Risk Factors for CHD- Indications for Fetal Echo Revisited

Risk Factors for CHD- Indications for Fetal Echo RevisitedAmy Svenson, MDDivision of Pediatric CardiologyArizona Pediatric Cardiology ConsultantsPhoenix Childrens HospitalPhoenix, Arizona

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Screening for CHDCongenital 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 lowAt 20 weeks gestation, the fetal heart is a little bigger than the size of a quarter

Screening for CHDCardiac anomalies are among the most frequently missed congenital malformations and rely heavily on the expertise of those performing the examThose specialized physicians performing and interpreting detailed fetal echocardiograms can detect nearly all cases of CHD, but they are a very limited resourceThus, much research has gone into identifying markers for CHD outside of the detailed fetal echocardiogram Screening for CHDMaternal patients may be referred for a detailed fetal echocardiogram by a qualified specialist if:the basic screening ultrasound is abnormalConcern for structural heart defectConcern 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 populationWhich patients are considered to be at increased risk and thus should be referred for a detailed fetal echocardiogram?Fetal indicationssuspected cardiac anomaly or abnormal cardiac axis incomplete cardiac evaluation on OB screening ultrasoundUnexplained polyhydramnioschromosomal abnormalities extracardiac abnormalities Arrhythmias (50% of fetuses with CHB have complex CHD)non-immune fetal hydrops (15-20% are of cardiac etiology)increased nuchal translucencyMonochorionic twins 7Maternal teratogens (Isotretinoin, lithium, phenytoin, VA, trimethadione, carbamazepine)Maternal indicationsMaternal metabolic disordersPre-gestational diabetes or early onset diabetes during pregnancy6-10% congenital malformation rate, of which 40-50% are cardiacStructural defects (TGA, DORV, VSD, heterotaxy syndrome)Hypertrophic cardiomyopathy (late 2nd or 3rd trimester) Maternal PKU (7 fold increase in CHD)

Maternal indicationsAutoantibodies (anti-Ro/SSA and anti-La/SSB) associated with Sjogren syndrome (40-95%) and SLE (15-35%)1-2% risk of complete heart blockRecurrence risk of 15-20%Pregnancies conceived with assisted reproductive technology (ART)Exposure to known teratogens or certain medicationsFamilial indicationsFamily history of CHD in a first degree relative 2-3% recurrence risk if a sibling has CHD2% recurrence risk if dad has CHD5-10% recurrence risk if mom has CHDLeft heart obstructive lesions appear to have a higher recurrence risk

Familial IndicationsInheritable genetic syndromeTuberous 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 2014Assisted Reproductive Technology

ARTFertility related services (artificial insemination, inductors of ovulation)Removal of a womans eggs from her body, mixing them with sperm to make an embryo, and then reintroduce them to the womans bodyIn vitro fertilization/IVF (1978)Intracytoplasmic sperm injection/ICSI (1992)Represents 1% to 4% of births in developed countriesARTFirst infant born to ART was over 30 years ago (1978)CDC started collecting data on ART in the US in1996National data from the CDC on ART in 2010:147,260 total ART procedures47,090 live births= 61,564 infantsART contributed to 1.5% of all US live births in 2010ART contributed to 20% of all multiple births46% of infants conceived with ART are multiples

ARTThe 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 CHDTarabit, K. et al., Euro Heart J, 2011 Utilizing the Paris Registry of Congenital MalformationsCompared 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 ART40% 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 birthART and the risk of CHDSpecific types of CHD were more commonly found in children exposed to ART (IVF and ICSI) including:Malformations of the outflow tractsAbnormalities of the ventricular-arterial connectionsDouble outlet right ventricleART and risk of all birth defectsDavies, M et al., NEJM, 2012Utilized the Australian registry of births and terminations between 1986 and 2002Compared 4 group types for identification of major birth defects up to 5 years of age:ART pregnanciesSpontaneous pregnancy but with a history of a previous ART birthSpontaneous pregnancy but with a history of infertility (no ART)Spontaneous pregnancy with no history of infertilityART and risk of all birth defects8.4% 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 infertilityWhen comparing pregnancies with multiples, there was no significant increase in risk of birth defectsART pregnancies were more likely to have multiple birth defectsSpecifically, the risk for cardiovascular, musculoskeletal, urogenital, GI defects and cerebral palsy had the highest OR.ART and risk of all birth defectsThe 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. experienceKelley-Quon, L. et al., J of Ped Surg, 2013Utilized 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. experienceAfter 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=99th percentile is 19.5% and 99.1% respectivelyThe risk for major CHD is more than 20 times increased if the NT is >99th percentileNT- pooled data

*In general, there was a high heterogeneity in the data setsMaternal obesity

Maternal ObesityData from the National Health and Nutrition Examination Survey, 2011-201234.9% of adults were obese in 2011-2012Highest among middle-aged adults, when compared to younger and older adultsObesity 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, 2012ObesityMaternal obesity has long been linked to an increased risk for infants with neural tube defectsOver the last decade, data is accumulating that also links maternal obesity to infants with CHDObesityMills, J, American Journal of Clinical Nutrition, 2010Maternal BMI in 7,392 infants with CHD and 56,304 controls without major malformations born during 1993 to 2003 in New York StateOverweight defined as BMI 25-29.9Obesity defined as BMI >30, morbid obesity >40Overweight women(BMI 25-30) were not at an increased risk to have a child with CHD

ObesityFindings: Overweight women(BMI 25-30) were not at an increased risk to have a child with CHDall 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 BMI15% 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.

ObesityLui et al., Circulation, 2013Population 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 coding2.3 million infants screened with a prevalence of CHD 10/1,000 (excluding PDAs in preemies) and 2.2/1,000 being severe CHDMaternal conditions evaluated included: age, tobacco use, substance use, obesity, DM, HTN, thyroid disorders, CHD, CAD, anemia, connective tissue disorder, epilepsyObesityCHD 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 associationMaternal 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 SklanskyReferenced from Textbook: Creasy & Resniks Maternal-Fetal Medicine, Chapter 19. Fetal Cardiac Malformations and Arrhythmias- Detection, Diagnosis, Management and Prognosis

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