:
- 147260 IVF cycles
- 61564 newborns
- over 1% of all newborns conceived with ART
- large Western Australia registry- 1993 to 1997
- prevalence of birth defects by 12 mo of age
301 ICSI
837 IVF
4000 SC
ICSI
8.6%
IVF
9.0%
Spont Concep
4.2%
- including pregnancies terminated for abnormalities:
ICSI
8.6%
IVF
9.4%
Spont Concep
4.5%
- effect more pronounced
for singletons alone
- twin effect, zygosity
- “infants born as a result of assisted reproductive
technology were more than twice as likely as naturally
conceived children to have major birth defects”
2005 - Two large
meta-analyses
Int J Epidem 2005
Hum Reprod 2005
ICSI vs IVF:
- “weak evidence of an increased risk of major birth
defects as compared with standard IVF”
- “the microinjection procedure used in ICSI does not
represent a large increase in risk of birth defects in
addition to the risks involved in IVF in general”
- subanalyses of 5 categories of defects, including
cardiac, had limited power to detect differences
IVF, ICSI vs SC
- 25 studies; pooled results
- subset of 7 studies; population based with large
sample size, clear definition of birth defect,
ascertainment without knowledge of conception status
- statistically significant increased risk of birth defects
in infants conceived with ART of the order of 30-40%
Biological Plausibility?
- factors associated with ART that may increase the
risk of defects:
- underlying cause of infertility
- procedure related
- freezing, thawing of embryos
- delayed fertilization of oocytes
- culture media composition
- medications used for ovulation induction
NEJM 2012
- “is excess of defects seen after IVF/ICSI attributable
to patient characteristics rather than treatment, and is
the risk similar across all technologies and therapies?”
- large population based registry, >300,000 births
- included data on terminations for anomalies
- assessed risk by system affected by defect
Overall:
After any ART- significantly increased risk; 8.3% vs 5.8%
- significantly increased ORs for cardiovascular,
musculoskeletal, GI, urogenital, multiple defects
- effect not seen with twins
- risk lower with frozen embryos than fresh
- increased risk with infertility, IUI, clomiphene
- after multivariate adjustment, “the association
between IVF and the risk of birth defects was no
longer significant, whereas the increased
risk....associated with ICSI remained significant.”
- CHD cases vs malformed controls for which no
associations with ART are reported
- assessed subcategories of CHD
- Combination of IVF + ICSI exposure:
1.5x increase in CHD without aneuploidy
1.7x increase when VSDs excluded
Exposure to ART:
Controls:
3.6%
CHD/no aneupl:
4.9%
CHD/no aneupl
excl VSD:
5.0%
- Specific statistically significant associations of ART with:
- malformations of outflow tracts and ventriculoarterial connections
- cardiac neural crest defects/DORV
- Combination of IVF + ICSI:
OR- 1.8
OR- 1.7
ART- Summary:
- overall, associated with a 30-40% increase in structural
anomalies, of which cardiac is highly represented
- though inconsistent through all studies, risk of
ICSI exposure may be higher than IVF alone
- specific associations may exist between ART and
subcategories of CHD
Twin Gestation
more than one embryo
early splitting of single embryo
Dizygotic
Monozygotic
Dichorionic Diamniotic
Dichorionic Diamniotic
Monochorionic
Monoamniotic
Monochorionic
Diamniotic
DC/DA
MC/DA
MC/MA
Twin Perinatal Mortality
4
4
Perinatal Mortality %
3
3
2.5
2.4
2
1
0
Singleton
All Twins
Monochorionic
Dichorionic
Excess mortality almost exclusively due to monochorionic twins
Monochorionic Twins:
- increased risk of all structural abnormalities, which
contributes significantly to excess perinatal risk
- specifically carry an increased risk of CHD
- MC twins complicated by TTTS- at even greater risk
-flow related abnormalities, RVOT obstruction abnormalities
- almost universal presence of placental anastomoses,which
may change flow dynamics even without severe TTTS
Literature Review of CHD in Monochorionic Diamniotic Twins
Bahtiyar, et al; J Ultrasound Med, 2007
- 9-fold increase in CHD in MC/DA twins
- when complicated by TTTS, 13-14-fold increase
- overall, VSD most common lesion
- when TTTS present, PS and ASD significantly
increased
- based on this review, 12 sets (24 fetuses) of MC twins
would need to undergo echo to detect 1 case
- increased aortic and pulmonary velocities in recipient
twin vs co-twin or unaffected MC/DA pregnancies
- recipient- 57% RV hypertrophy, 24% significant TR
- increased vasoactive substances, including endothelin-1
and VGEF, contribute to RVOT obstructions/PS
- endothelin-1 highest in fetuses requiring balloon valvuloplasty
Hidaka, et al; J Perinat Med 2007:
