Lecture 2: Development and Teratogenesis Flashcards
How does movement of sperm occur in fertilization?
occurs primarily through the muscular contractions of the uterus
Where does fertilization usually occur?
in the widest part of the fallopian tube, the ampullary region
What is the first phase of human development?
pre-embryonic
What is the time period for the pre-embryonic stage?
occurs after fertilization and ends with implantation= week 1
When does a zygote start to undergo cellular division and in what developmental stage is this?
at day 3 and this is in the pre-embryonic stage
What are the developmental steps in pre-embryonic stage?
zygote forms as sperm enters the ovum -> forms a morula -> morula accumulates fluid and forms into a blastocyte -> inner cell mass develops into an embryo -> trophoblast (trophoectoderm) develops into placenta -> at day 6 or 7 blastocyte will attach to the uterine wall and begins to digest uterine wall for nourishment -> end with implantation
What is the time period for the embryonic stage?
occurs from day 8 through week 8
What are the developmental steps in the embryonic stage?
uterine wall grows over blastocyte -> tissues continue to become placenta -> amniotic cavity forms -> 3 germ layers begin to differentiate (ectoderm, mesoderm, and endoderm form in blastocyte)
When do the three germ layers give rise to the organs in the embryonic stage?
around day 16
What comprises the endoderm?
digestive tract lining, respiratory tract lining, urethra and bladder, gallbladder, liver and pancreas, thyroid and parathyroid, thymus, kidneys
What comprises the mesoderm?
dermis, muscles, cartilage, bone, blood, other connective tissue, reproductive organs, teeth enamel
What comprises the ectoderm?
epidermis, hair, nails, sweat glands, brain and spinal cord, cranial, spinal nerves, ocular structures, inner ear, nasal and oral and anal epithelium
When do the endoderm, ectoderm, and mesoderm form?
during gastrulation the cells of the blastocyte push inward forming the endoderm, the cells that remain on the outside are the ectoderm, and the mesoderm is formed when additional cells move inward in-between the endoderm and ectoderm
What is the time period for the fetal stage of development?
begins at week 8 of pregnancy and ends at birth
When does rapid weight accelerations occur?
in the fetal stage in the last 2 months of pregnancy
Is teratogenesis dose dependent?
YES! and the mechanism is specific for each teratogen
What is the percentage of fertilizations that end in spontaneous abortion?
31%
What is the critical period for teratogenesis?
between 3-16 weeks due to impairment of organogenesis
What is the effect when there is teratogenic exposure to the fetus during preimplantation?
spontaneous abortion
What is the effect when there is teratogenic exposure to the fetus during the embryonic stage (2-8 weeks)?
spontaneous abortion or structural malformations
What is the effect when there is teratogenic exposure to the fetus during the fetal stage of development (8-40 weeks)?
central nervous system, growth restriction, neurobehavioral, reproductive effects, fetal demise
When do most birth defects occur?
prior to 8 weeks, which is before the first prenatal appointment usually
How can medications in mothers blood cross the placenta to the fetus’s blood?
some of the fetuses blood vessels are contained in tiny hairlike projections (villi) of the placenta that extend into the wall of the uterus; there is only a thin membrane that separates the mothers blood in the intervillous space from the fetus’s blood in the villi; drugs can then pass through the umbilical cord to the fetus
In the 1950’s what was thalidomide used for?
as an effective medication to treat nausea in pregnant women
What did the tragedy of thalidomide use lead to?
the development of testing pharmaceuticals for adverse effects of fetal development
What are the deformities associated with thalidomide use?
Amelia- complete absence of limbs
Meromelia- partial absence of a limb
Phocomelia- absence of long bones; hands and feet attached to trunk by small bones
deafness, blindness, cleft palate, congenital heart disease, malformations of inner and outer ear, intellectual disability and autism, urogenital and gastrointestinal defects
What is diethylstilbestrol?
DES is a potent estrogen that was used in order to prevent spontaneous abortion and premature labor
What were the effects on women prescribed DES while pregnant?
some studies found an increase in risk for breast cancer; in these patients mammograms and self exams should be encouraged
What were the effects of DES on daughters?
vaginal clear cell adenocarcinoma, two fold increase in vaginal and cervical intraepithelial neoplasm, structural defects in cervix, uterus or fallopian tubes, infertility and poor pregnancy outcomes due to malformation of uterus
What is vaginal clear cell adenocarcinoma?
a rare form of vaginal cancer; seen in DES exposure; incidence peaks at age 20 in DES daughters; the incidence peaks at age 60 for those not exposed to DES
What were the effects of DES on sons?
increased risk for epididymal cysts, microphallus, undescended testicle, testicular hypoplasia, decreased sperm count… but there is no decrease in fertility or increase in cancer risk
What is the amount of Vitamin A that has showed an increase risk in deformity in the fetus?
more than 10,000 units
What deformities could babies born to mothers taking 20,000 units or more of Vitamin A have?
they are 4x more likely to have a cleft lip, cleft palate, hydrocephalus, cardiac deformities
What vitamin A isomer has not been associated with teratogenicity?
beta-carotene
What is isotretinoin?
a vitamin A isomer used in the treatment of cystic acne (Accutane)
What is the percent of neonates that have evidence of abnormalities with use of isotretinoin?
