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Premium member Presentation Transcript Prenatal Risk Factors for congenital anomalies: Prenatal Risk Factors for congenital anomalies December 6, 2011 Dr. Amy Thompson Obstetrics and Gynecology, Generalist Division Dr. Jodi Ragan Obstetrics and Gynecology, Maternal-Fetal Medicine DivisionObjectives: Objectives Discuss the principles of teratology Review common congenital anomalies caused by environmental factors Review the use of medications in pregnancy and those with known teratogenic effects Discuss issues related to maternal substance abuse Fetal Alcohol Syndrome Review congenital anomalies caused by multi-factorial inheritance Neural tube defectsDid you read the assignment?: Did you read the assignment? Yes NoIf you did read the assignment – estimate your level of comprehension: If you did read the assignment – estimate your level of comprehension Enter answer text...What percentage of newborns are born with a single minor anomaly?: What percentage of newborns are born with a single minor anomaly? <1% 14% 25% 50% 75%Of infant deaths in North America, what percentage are due to birth defects?: Of infant deaths in North America, what percentage are due to birth defects? <1% 20% 50% 75% 90%Leading causes of neonatal and postnatal deaths – United States, 2002: Leading causes of neonatal and postnatal deaths – United States, 2002Prevalence of live births in the US with specific birth defects, 1999-2005: Prevalence of live births in the US with specific birth defects, 1999-2005 Table 20-7 Incidence of Major Anomalies at Birth Brain 10:1,000 Heart 8:1,000 Kidneys 4:1,000 Limbs 2:1,000 All other 6:1,000 Total 30:1,000 http://cfpub.epa.gov/eroe/index.cfm?fuseaction=detail.viewInd&lv=list.listbyalpha&r=216634&subtop=381The most common causes of human congenital anomalies are?: The most common causes of human congenital anomalies are? Unknown Multi-factorial Chromosomal Mutant genes Environmental agentsThe causes of human congenital anomalies: The causes of human congenital anomaliesWhen considering the possibility of a teratogenic agent, which important principle must be considered?: When considering the possibility of a teratogenic agent, which important principle must be considered? Critical periods of development Amount of exposure Duration of exposure Genotype All of aboveCritical periods in human prenatal development: Critical periods in human prenatal developmentIncreasing risk of birth defects during organogenesis: Increasing risk of birth defects during organogenesisEnvironmental teratogens known to cause congenital anatomic anomalies include: Environmental teratogens known to cause congenital anatomic anomalies include Infections Drugs Chemicals Radiation All of aboveWhat was the first well-documented environmental agent known to act as a teratogen: What was the first well-documented environmental agent known to act as a teratogen Warfarin Ionizing radiation Thalidomide Rubella virus Toxoplasmosis gondiiInfections: Infections 1941 – Rubella virus first documented case of environmental agent acting as a teratogen. Results in eye defects (glaucoma and cataracts), deafness, cardiac anomalies. Rubella also can cause IUGR and postnatal growth retardation, and mental retardation.Risks of rubella infection during pregnancy: Risks of rubella infection during pregnancy Preconception minimal risk 0-12 weeks 100% risk of fetus being congenitally infected resulting in major congenital abnormalities. Spontaneous abortion occurs in 20% of cases. 13-16 weeks deafness and retinopathy 15% after 16 weeks normal development, slight risk of deafness and retinopathyRubella History: Rubella History History 1881 Rubella accepted as a distinct disease 1941 Associated with congenital disease (Gregg) 1961 Rubella virus first isolated 1967 Serological tests available 1969 Rubella vaccines availableCongenital Infections: Congenital Infections CMV - Cytomegalovirus HSV – Herpes simplex virus Parvovirus B19 Rubella virus Toxoplasma gondii Treponema pallidum Venezuelan equine encephalitis virus Varicella virusFDA Classification of Drugs in Pregnancy: FDA Classification of Drugs in PregnancyWhat percentage of US pregnancies are unplanned?: What percentage of US pregnancies are unplanned? 10% 25% 50% 68% 75%What research methods have been used to document teratogenic risks?: What research methods have been used to document teratogenic risks? Prospective and/or Retrospective approaches Randomized control trials Case reports A&C All of aboveProof of Teratogenicity: Proof of Teratogenicity Prospective approach Must show either the frequency of the anomalies is increased above the spontaneous pregnancy rate Retrospective approach Malformed infants have a history of maternal exposure to the agent more often than normal children Case reports Useful only in agents rarely used and rare anomalies Animal testing Can suggest human risks Must consider dose used More convincing if drug/agent produces same effect in two speciesDrugs known to cause human congenital birth defects: Drugs known to cause human congenital birth defects