Teratogenic Agents & Pediatric Diseases - Notes PDF

Pediatric diseases o Children are not merely little adults o Children diseases are not merely variants of adult diseases. o Many childhood conditions are unique or at least, take distinctive forms o Diseases originating in the perinatal period are major c...

Pediatric diseases o Children are not merely little adults o Children diseases are not merely variants of adult diseases. o Many childhood conditions are unique or at least, take distinctive forms o Diseases originating in the perinatal period are major cause of morbidity and mortality.  in US congenital defects AND factors associated with events at or immediately after birth are responsible for at least 50% of deaths in children under 1 year of age. Overall frequency is 1 in 33 live births  Fetal: 20 weeks or more of gestation: 5.7 per 1,000 [live births and fetal deaths]  Neonatal: 0-4 weeks: 3.84 /1,000 live births  Infancy < 1 year: 5.79 /1,000 live births  https://www.cdc.gov/nchs/data/dvs/lcwk/lcwk4_hr_2017-508.pdf  Etiology  Genetic 12%-25%: Chromosomal defects and single genes  Environmental 10%-15%: Maternal infections, diseases, exposure to harmful chemical and radiations  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114826/pdf/ehp-119- 878.pdf  Multifactorial inheritance 20-25%  Unknown causes 40%-60%  Developmental = impairment of certain areas of growth typical for a person of that age = abnormal developmental process = malformations, deformations / disruptions  Sequence: multiple anomalies as a result of an initial single aberration:  → neurodevelopmental disorders = conditions that can interfere with the acquisition, retention, or application of specific skills or sets of information. Developmental diseases Depends on the stage in development of the exposure Effects on the different developmental stages o (Pre-)implantation ((1)-2 weeks) & early embryonic (2 - 3 weeks) either the conceptus (embrio) is lost or the non-affected cells are enough to replace and recover with no apparent effect (20% are not surviving) o During late embryonic stage (up to 8 weeks) – formation of the primitive organ systems → malforma ons o Fetal stage (from 9th week after fertilization) – growth and maturation →disrup ons, deformations Dr M Hossu Notes 132  Malformations Failure of a space to close properly o Neural tube defects  Folic acid – major identified deficiency, with B12  Second trimester ultrasound & Alpha-fetoprotein:  Maternal AFP Serum level screening for neural tube defects, Down syndrome, and other chromosomal abnormalities  Anencephaly  usually blind, deaf, unaware of its surroundings, and unable to feel pain.  born with a main brainstem  have almost all the primitive reflexes of a newborn: auditory, vestibular, touch, and pain  Spina bifida  Spina bifida occulta: just osseous defects  Meningocele: herniation of the meninges but not spinal tissue – no/minor neurological symptoms;  Myelomeningocele: herniation of the meninges and spinal tissue → neurological symptoms (sensory & motor loss from affected nerves), Arnold-Chiari malformation,  Complete spina bifida: exposure of nervous tissue without covering membranes – as previous plus infections (meningitis) o Cardiac: ASD or VSD Failure of a tissue to divide o Syndactyly Failure of an embryologic structure to disappear properly o Thyroglossal duct cytst – from thyroid descent o Meckel’s diverticulum – from the vitelline duct or yolk stalk Failure of a tissue or organ to form or develop properly o Agenesis o Aplasia o Hypoplasia o Dysplasia During the fetal period o Failure of an organ or body part grow properly – hypoplasia o Failure of an organ to end up in its proper position – ectopia, dystopia o Failure of an organ to mature properly Dr M Hossu Notes 133  o Deformations – fetus is affected by outside influences, usually occurs during the last few weeks of pregnancy when the fetus can be compressed by the uterine wall. o The Potter Sequence, an example of a deformation event: cascade of events due to lack of amniotic fluid o Failure or the whole organism to grow: Low birth weight baby →described in neonatal section Teratogenic agents causing congenital abnormalities Irradiation, Chemical substances, Infections (maternal), and other Maternal Diseases Irradiation  Mostly ionizing radiation: penetrating high energy radiation  Direct action- changes molecules in the cells  Indirect action- causes formation of free radicals that damage the cells  Effects depending on exposure and timing of the pregnancy  Before implantation: mostly conceptus death  During the first trimester: miscarriage and major genetic and chromosomal  During the later trimesters: miscarriage, still birth, deformation (fibrosis), tumors  Nonionizing radiation - recent studies shows normal light affects development starting from embryonic stage: multifactorial and modulating effects on mouse embryos o Jeon et all. Effects of light wavelength exposure during in vitro blastocyst production on preimplantation development of mouse embryos. Reprod Fertil Dev. 2022 Oct;34(16):1052-1057 o Campugan et all. The effect of discrete wavelengths of visible light on the developing murine embryo. J Assist Reprod Genet. 