1. Risk Factors for CHD- Indications for Fetal Echo Revisited
Amy Svenson, MD
Division of Pediatric Cardiology
Arizona Pediatric Cardiology Consultants
Phoenix Children’s Hospital
Phoenix, Arizona

2. None

3. Screening for CHD
Congenital heart disease continues to be the most common congenital malformation, at a rate of ~8/1,000 live births.
Most cardiac defects are screened for on the routine week anatomy scan by the OB, but the rates of detection of CHD remain low
At 20 weeks gestation, the fetal heart is a little bigger than the size of a quarter

4. Screening for CHD
Cardiac anomalies are among the most frequently missed congenital malformations and rely heavily on the expertise of those performing the exam
Those specialized physicians performing and interpreting detailed fetal echocardiograms can detect nearly all cases of CHD, but they are a very limited resource
Thus, much research has gone into identifying markers for CHD outside of the detailed fetal echocardiogram

5. Screening for CHD
Maternal patients may be referred for a detailed fetal echocardiogram by a qualified specialist if:
the basic screening ultrasound is abnormal
Concern for structural heart defect
Concern for abnormal heart rhythm
there is a recognized risk factor that raises the likelihood of congenital heart disease beyond what is expected in the low risk population

6. Which patients are considered to be at increased risk and thus should be referred for a detailed fetal echocardiogram?

7. Fetal indications suspected cardiac anomaly or abnormal cardiac axis
incomplete cardiac evaluation on OB screening ultrasound
Unexplained polyhydramnios
chromosomal abnormalities
extracardiac abnormalities
Arrhythmias (50% of fetuses with CHB have complex CHD)
non-immune fetal hydrops (15-20% are of cardiac etiology)
increased nuchal translucency
Monochorionic twins
Maternal teratogens (Isotretinoin, lithium, phenytoin, VA, trimethadione, carbamazepine)

8. Maternal indications Maternal metabolic disorders
Pre-gestational diabetes or early onset diabetes during pregnancy
6-10% congenital malformation rate, of which 40-50% are cardiac
Structural defects (TGA, DORV, VSD, heterotaxy syndrome)
Hypertrophic cardiomyopathy (late 2nd or 3rd trimester)
Maternal PKU (7 fold increase in CHD)

9. Maternal indications
Autoantibodies (anti-Ro/SSA and anti-La/SSB) associated with Sjogren syndrome (40-95%) and SLE (15-35%)
1-2% risk of complete heart block
Recurrence risk of 15-20%
Pregnancies conceived with assisted reproductive technology (ART)
Exposure to known teratogens or certain medications

10. Familial indications Family history of CHD in a first degree relative
2-3% recurrence risk if a sibling has CHD
2% recurrence risk if dad has CHD
5-10% recurrence risk if mom has CHD
Left heart obstructive lesions appear to have a higher recurrence risk

11. Familial Indications Inheritable genetic syndrome
Tuberous sclerosis (intracardiac tumors)
Marfan syndrome (AV valve abnormalities, dilated root, CM)
Ellis-van Creveld syndrome (AV canal, coarc, HLHS)
Noonan syndrome (pulmonary stenosis, HCM)
DiGeorge/velocardiofacial syndrome (TOF, IAA, truncus arteriosus)
Maternal LQTS

12. APCC experience
*Database collected and managed by Lynn Litwinowich, APCC fetal nurse coordinator, from January 2011 to
January 2014

13. Assisted Reproductive Technology

14. ART
Fertility related services (artificial insemination, inductors of ovulation)
Removal of a woman’s eggs from her body, “mixing” them with sperm to make an embryo, and then reintroduce them to the woman’s body
In vitro fertilization/IVF (1978)
Intracytoplasmic sperm injection/ICSI (1992)
Represents 1% to 4% of births in developed countries

15. ART First infant born to ART was over 30 years ago (1978)
CDC started collecting data on ART in the US in1996
National data from the CDC on ART in 2010:
147,260 total ART procedures
47,090 live births= 61,564 infants
ART contributed to 1.5% of all US live births in 2010
ART contributed to 20% of all multiple births
46% of infants conceived with ART are multiples

16. ART
The majority of the more recent population based studies do show a statistically significant increase in birth defects in pregnancies utilizing ART versus natural pregnancies.
Is this increased risk due to the ART protocols themselves or the underlying disturbance leading to a couples infertility?
There are few studies looking at the relationship of specific birth defects and ART