Alcohol Androgens Aminopterin Cocaine DES – Diethylstilbestrol Isotretinoin Lithium carbonate Methotrexate Phenytoin - Dilantin Tetracycline Thalidomide Trimethadione Valproic acid WarfarinWhich statement is true about maternal alcohol consumption: Which statement is true about maternal alcohol consumptionWhich statement is true about maternal alcohol consumption?: Which statement is true about maternal alcohol consumption? Alcohol can be prescribed to prevent preterm labor The prevalence increased from 1991-1995 The prevalence decreased from 1991-1995 1-2 drinks a week in the third trimester has been determined to be safe Newborn and maternity discharge records report a higher incidence of FAS than do pediatric clinic recordsInstitute of Medicine FAS Diagnostic Criteria - 1996: Institute of Medicine FAS Diagnostic Criteria - 1996 History of maternal alcohol use during pregnancy Excessive drinking characterized by regular intake or heavy episodic drinking Characteristic facial anomalies Growth retardation CNS neurodevelopmental findingsWhich toddler exhibits the features of FAS?: Which toddler exhibits the features of FAS? A B C D All of above A B C DFetal Alcohol Syndrome: Fetal Alcohol Syndrome Facial anomalies Short palpebral fissures Ptosis Flat midface Upturned nose Smooth Philtrum Thin Upper lip Am Fam Physician. 2005 Jul 15;72(2):279-285. Thackray H M , Tifft C Pediatrics in Review 2001;22:47-55Fetal Alcohol Syndrome – Lip/Philtrum Guide: Fetal Alcohol Syndrome – Lip/Philtrum Guide Am Fam Physician. 2005 Jul 15;72(2):279-285.Fetal Alcohol Syndrome: Fetal Alcohol Syndrome Am Fam Physician. 2005 Jul 15;72(2):279-285. Clinodactyly and “Hockey stick” crease “Railroad track” earCharacteristic findings of children exposed to alcohol in utero: Characteristic findings of children exposed to alcohol in utero Facial Anomalies Growth retardation Low relative birthweight Growth retardation despite adequate nutrition Low weight relative to height Birth defects (including, but not limited to) Congenital heart defects Skeletal and limb deformities Renal abnormalities Opthalmologic abnormalities Cleft lip/palate CNS Neurodevelopmental findings Microcephaly Structural brain abnormalities Agenesis of corpus callosum cerebellar hypoplasia Other neurologic signs Fine motor difficulties Sensorineural hearing loss Poor gait coordination Poor eye-hand coordination Thackray H M , Tifft C Pediatrics in Review 2001;22:47-55Behavioral Abnormalities Associated with FAS: Behavioral Abnormalities Associated with FAS Learning disabilities Poor school performance Poor impulse control Problems with social perception Poor language abilities Poor abstract reasoning Poor math skills Impaired memory and judgement Thackray H M , Tifft C Pediatrics in Review 2001;22:47-55What is the proposed pathogenesis for the clinical findings of FAS?: What is the proposed pathogenesis for the clinical findings of FAS? Free radical formation Excessive cell death in midline of embryo Maternal nutrient mal-absorption Use of other illicit substances with alcohol All of abovePowerPoint Presentation: Thackray H M , Tifft C Pediatrics in Review 2001;22:47-55 ©2001 by American Academy of Pediatrics 9 months 5 years 14 yearsPowerPoint Presentation: Thackray H M , Tifft C Pediatrics in Review 2001;22:47-55 ©2001 by American Academy of Pediatrics 5 years 9 yearsPreventative Medicine: Preventative Medicine Primary prevention Methods to avoid occurrence of disease. [ Most population-based health promotion efforts are of this type Secondary Prevention Methods to diagnose and treat extant disease in early stages before it causes significant morbidity. Tertiary Prevention Methods to reduce negative impact of extant disease by restoring function and reducing disease-related complicationsAlcohol and Pregnancy: Mandatory Warning Signs as of January 1, 2004 : Alcohol and Pregnancy: Mandatory Warning Signs as of January 1, 2004 WARNING: Drinking alcoholic beverages such as beer, wine, wine coolers, and distilled spirits or smoking cigarettes during pregnancy can cause birth defects. http://pathwayscourses.samhsa.gov/ev/ev_3_pg13.htmPrenatal care counseling on alcohol use during pregnancy Pregnancy Risk Assessment Monitoring System (PRAMS) Report New York State excluding New York City, 2000-2008 : Prenatal care counseling on alcohol use during pregnancy Pregnancy Risk Assessment Monitoring System (PRAMS) Report New York State excluding New York City, 2000-2008 During any of your prenatal visits, did any nurse, doctor or other healthcare provider talk to you about how drinking alcohol could affect your baby?Tertiary Prevention: Tertiary Prevention Early diagnosis key Evaluate growth and nutrition Manage medical issues related to birth defects Educational evaluation and use of community resources Improve family support in impaired homes Evaluate all siblings – youngest child most often most severely affectedMulti-factorial Inheritance: Multi-factorial InheritanceProposed Multi-factorial threshold model: Proposed Multi-factorial threshold model Cleft lip Isolated cleft-palate NTD Pyloric stenosis Congenital