Teratogens AM Report: August 1, 2007 Sarah, Rachana, Diana Periods of Sensitivity During Development Case Vignette You are called to the newborn nursery to evaluate a baby who has dysmorphic features. The baby was born at term. He has a wide anterior fontanelle, a broad depressed nasal bridge, short nose, hypertelorism, and hypoplastic nails. On auscultation of his heart, you appreciate a holosystolic murmur. What is the teratogen? Dilantin Exposure in utero Fetal Hydantoin Syndrome • Affects ~10% of babies born to moms on phenytoin • May alter placental tx of Vit K and metabolism of Vit D Hemorrhagic Disease of Newborn/ Hypocalcemia remain small after birth • Growth: IUGR • Craniofacial anomalies: microcephaly, midface hypoplasia (broad depressed nasal bridge, short nose), cleft lip/palate, hypertelorism, short neck, ophthalmologic abnormalities • Cardiac anomalies: pulmonic/aortic valve stenosis, VSD • Neurodevelopmental Abnormalities: DD/MR • Other: hirsutism, hypospadias, hypoplasia of distal phalanges and nails, digitalized thumbs, rib anomalies • A preterm baby whose prenatal US were significant for IUGR is born. She is LBW and microcephalic. The baby has seizures on day 2 of life and head imaging reveals evidence of stroke. What is the teratogen? COCAINE !!! Gastroschisis secondary to maternal cocaine abuse COCAINE • Crosses placenta and concentrates in amniotic fluid • Associated with: - placental abruption - PROM & preterm delivery - gastroschisis - vascular malformations - microcephaly - neurobehavioral and learning disorders What is the teratogen? • You are called to evaluate an infant in the NICU with contractures, lung hypoplasia, and craniofacial defects. Similarly, the infant has renal tubular dysplasia, PDA, and had prolonged neonatal hypotension. Answer: ACE Inhibitors! ACE Inhibitors and the Second and Third Trimesters • Most common effects involve kidney, oligohydramnios, in-utero death, anuria, and renal failure • Other effects include hypocalvaria, lung hypoplasia, and limb contractures • ARBs demonstrate similar fetal outcomes How do ACE inhibitors cause adverse fetal effects? • ACE inhibitors and ARBs cross placenta and interfere with fetal renal hemodynamics • ACE inhibitor-induced decline in GFR in fetal kidneys leads to decreased urine production and oligohydramnios • Results: limb contractures, lung hypoplasia, cranial ossification defects, renal tubular dysplasia, prolonged hypotension, and PDA Case Vignette A mother brings in her newborn for her first visit after being discharged from the hospital. On exam, the baby has epicanthal folds, a broad nasal bridge, anteverted nostrils, a long philtrum and a small mouth. Knowing the mother’s medical history, you are especially concerned for a teratogenic exposure as a cause for the baby’s dymorphic features. What is the teratogen? Valproic Acid exposure in utero Fetal Valproate Syndrome • Craniofacial Anomalies: high forehead, epicanthal folds, broad nasal bridge, anteverted nostrils, long philtrum, small mouth, cleft lip, microcephaly • Cardiac Anomalies: Coarctation of aorta, HLHS, aortic valvular stenosis, ASD, VSD • Neurodevelopmental Abnormalities: Neural tube defects, DD/MR • Other: Long thin digits, hyperconvex nails, hypospadias Case Vignette This medication was initially introduced in the mid-1950s as a mild sedative to help combat nausea. It was taken off the market in the 1960s due to unexpected effects on fetuses. The deformity it best known to cause is phocomelia. What is the teratogen? Thalidomide Exposure in utero Thalidomide Baby • Increased risk of miscarriage • Limb defects: symmetric preaxial limb defects, phocomelia (long bones of limb are shortened or completely absent); upper limb > lower limb) • Craniofacial anomalies: developmental abnormalities of the ear and eye (deafness, coloboma), and abnormalities of innervation of the external ocular muscles, the facial muscles, and the tear glands (crocodile tears: tears produced at inappropriate times, i.e. while eating) • Internal organ defects: many affect any organ system • Neurodevelopmental Defects: DD/MR, seizure d/o, behavioral d/o, involuntary movements Case Vignette A newborn is evaluated for a heart murmur and found to have a VSD. History is notable for lack of prenatal care. At the time of delivery ultrasound evaluation showed IUGR. On exam the child is noted to have symmetric growth retardation, small palpebral fissures, thin upper lip, and underdeveloped philtrum. What is the teratogen? Alcohol !! Fetal Alcohol Syndrome To Diagnose • • • • Confirmed maternal EtOH exposure Characteristic facial anomalies Growth retardation CNS neurodevelopmental findings Characteristic Findings of FAS • Facial: short palpebral fissures, flat midface, upturned nose, smooth philtrum, thin upper lip, ptosis (later) • Growth Retardation: SGA, poor growth postnatally • Neurodevelopmental: Microcephalic, structural brain anomalies, hypotonia, irritable/poor bonding • Behavioral Abnormalities: LD, MR (mean IQ 66), ADHD • Congenital