2022 Aug;39(8):1825-1837 Drugs and chemicals  Thalidomide o introduced in 1956 as a sedative, but it was never tested on pregnant women. o was particularly effective antiemetic & morning sickness → "wonder drug" for insomnia, coughs, colds, and headaches o Neurological defects, Limbs abnormalities: phocomelia, 40% died first year o In November 1961 taken off the market ← led to the death of approximately 2,000 children and serious birth defects in > 20000 children o Still used for treatment of leprosy and some cancers  Alcohol / Fetal Alcohol Syndrome (FAS) o Affects 1 in 100 live births, approximately 40,000 infants born every year o Leading known and preventable cause of mental retardation and birth defects  Also impulse control (aggressiveness) and disconnection of cause-effect o Many more children have Fetal Alcohol Effects (FAE), but not the full blown syndrome o Effect is most likely seen with binge-drinking rather than low level exposures, but the level at which this occurs is unclear Dr M Hossu Notes 134  o NO ALCOHOL DURING PREGNANCY AT ALL  Cigarette smoking during pregnancy o Higher likelihood of abnormalities of the fingers and toes o Increases the risk of miscarriage o Increases the risk of complications o Increases the risk of preterm delivery o Increases the risk of having a low birth weight baby with increased risk of death o Increases the risk of the child developing behavioral problems o Risk is highest when the mother smokes, but a father who smokes also causes an increased risk  Androgens (anabolic steroids / steroids)  Valproic acid – antiepilectic  Retinoic acid o A derivative of vit A – for acne o Absence: malformations affecting multiple organ systems, including the eyes, genitourinary system, cardiovascular system, diaphragm, and lungs o Excess → CNS, cardiac & facial defects (cle lips & palace)  DES (Diethinylstilboestrol) o given to women with a history of repeated miscarriages to prevent a spontaneous abortion. (~ progesterone) o Effect on females who were exposed in-utero included development of a “clear cell adenocarinoma of the vagina”, cervical abnormalities and menstrual and reproductive problems, breast cancer. o Epididymal cysts in males. Maternal infection TORCH syndrome o Causes of the TORCH syndrome  Toxoplasmosis- cat parasite contracted by changing the cat litter box. Mild problem for the mother, but after the fourth month the parasite can cross the placenta and affect the developing fetus.  Others: Syphilis, Zika, etc  Rubella- Congenital rubella was the first described component of the TORCH syndrome. No effect on the mother who has a mild illness, but during the first trimester of pregnancy the virus can affect the embryo and produce devastating effects. No longer seen due to the fact of widespread immunizations (part of the MMR).  Cytomegalovirus- usually an upper respiratory tract infection that doesn’t causes any problems in the mother, but can infect the developing embryo or fetus. This can cause problems even in the third trimester of pregnancy. Dr M Hossu Notes 135   Herpes- This can infect the embryo from the mothers blood, but most cases are from passage through an infected birth canal with active lesions of genital herpes. The infected new born develops a generalized infection that can lead to the changes of the TORCH syndrome → pneumonia, conjunctivitis, meningoencephalitis (→mental retardation). o Components of the TORCH syndrome (Figure 7-3)  Microcephaly  Hepatosplenomegaly, anemia, jaundice,  petechiae, purpurae,  Chorioretinitis or conjunctivitis.  fever, lethargy, difficulty feeding,  The specific infection may cause additional symptoms  TORCH syndrome may develop before birth, causing stillbirth, in the neonatal period, or later in life Syphilis  Fetal syphilis from mother who has secondary syphilis (blood disseminated)  Neonate has secondary syphilis. (before 2nd yoa) o abnormalities, miscarriages, premature births, stillbirths, or death in newborns. o rash, fever, an enlarged liver and spleen, and skeletal abnormalities  saddle nose, lower extremity o mucopurulent discharge from the nose (the snuffles) that is highly contagious. o low birth weight.  Late syphilis (after 2 yoa) tertiary syphilis o may have the stigmata of congenital syphilis such as Hutchinson’s teeth, “saddle nose”, deafness, neurological symptoms (meningitis, tabes dorsalis). HIV  Contracted across the placenta  Contracted by exposure to blood during the labor and delivery  Contracted in breast milk Gonorrhea  contracted by passage through an infected birth canal (many women don’t know they have it)  m/c cause of blindness before use of AgNO3  the baby develops an eye infection known as Ophthalmia Neonatorum. Other maternal disease Diabetes mellitus  Gestational diabetes- diabetes that usually develops in the mother in the last trimester of pregnancy and goes away once the baby is born. Affects 4% of pregnancies in the US. Dr M Hossu Notes 136  o Mother is at risk for complications of pregnancy o Baby is at risk for premature delivery but the baby may still be very large. o The lungs may not be producing surfactant and so the baby can develop NRDS. o The baby is also at risk for rebound hypoglycemia at birth (too much insulin intrauterine for the high glicemia).  