17. ART and the risk of CHD Tarabit, K. et al., Euro Heart J, 2011
Utilizing the Paris Registry of Congenital Malformations
Compared exposure to ART between cases of CHD vs. other malformations in chromosomally normal infants (picked malformations that have not be previously reported to be associated with ART)
4.7% of children born with CHD versus 3.6% of children born with a different malformation (p= 0.008) were exposed to ART
40% increase in the overall risk of CHD without chromosomal abnormalities in children conceived following ART after taking into account maternal age, socioeconomic factors, and year of birth

18. ART and the risk of CHD
Specific types of CHD were more commonly found in children exposed to ART (IVF and ICSI) including:
Malformations of the outflow tracts
Abnormalities of the ventricular-arterial connections
Double outlet right ventricle

19. ART and risk of all birth defects
Davies, M et al., NEJM, 2012
Utilized the Australian registry of births and terminations between 1986 and 2002
Compared 4 group types for identification of major birth defects up to 5 years of age:
ART pregnancies
Spontaneous pregnancy but with a history of a previous ART birth
Spontaneous pregnancy but with a history of infertility (no ART)
Spontaneous pregnancy with no history of infertility

20. ART and risk of all birth defects
8.4% of ART pregnancies vs.. 5.8% of non-ART pregnancies had a major birth defect present (OR 1.47)
The risk is highest for ICSI (OR 1.77) than IVF (OR 1.26)
There is an increased risk of birth defects in pregnancies of women with history of infertility
When comparing pregnancies with multiples, there was no significant increase in risk of birth defects
ART pregnancies were more likely to have multiple birth defects
Specifically, the risk for cardiovascular, musculoskeletal, urogenital, GI defects and cerebral palsy had the highest OR.

21. ART and risk of all birth defects
The increased risk of birth defects for IVF, but not ICSI, became insignificant when adjustments were made for maternal age, maternal conditions in pregnancy, etc.

22. ART- the U.S. experience Kelley-Quon, L. et al., J of Ped Surg, 2013
Utilized the California Infant and Maternal Birth Cohort Dataset ( )
California currently has the highest national rates of infants born after ART (66% ICSI)
No significant increase in birth defects when using fertility related services (ovulation induction and artificial insemination) alone

23. ART- the U.S. experience
After adjusting for maternal and infant factors, there was an overall increase in birth defects associated with ART pregnancies when compared with naturally conceived controls (9% versus 6.6%, p=<0.001)
Specific organs affected:
Eye (0.3% vs.. 0.2%, p= 0.008)
Head and neck (1% vs. 0.7%, p= 0.03)
Heart (4.8% vs. 3%, p= <0.001)
GU (1.5% vs. 1%, p= 0.002)

24. ART- a review of the literature
Simpson, JL, Seminars in Fetal & Neonatal Med, 2014 (in press)
literature review of 50 of the large population based cohort studies to date
Conclusions:
ART is associated with a small increase in birth defects (baseline anomaly rate 2-3% vs. 3-4% for ART, OR 1.3)
No particular organ system seemed disproportionately affected other than sex chromosomal abnormal and hypospadias in ICSI
No additive risk for exist in ART twins compared with non-ART twins

25. ART- long term CV profile
Valenzuela-Alcaraz et al., Circulation, 2014
Prospective cohort study to evaluate 100 ART pregnancies and 100 spontaneous pregnancies
Patients evaluated at weeks prenatally, neonatal (1st month of life), and 6 months of age to comprehensively assess cardiac and vascular function.
Parameters evaluated included: cardiac dimensions, ventricular sphericity index, wall thickness, ejection fraction, stroke volumes, AV valve annular displacement, tissue Doppler

26. ART- long term CV profile
Demonstrated the presence of cardiac and vascular remodeling in fetuses and infants of ART pregnancies
Fetuses conceived by ART showed more globular hearts, increased wall thickness, decreased right longitudinal function, impaired relaxation and dilated atria (but still mostly within normal limits).
These differences persisted after birth

27. Nuchal Translucency

28. Nuchal Translucency
Hypoechogenic fluid between the skin and the subcutaneous tissue that covers the cervical spine in all fetuses
Seen on ultrasound at weeks gestation, and then regresses
Pathophysiology remains unknown, but this is the time period where the fetal lymphatic system is still developing and the placental resistance is high

29. Nuchal Translucency

30. Nuchal Translucency
Strong association with fetal aneuploidy when increased
Non-specific maker for a disturbance in normal early development.
95th percentile measurement increases with GA but is ~ 2.5 mm for an week fetus
99th percentile is ~3.5mm

31. Nuchal Translucency
Thus far in the literature, there is consensus that an increased NT in a fetus with a normal karyotype is associated with an increased risk for congenital heart disease
There also appears to be agreement that the more abnormal the NT measurement is, the higher he risk for a major congenital heart defect.