Defects: CHD (VSD), skeletal deformities, ophthalmologic problems, hypoplasia of nails Case Vignette You are called to deliver a newborn of mother who did not receive any prenatal care. At the time of delivery, the baby is found to have a myelomeningocele and dysmorphic facial features. What is the teratogen? Carbamazepine Exposure in utero Carbamazepine Exposure • May alter placental tx of Vit K and metabolism of Vit D Hemorrhagic Disease of Newborn/ Hypocalcemia • Craniofacial Defects • Neurodevelopmental Abnormalities: NTD, DD/MR • Other: Nail Hypoplasia • A pregnant female has an eating disorder and is regularly using a “diet pill” throughout pregnancy. The baby is born preterm and noted to be irritable, jittery, and with a high pitched cry. What is the teratogen? Amphetamines • • • • • Preterm delivery IUGR and SGA Placental abruption Withdrawal symptoms Congenital heart disease What is the teratogen? • You are in your continuity clinic and see a patient with Ebstein’s anomaly. What question should you ask the infant’s mother about her medical history? Ebstein’s Anomaly Answer: Lithium Summary: Lithium • Lithium has no documented association with fetal development • Soft evidence exists that it is associated with Ebstein’s anomaly • Pregnancy class D: evidence of risk, but benefits to mother may outweigh risks to fetus What is the teratogen? • You are in the GCN, and you are called to evaluate a 5-day-old infant. You are concerned because he is tremulous, has a high-pitched cry, poor feeding, and diarrhea. Answer: Heroin…Or Other Opioids Neonatal Narcotic Abstinence Syndrome • • • • • • Tremors Irritability Increased wakefulness High-pitched crying Increased muscle tone Hyperactive deep tendon reflexes • Exaggerated Moro • Seizures • Frequent yawning and sneezing • Poor feeding • Uncoordinated and constant sucking • Vomiting and diarrhea • Poor weight gain • Nasal stuffiness • Fever • Mottling • Temperature instability Case Vignette The anxious parents of a 7 day old baby bring her back to see you with the concern that she has been acting different for the last 2 days. They report restlessness, jitteriness, and an insatiable hunger. They also report that she has been difficult to console and has been sleeping less than usual. At the time of birth, she was noted to have a cleft lip but otherwise has been healthy. What is the teratogen? Phenobarbitol Exposure in utero Phenobarbitol Exposure • Exposure during 3rd trimester is most detrimental • May alter placental tx of Vit K and metabolism of Vit D Hemorrhagic Disease of Newborn/ Hypocalcemia • Craniofacial Defects: Cleft Lip/Palate • Cardiact Defects • Neurodevelopmental Abnormalities: Risk of withdrawal presenting at DOL ~4-7. Sx include: overactivity, restlessness, insomnia, tremors, hypertonicity, vasomotor instability, and hyperphagia. Withdrawal sx may last up to weeks or months. What is the teratogen? • You are called to evaluate an infant in the NICU with microcephaly, microphthalmia, microtia with atresia of the ear canal, truncus arteriosus, and an absent thymus. What medicine do you think that the mother took during pregnancy? Microtia and Truncus Arteriosus Answer: Isotretinoin Summary: Isotretinoin • Ear anomalies: microtia with or without atresia of the ear canal • CNS malformations: hydrocephalus, neuronal brain migration defects, cerebellar abnormalities • Severe MR • Seizures • Dysmorphic features • Absent thymus • Truncus arteriosus • Pregnancy class X: contraindicated in pregnancy What is the teratogen? • You are in the GCN and note one of the newborns has a depressed nasal bridge, a short nose, and hypoplastic distal phalanges. You have x-ray vision, and you also see stippling of his epiphyses. Depressed Nasal Bridge and Short Nose Answer: Warfarin Summary: Warfarin • Teratogenic effects during 6th-9th week • Most common effects are on bone and cartilage • Mechanism of teratogenicity may be related to drug’s interference with posttranslational modifications of calciumbinding proteins that are key to the development of bony structures Summary: Warfarin • Less well-documented risks during any stage of pregnancy – Optic atrophy – Microcephaly – MR – Spasticity – Hypotonia • Pregnancy risk factor X: contraindicated in pregnancy Neonatal Abstinence Scores • Used to initiate, adjust, and wean pharmacologic therapy. • Domains of scoring system – Vasomotor, metabolic, and ventilatory disturbances – CNS disturbances – Gastrointestinal disturbances A full term baby is born SGA and with a cleft lip. Mom did not have any infections during pregnancy and had regular PNC. Her ultrasounds consistently demonstrated poor prenatal growth. She denies illicit drug use. Family history is notable for a 4 mo old sibling who died from SIDS. What is the most likely cause of the newborn’s findings? TOBACCO !!! Tobacco exposure • Poor prenatal growth: - Dose related - symmetric - up to 5% weight reduction for every pack per day smoked • SGA • Cleft lip & palate • Placental abruption • Associated with SIDS