- 87 MC twin pairs; 11 discordant for CHD
- in all cases affected twin was the smaller one
Manning et al; Prenat Diag 2006:
- 165 MC twin pairs
9.1%
CHD in at least
one twin
7.0% MC/DA
57.1% MC/MA
- if 1 twin affected, risk to other twin is 26%
AlRais et al, Prenat Diag 2011:
- 356 MC twin pairs; 29 discordant for CHD
laterality, heterotaxy
valvar dysplasias in TTTS recipients
conjoining
ventricular hypoplasia
other- conotruncal
14%
24%
21%
14%
27%
Risk Factors for Heart Disease Associated with Abnormal Sidedness
Kuehl, Teratology 2002
- OR 4.8 for isomerism/heterotaxy disorders in monozygotic twin
gestations
? Chorionicity
? Zygosity
- roughly 30% of same-sex DC/DA twins will be monozygous
“Congenital heart disease in a population of
dizygotic twins: an echocardiographic study”
Caputo et al, Int J Cardiol; 2005
- incidence of CHD in co-dizygotic twin vs full sibling
- designed to test twinning vs monozygosity as risk
Recurrence risk in
non-twin sibling:
4%
Risk in Co-DZ twin:
13.6%
higher recurrence and concordance of CHD found in dizygotic
twins than in non-twin siblings
Twins- Summary
- monochorionic twins are at increased risk overall of
structural abnormalities, especially cardiac, by a factor of 9
- specific risks associated with TTTS- including RVOTO and
PS in the recipient- which may be partly related to
angiogenic factors such as endothelin-1 and VEGF
- issue of chorionicity vs zygosity poorly studied; twinning
itself may increase risk even in the absence of
monozygosity, and monozygosity has been poorly studied
when accompanied by dichorionicity
Obesity
- >1/3 of US adults (37.5%) are obese (CDC, 2012)
African Am- 49.5%
Hispanic- 39.1%
Caucasian- 34.3%
JAMA 2010
JAMA 2009
- 18 articles included in meta-analysis, 9400 cases of CHD
- obese mothers at significantly increased risk of CHD
overall with an OR of 1.3
- OR highest for “septal anomaly”, but also association
present for TGA
Am J Clin Nutr 2010
- population based cohort study, 1.5 million births
7329 CHD
56304 Controls
- type of CHD, maternal BMI, other risk factors
Adjusted analysis:
- both obesity and morbid obesity strongly associated with
CHD
- Statistically increased risk for:
All CHD
All LVOTO
All RVOTO
All Conotruncal
ASD
PS
TOF
VSD
HLHS
DORV
Aortic Stenosis
- BMI at which increase noted = 30; OR become greater as
BMI increases
Prepregnancy Body Mass Index and Congenital Heart
Defects Among Offspring: A Population-Based Study
Madsen et al, Congenit Heart Dis, 2012
1.5
- 14142 cases of CHD
identified 1992-2007
- infants with CHD more
likely to have obese mother
(OR 1.22)
1.49
1.25
1.25
1.16
1
0.75
0.5
0.25
- marked association for HLHS with OR 1.86
- also strong association for R and LVOTOs
0
30-35
35-40
>40
Association Between Prepregnancy Body Mass Index and
CongenitalHeart Defects
Gilboa et al, Am J Obstet Gynecol 2010
6440 CHD
5673 Controls
Overweight
Mod Obese
Severely Obese
1.16 OR
1.15 OR
1.31 OR
- specific phenotypes include conotruncal (TOF),TAPVR, HLHS,
RVOTO, septal defects
Combined Adverse Effects of Maternal Smoking and High
Body Mass Index on Heart Development in Offspring:
Evidence for Interaction?
Baardman et al, Heart, 2012
- 797 cases of isolated, non-syndromic CHD
- controls- 322 aneuploid fetuses without CHD
Smoking + BMI>25
All septal defects
OR 2.60
OR 2.65 for all
CHD
Outflow Tract Anomalies
OR 3.58
“ interaction between high maternal BMI and smoking contributed
significantly to the occurence of all offspring CHD combined and to
specific subgroups”
Higher CHD Risk
Obesity
Poorer Detection
Unfortunate intersection of common population risk for
CHD and factors that make detection more challenging
Dashe et al, Obstet Gynecol 2009
- retrospective study of over 10000 US examinations, stratified by
class of obesity
Obesity Class
Standard US
Targeted US
Normal BMI
66
97
Overweight
49
91
Class I
48
75
Class II
42
88
Class III
25
75
Impact of Maternal Obesity and Maternal Overweight on
the Detection Rate of Fetal Heart Defects and the Image
Quality of Prenatal Echocardiography
Uhden et al, Ultraschall Med, 2011
- retrospective cohort, 54000 pregnancies
- prevalence of CHD significantly higher in overweight/
obese women with a RR of 2.04
- substantial decrease in image quality with increasing
BMI
- up to 20% difference in detection rate
Obesity- Summary
- common population characteristic that increases risk
for CHD
- may co-exist with other risks (IDDM, etc) but likely also
represents it’s own a-priori risk; synergy with other
environmental factors like smoking may further increase
risk
- added *bonus* of technical difficulty and decreased
detection rate
- likely prohibitive re: resources and cost to offer echo, but
should be considered
END