20-30%
What program began to reduce prenatal exposure to isotretinoin?
iPLEDGE program - all female patients of childbearing age must start two forms of birth control 1 month prior to starting, during, and 1 month after isotretinoin use
What must female patients do in order to be prescribed isotretinoin?
they must have two negative urine or blood pregnancy tests and they must have additional test monthly during therapy and one month after end of therapy
What defects can taking ACE inhibitors during the 2nd and 3rd trimester cause?
growth retardation, renal dysfunction, fetal demise, and oligohydraminos
What are the 1st trimester risks associated with ACE inhibitors?
risks are unclear but possible cardiovascular and central nervous system abnormalities
What are some common medication names for ACE inhibitors?
lisinopril, captopril, ramipril, enalapril,
What are ACE inhibitors commonly used to treat?
hypertension
What are selective serotonin reuptake inhibitors (SSRIs) used to treat?
depression, anxiety, OCD, and a variety of other mental illnesses
What risks are involved with taking SSRIs during pregnancy?
increased risks to cardiovascular defects, may increase risk for spontaneous abortion, inhibit serotonin signaling in heart development, late exposure can be associated with transient newborn respiratory distress
What are some common SSRI medication names?
fluoxetine, sertraline, paroxetine
When are anticonvulsants used?
can treat seizure disorders and bipolar disorder
What are the abnormalities associated with anticonvulsants?
cleft palate, cleft lip, atrial septal defects, spina bifida, developmental delay, limb abnormalities
What are some common medication names for anticonvulsants?
Valproic acid, carbamazepine, phenytoin
What are the risks associated with taking NSAIDs during the first trimester?
increased risk of having a baby with cardiac ventricular and septal defects
What are the risks associated with taking NSAIDs during the third trimester?
can result in pulmonary hypertension in newborn
What are some common NSAIDs?
Aleve, Ibuprofen, Advil, Naproxen, Ketoprofen, Celebrex, Indocin
What are the first trimester risks associated with Warfarin?
skeletal abnormalities- nasal hypoplasia, long bone development abnormalities, limb hypoplasia
What are benzodiazepines?
used in treatment on general anxiety - Alprazolam, Diazepam, Lorazepam, Clonazepam, Chlordiazepoxide
What are the risks associated with taking benzodiazepines during pregnancy?
fetotoxic- neonatal withdrawal, hypotonia, cyanosis, floppy infant syndrome
What is the lifetime cost of one individual with fetal alcohol syndrome?
around 2 million dollars
What is the incidence of FAS?
.2 to 1.5 cases of fetal alcohol spectrum disorder occur per 1,000 births
What is the rate at which a fetus eliminates alcohol?
fetus eliminates alcohol at a rate only 3-4% of that of the mother
What are the smallest effects that have been recognized in FASD?
low birth weight at 2 drinks per day and it becomes more evident at 4 drinks per day
What are the effects associated with prenatal exposure to alcohol?
abnormal brain structure and reduction of brain volume -> decreased impulse control, abnormal transfer of information between the hemispheres, deficiency in memory and learning, motor coordination, abnormal perception of time
How is the central nervous system involved in FASD?
infants show irritability, balance abnormalities, diminished IQ, memory impairment, attention and hyperactivity deficits, inappropriate behavior
What are the common features of someone with FASD?
small head, low nasal bridge, epicanthal folds, small eye openings, short nose, flat midface, smooth philtrum, thin upper lip, underdeveloped jaw, railroad track ears, ptosis, decreased elbow pronation, incomplete extension of digits, defects in palmar crease
What is the pathophysiology behind tobacco affects on a fetus?
nicotine induced vasospasm causes impaired fetal oxygen delivery; there are structural changes within placental contribution to a reduction in gas exchange; increase in SIDS
What is the average weight of a newborn exposed to tobacco during development?
they weight on average 200 grams less
What percent of preterm deliveries were caused by smoking?
5-8%
What percent of low birth weight babies were caused by smoking?
13-19%
What percent of SIDS deaths were caused by smoking?
34%
What increased risks are associated with tobacco use during pregnancy?
infertility, placenta previa, preterm premature rupture of membranes, placental abruption
What defects are associated with tobacco use during pregnancy?
cleft lip, cleft palate, gastroschisis (organs form on outside), anal atresia, limb reduction defects, cardiac defects, digital defects, renal aplasia or dysplasia
What are the effects of cocaine use on the mother?
effects are related to vasoconstriction and hypertension - MI, arrhythmias, aortic rupture, CVA, seizure, bowel ischemia, sudden death
What are the effects of cocaine use on the fetus?
spontaneous abortion, fetal demise, placental abruption, premature birth, IUGR (intrauterine growth retardation)
How long can cocaine stay in an infants system?