32. Nuchal translucency Hyett et al., 1999, BMJ
Retrospectively analyzed 29,154 singleton pregnancies with presumed normal chromosomes
Evaluated for major CHD in those pregnancies (and up to one month postnatally) identified to have an NT between 95-99th percentile
55% of fetuses with major CHD were associated with an increased NT at weeks gestation

33. Nuchal Translucency Major CHD occurred in 1.7/1,000 live births
The prevalence of CHD was 0.8/1,000 live births if the NT was <95th percentile but jumps up to 63.5/1,000 if the NT was >99th percentile

34. Nuchal translucency
Hyett et al. continued

35. Nuchal Translucency Sotiriadis, A., Ultrasound Obstet Gynecol, 2013
Pooled all available published data on nuchal translucency and congenital heart defects between Jan 1990 and Dec 2012
20 large studies met inclusion criteria
205,232 total fetuses, 537 fetuses with major CHD and normal karyotypes were screened and evaluated
61% of major CHD cases had an NT <95th percentile (normal)
16% of major CHD cases had an NT between the 95th and 99th percentile
23% of major CHD cases had an NT >99th percentile

36. Nuchal Translucency Conclusions from Sotiriadis et al.:
Sensitivity and specificity of identifying major CHD if the NT is >95th percentile is 44.4% and 94.5% respectively
Sensitivity and specificity of identifying major CHD if the NT is >99th percentile is 19.5% and 99.1% respectively
The risk for major CHD is more than 20 times increased if the NT is >99th percentile

37. NT- pooled data
*In general, there was a high heterogeneity in the data sets

38. Maternal obesity

39. Maternal Obesity
Data from the National Health and Nutrition Examination Survey,
34.9% of adults were obese in
Highest among middle-aged adults, when compared to younger and older adults
Obesity is higher among certain ethnicities: black (47.8%) and Hispanic (42.5%) adults

41. Imaging for a BMI of 20

42. Imaging for a BMI of 65

43. Adult Obesity Rate by State, 2012

44. Obesity
Maternal obesity has long been linked to an increased risk for infants with neural tube defects
Over the last decade, data is accumulating that also links maternal obesity to infants with CHD

45. Obesity Mills, J, American Journal of Clinical Nutrition, 2010
Maternal BMI in 7,392 infants with CHD and 56,304 controls without major malformations born during 1993 to 2003 in New York State
Overweight defined as BMI
Obesity defined as BMI >30, morbid obesity >40
Overweight women(BMI 25-30) were not at an increased risk to have a child with CHD

46. Obesity
Findings:
Overweight women(BMI 25-30) were not at an increased risk to have a child with CHD
all obese women were significantly more likely than normal weight women to have a child with a CHD (OR 1.15)
Found an increasing risk of having a child with CHD with increasing maternal BMI
15% higher risk for all obese mothers having a child with CHD if the BMI was >30 and a 30% higher risk if the maternal BMI was >40.

47. Obesity Lui et al., Circulation, 2013
Population based cohort study of all live births in Canada to 2011 looking the association of maternal conditions and CHD in their offspring.
They were able to separate out very specific maternal conditions and specific types of CHD utilizing ICD-10 coding
2.3 million infants screened with a prevalence of CHD 10/1,000 (excluding PDAs in preemies) and 2.2/1,000 being severe CHD
Maternal conditions evaluated included: age, tobacco use, substance use, obesity, DM, HTN, thyroid disorders, CHD, CAD, anemia, connective tissue disorder, epilepsy

48. Obesity
CHD prevalence was significantly higher among women with chronic medical conditions, and specifically with multifetal pregnancy, DM, CHD and systemic connective tissue disease having the strongest association
Maternal obesity was associated with a 1.5 to 2x greater risk for CHD (consistent with previous studies)

50. “Ultimately, the decision of whom to refer for formal fetal echocardiography should reflect both the perceived likelihood of fetal heart disease and the additional expertise anticipated from referral” - Mark Sklansky
Referenced from Textbook: Creasy & Resnik’s Maternal-Fetal Medicine, Chapter 19. “Fetal Cardiac Malformations and Arrhythmias- Detection, Diagnosis, Management and Prognosis”

51. THANK YOU!