hip dislocationWhich statement is true about neural tube formation?: Which statement is true about neural tube formation? Completed by the end of the 4 th embryonic week Defects in neural tube closure are among the most common congenital anomalies Neural tube formation is a complex cellular process involving a cascade of factors Is considered complete once closure of the cranial neuropore has occurred A, B, C are correctNeural Tube Defects: Neural Tube Defects Failure of portion of neural tube to close or a re-opening of region after successful closure Involve some combination of neural tissue, meninges, overlying bone, or soft tissues Encephalocele Diverticulum of malformed tissue through cranium Typically occipital or posterior fossa location Spinal dysraphism (Spina bifida) Most common and involve caudal portion of neural tubeIncidence of NTD: Incidence of NTD British Isles 4.5-5/1000 Decreases with immigration to US Ireland/Scotland/Wales 7.8/1000 Decreases with immigration to US United States 1.5-2/1000 Lower for African or Asian ancestry Recurrence risks 2-3% for second child of couple with one affected child 5% for third child of couple with two affected childrenProposed mechanisms for defects: Proposed mechanisms for defects Folate deficiency during initial weeks of gestation Decreased dietary intake Decreased conversion to mono-glutamate form by pancreatic conjugases Polymorphisms in enzymes of folic acid metabolismFolic Acid: Folic Acid Water soluble vitamin Widely available in the diet Absorbed in proximal jejunum Reduced to mono-glutamate form by pancreatic conjugases These are reduced by anti-convulsants, OCP’s, sulfa drugs, and alcoholFolic Acid Supplementation Guidelines: Folic Acid Supplementation Guidelines Although many foods are rich in folate, all interventional studies have used supplemements Folic acid supplements and fortified foods are more bio-available at cellular level Not subject to inactivation with cooking FDA - Recommended Daily Allowance 400 m g of dietary folate – non-pregnant 1 m g of dietary folate = 0.5 m g folic acid on an empty stomach = 0.6 m g folic acid take with mealsFolic Acid Supplementation Guidelines: Folic Acid Supplementation Guidelines Institute of Medicine 400 m g of synthetic folic acid daily, in addition to diet rich in folate High risk pregnancies (family history or medication) 4 mg folic acid daily Do not simply take 10 prenatal vitaminsSpinal Dermal Sinus: Spinal Dermal SinusSpina bifida cystica: Spina bifida cysticaDiagnosis of Neural Tube Defects: Diagnosis of Neural Tube Defects Antenatal Screening Use of Maternal Serum to screen for NTD was the first attempt at screening for congenital anomalies 95% of defects occur in families without risk factors Detection before 1980 was largely fortuitous Alpha-fetal protein Normal pregnancies – will be low in maternal serum Spina bifida and anencephalic pregnancies have increased leak into amniotic fluid from open defects. UltrasoundNormal Fetal Spine: Normal Fetal Spine http://www.ultrasound-images.com/fetal-spine.htmMeningocele: Meningocele http://www.ultrasound-images.com/fetal-spine.htmRisks associated with lumbosaccral myelomeningocele include: Risks associated with lumbosaccral myelomeningocele include 40% risk of neonatal death Problems with bladder/bowel function and lower extremity paralysis Upper extremity paralysis Hydrocephalus with Arnold-Chiari II malformation and need for CSF shunt Both B&DWhich was a reported finding of the MOMS study?: Which was a reported finding of the MOMS study? Decreased rates of shunt placement in prenatal repair group Increased rates of ambulation without devices in prenatal repair group Decreased cognitive function scored in post-natal repair group Increased rates of preterm delivery for both groups, especially before 30 weeks gestation No difference in maternal or pregnancy complications between groupsMOMS: MOMS Inclusion criteria Singleton pregnancy Myelomeningocele between T1 and S1 Evidence of hindbrain herniation Gestational age 19-25.9 weeks Normal karyotype US resident Age>18 years Exclusion criteria Fetal anomaly unrelated to NTD Severe kyphosis Risk of preterm birth Placental abruption BMI ≥ 35 Contraindication to surgery Previous hysterotomyMOMS Outcomes: MOMS Outcomes Primary outcome Fetal or neonatal death 2 perinatal deaths in each group Need for CSF shunt by 12 months of age 40% versus 80% Secondary outcomes Bayley Mental Development Index – difference between functional and anatomical lesion at 30mos Prenatal group more likely to have function 2 or more levels better than expected compared to post-natal goup.Important Take Home Points: Important Take Home Points Pre-conception counseling is important Review prescribed medications Discuss substance abuse Prenatal Vitamins and Folic Acid supplementation Early prenatal care is important Review prescribed medications Screen and counsel on substance abuse Antenatal screening for congenital anomalies via serum screens and imaging You do not have the permission to view this presentation. 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