Pre-diabetic mother o Mother is at risk for developing complications associated with pregnancy. Her diabetes also becomes much more difficult to control. o Baby is at risk for increased rate of congenital abnormalities, increased incidence of miscarriage and premature delivery. o Arteriolosclerosis of uterine arteries → baby may be of a low birth weight. Hypertension  Pre-existing hypertension  Mother at risk for developing complications associated with pregnancy,  blood pressure management that may put her kidney function at risk  Toxemia of pregnancy o Pre-eclampsia  HBP > 140/90 more than twice 4 hours apart, after week 20, and proteinuria/albuminuria (nephrotic syndrome)  abnormal development of the placenta with poor placental perfusion and poor trophoblastic invasion  → oxida ve stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, vasoconstriction, and end-organ ischemia  → eclamsia  → increased frequency of Caesarean sec on, preterm delivery, and placental abruption.  → Fetal growth restriction/intrauterine growth restriction and potential fetal or perinatal death.  increased risk for recurrence in subsequent pregnancies. o Eclampsia  the onset of seizures (convulsions) in a woman with pre-eclampsia. (tonic-clonic, loss of consciousness, cyanosis,  +/- associated signs: headaches, visual disturbance, photophobia Abdominal pain (epigastric or right upper quadrant)  Risk for both baby & mother: during convulsion diaphragm spasm → no breathing→ hypoxia and ischemia for both, hemorrhages, placental abruption → Delivery by cesarean section may be necessary Renal Disease  Mostly growth restriction and vasculitis / arteriolosclerosis of the baby’s blood vessels Dr M Hossu Notes 137  Pediatric Diseases Age Distinctions and causes of death  Neonatal, Birth – 1 month- prematurity & low birth weight, congenital abnormalities, complications at or around birth (mother & placenta), sepsis, NRDS, Hypoxia/asphyxia,  Infancy, 1 month – 1 year- congenital abnormalities, SIDS, prematurity& Low birth weight, infections, NRDS,  Early childhood, 1 – 5 yoa Accidents, congenital abnormalities, assault, neoplasm  Late childhood, 5 – 9 yoa Accidents, neoplasm, congenital abnormalities, assault, infections Prematurity and Intrauterine Growth Retardation Definitions o Low Birth Weight – Less than 5 lbs or 2500g o Prematurity –Less than 37 weeks of pregnancy o AGA appropriate for gestation age may be of low weight due to prematurity o SGA small for gestational age: may be normal age but small weight Incidence Low birth weight o 12% blacks majority are SGA Prognosis o 500-600g 1.5 lbs - 2% survive o 1% < 1500g (3 lbs) VLBW 50% survive o 1250g >2 ½ lbs 90% survive Premature Birth  Causes o Premature rupture of membranes o Maternal illness including intrauterine infections o Uterine abnormalities o Placenta abnormalities o Fetal disorders o Multiple gestation o Unknown  Associated diseases in the baby after it is born due to immaturity of the organs o Neonatal respiratory distress syndrome (NRDS)  Cause is a lack of surfactant due to immaturity of the lungs → the alveoli tend to collapse in expiration due to high surface tension forces.  A short time after delivery the baby begins to have more problems with respiration and has to work harder to move air in and out of the lungs Dr M Hossu Notes 138   The ability of the lungs to exchange oxygen decreases and the baby experiences hypoxia that is overcome by ventilating them with gases containing an increased concentration of oxygen.  Eventually get formation of a "hyaline membrane" on the inside of the alveoli which further impairs exchange.  Retinopathy of prematurity = complication of therapeutic hyperoxygenation due to retinal neovascularisation  Test to tell if the lungs of the fetus are mature is to measure the lecithin/sphingomyelin levels in the amniotic fluid. A ratio of greater than 2:1 implies that the baby will NOT experience NRDS o Cardiovasculat problems  May have problems such as an ASD, PDA, patent DA  Since these structures are not fully mature and so not ready or able to close over following birth. o Bacterial sepsis  The immune response is not adequate for the baby to defend itself, and since the baby was born too early there has not been transfer of maternal antibodies across the placenta to protect the baby that way.  Majority though are acquired at birth →pneumonia, meningi s, entero-colitis, sepsis o Necrotizing enterocolitis  1 out of 10 very low birth weight infants (