Risk Factors for CHDIndications for Fetal Echo Revisited Amy Svenson, MD Division of Pediatric Cardiology Arizona Pediatric Cardiology Consultants Phoenix Children’s Hospital Phoenix, Arizona None 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 18-20 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 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 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 Which patients are considered to be at increased risk and thus should be referred for a detailed fetal echocardiogram? 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 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) 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 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 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 APCC experience *Database collected and managed by Lynn Litwinowich, APCC fetal nurse coordinator, from January 2011 to January 2014 Assisted Reproductive Technology 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 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 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 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 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 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: 1. ART pregnancies 2. Spontaneous pregnancy but with a history of a previous ART birth 3. Spontaneous pregnancy but with a history of infertility (no ART) 4. Spontaneous pregnancy with no history of infertility 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. 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. ART- the U.S. experience Kelley-Quon, L. et al., J of Ped Surg, 2013 • Utilized the California Infant and Maternal Birth Cohort Dataset (2006-2007) • 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 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) 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 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 28-30 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 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 Nuchal Translucency Nuchal Translucency • Hypoechogenic fluid between the skin and the subcutaneous tissue that covers the cervical spine in all fetuses • Seen on ultrasound at 11-14 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 Nuchal Translucency 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 11-14 week fetus • 99th percentile is ~3.5mm 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. 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 10-14 weeks gestation 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 Nuchal translucency Hyett et al. continued 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 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 NT- pooled data *In general, there was a high heterogeneity in the data sets Maternal obesity Maternal Obesity Data from the National Health and Nutrition Examination Survey, 2011-2012 • 34.9% of adults were obese in 2011-2012 • 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 Imaging for a BMI of 20 Imaging for a BMI of 65 Adult Obesity Rate by State, 2012 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 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 25-29.9 • 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 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. Obesity Lui et al., Circulation, 2013 • Population based cohort study of all live births in Canada 2002 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 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) “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” THANK YOU!