7 days because of its long half life
What effect can codeine have on the fetus?
increased risk of congenital heart defects
What effects are associated with chronic use of heroin?
fetal growth restriction, abruption placenta, fetal death, preterm labor, intrauterine passage of meconium - aspirate stool
What is included in routine prenatal testing?
CBC, blood group, RPR/VDRL (Syphilis), Hep B Surface Antigen, Rubella Antibodies, HIV, Gonorrhea/Chlamydia, Herpes Simplex Virus, Group B Strep- vaginal bacteria
What does TORCH stand for?
toxoplasmosis, other, rubella, cytomegalovirus, and herpes simplex
What is toxoplasmosis?
a protozoan parasite the infects humans
How is toxoplasmosis typically spread?
spread through the fecal matter of cats; can also spread from contaminated soil, undercooked meat, and unfiltered water
How many cases of congenital toxoplasmosis occur each year?
400-4000 cases in the U.S.
When is risk of congenital disease highest and lowest in toxoplasmosis?
highest in first trimester and lowest in third trimester
What are the symptoms of toxoplasmosis for the mother?
acute infection may be asymptomatic, fatigue, fever, headache, malaise, myalgia, lymphadenopathy
What are some signs and symptoms of congenital toxoplasmosis in infancy?
chorioretinitis, hydrocephalus, intracranial calcifications, learning or visual disability later in life
How does congenital syphilis occur?
transmission of treponema pallidum; occurs as spirochete crosses placenta or during birth
How many pregnancies does congenital syphilis affect per year world wide?
one million
What are some manifestations of congenital syphilis in a newborn?
nasal discharge, hepatomegaly, rash, lymphadenopathy, CNS involvement (seizures, hydrocephalus), hematologic abnormalities, long bone abnormalities of development
What are the manifestations of syphilis that occur after 2 years of age?
facial features- short maxilla, protuberant mandible, saddle nose
eyes- keratitis, glaucoma, optic atrophy, corneal scarring
mouth- abnormal tooth development
skin- fissures around mouth
neurologic- intellectual disabilities
skeletal- arthritis and joint abnormalities
When does the highest risk of rubella to the fetus occur?
in the first 10 weeks of pregnancy; there is little risk of effects after 20 weeks
How does infection of fetus from rubella occur?
maternal infection -> hematogenous spread -> infection of placenta -> spread to vascular system of fetus
What effects can the rubella virus have on a fetus?
affects cell division and has direct toxic effects on cells; fetal death, premature delivery, intrauterine growth retardation, low birth weight
What are some manifestation associated with rubella?
hearing impairment, congenital heart defects, microcephaly, cataracts, encephalitis, bone lesions, purpura and petechiae (blueberry muffin rash), hepatosplenomegaly, diabetes, thyroid dysfunction
What is cytomegalovirus?
member of herpes virus family; most commonly cause a mono like infection in its hose with fever, rhinitis, pharyngitis, myalgias, headache, and fatigue
What is the prevalence on CMV congenital viral infection?
0.5%
How is CMV transmitted?
via placenta, or less commonly during vaginal delivery or breastfeeding
What is the mortality rate of infants with CMV?
5%
What percent of newborns with CMV are asymptomatic at birth?
90%
What are the manifestations of congenital CMV?
progressive hearing loss, jaundice, small for gestational age, hepatomegaly, petechiae and purpura
What are the neurologic abnormalities associated with CMV?
microcephaly, seizures, feeding difficulties
What are some ocular abnormalitites associated with CMV?
chorioretinitis, retinal scars, optic atrophy, central vision loss
What are the abnormal lab findings associated with CMV?
abnormal blood counts, elevated liver function tests, elevated bilirubin, hemolytic anemia
How does genital herpes present in a mother?
painful genital ulcers with fever, lymphadenopathy, fever, dysuria and headache; usually worse in first outbreak and recurrent outbreaks are less severe
How can transmission to the fetus occur?
during delivery due to vaginal shedding; even when visible disease is absent
What effects are associated with intrauterine disease in herpes simplex virus?
infarcts of placenta, inflammation of umbilical cord, hydrops fetalis, fetal demise, skin abnormalitites, ocular damage, sever CNS deformities: microcephaly
What are the skin, eye, and mouth manifestations in herpes simplex virus neonatal disease?
vesicles on an erythematous base, ocular infections, HSV keratoconjunctivitis, cataracts, chorioretinitis, vision loss, ulcerations of mouth, throat, palate and tongue
How does CNS disease occur in infants with herpes simplex virus neonatal disease?
occurs in 33% of neonatal disease; spread of HSV from nasopharynx and olfactory nerves to CNS
