Teratogens

What are some ways a pregnant woman may help reduce her exposure to CMV?

-Washing hands frequently with soap and water, especially after changing diapers, feeding a child, wiping a child's nose or drool, or handling children's toys -Not sharing cups, plates, utensils, food, or toothbrushes -Not sharing towels or washcloths -Not putting a child's pacifier in her mouth -Cleaning toys, countertops, and anything else that comes in contact with children's urine or saliva

What is the incidence of prenatal exposure to cocaine? ___% of live births

.6-3% of live births

CMV affects ___% of all newborns

1-3%

Congenital toxoplasmosis can also be acquired by ingestion of tissue cysts, another form of the parasite found in raw or undercooked meat How?

Farm animals become infected and develop tissue cysts through ingestion of excreted oocysts of cats

Neonatal Herpes Simplex (HSV) Quite rare but very serious, perhaps ____ Infections typically caused by exposure to HSV type-2 via _____ Exposure in utero is rare

Fatal Cervical excretions during birth process (herpes 2 = herpes below the waist)

When are physicians more likely to use antivirals?

For symptomatic babies Babies that are symptomatic AND already have evidence of CNS involvement are getting the drugs

Susceptibility to teratogens depends on what 3 things?

Genes that exert some control over the impact of teratogens on the fetus (some genes are more protective than others) Nature and dosage of toxic agent Time of exposure (sensitive periods)

In addition, patients with congenital rubella will also have general intra-uterine ___ and post-natal ___

Growth retardation Growth retardation

The number of cases of congenital syphilis has been steadily increasing since the 1980s, why?

HIV/AIDs - more immunocompromised individuals More likely that penicillin was not effective against syphilis

CMV is a member of the ___ group of viruses

Herpes

What are oocysts?

Highly infectious form of protozoan parasite found in material contaminated by feces in cats

Those at greatest risk for CMV are ____ patients and ___ women

Immunocompromised patients Pregnant women

Thalidomide was withdrawn from the market but was re-introduced for use with a number of ___ and ___ disorders

Immunological and inflammatory

How has the culture of breast feeding changed over time?

In the past, you were considered "higher class" if you could afford formula and didn't have to breast feed However, since then we have learned about the value of breast feeding for infant's immune systems Now, it's more "trendy" to breast feed

Before distributing isotretinoin to patients, what are the requirements?

Informed patient consent Negative pregnancy test within 2 weeks prior to initiation of therapy Use of contraceptives 1 month prior through 1 month following use

Cocaine is generally ___ "Crack" is ___ or ___ Crack may be more dangerous because of the shorter time required for the drug to reach the brain

Inhaled Smoked or injected

The transmission of CMV requires ____

Intimate contact

Drug used to treat persistent and severe cystic acne Effects include abnormalities of opthalmologic, cardiovascular, vestibular, auditory and CNS

Isotretinoin (prescriptive retinoid or vitamin A derivative)

What's the problem with CMV?

It starts up an infection that stays with babies through their early ears Infection can go into the inner ear and affect hearing over time

What is the allure of meth?

It's cheap It's widely available It increases alertness and energy Perceptions of increased intelligence

Cocaine results in ___ ___ ___

LBW Prematurity Intrauterine growth retardation

What is the most common POSTNATAL cause of HL?

Meningitis

What are some postnatal causes of HL?

Meningitis Viral infection (e.g., mumps) Ototoxins/chemotherapy Trauma (acoustic, blunt, penetrating) Perilymph fistula Neoplasm (medulloblastoma,AN, fibrous dysplasia, histiocytosis) Autoimmune (rare in children)

During intrauterine life, the fetus is protected from many teratogens by...

Mom's immune system/placenta

Whether a child is affected by viral infection depends on

Mother's immunity (e.g., less likelihood of infant infection if mother has had repeated herpes infections) Gestational age of fetus -More detrimental during organogenesis Socio-economic status (baby could be more OR less likely to be impacted due to SES) -Marker of immunity -Culture of breastfeeding -Use of day care centers

Is CMV airborne?

NO

Do we routinely screen newborns for CMV?

No

How can we identify CMV? (2 different ways)

Polymerase chain reaction (PCR) amplification of viral DNA attracted from neonatal dried blood samples on Guthrie cards -Can be done quickly -99% sensitivity and specificity OR Isolation of CMV from urine collected within 1st week of life

What are the primary sources of CMV infection? Prenatal Perinatal Postnatal

Prenatal: transplacental (The prenatal time is when CMV is going to have the MOST detrimental impact on an individual) Perinatal: cervical secretions along the birth canal (Not as much of a concern with CMV specifically) Postnatal: contact with infected urine, saliva, feces, tears (primarily through contact with bodily fluids)

When is CMV going to have the most detrimental impact on an individual?

Prenatally

What is the infection path of CMV?

Prenatally- infection crosses the placenta Produces persistent infections in the fetus Direct infiltration of virus via the internal meatus to cause hearing loss

Maternal drug use includes which types of drugs?

Prescription OTC Recreational Illicit

CMV is easy to get and easy to...

Prevent

Why is it difficult to identify the impact of various teratogens and their different dosages?

Recall of mothers may not be reliable Mothers have a variety of exposures Mothers may not be forthcoming with exposure

___ is one of the only teratogens whos transmission rate increases during the last trimester

Rubella However, this is OK because after 4 months gestation, there's low risk of damage to the fetus

The Rubella epidemic in the US (1964-1965) resulted in more than 20,000 neonates born with congenital rubella syndrome Since then there has been the development of...

Rubella vaccine, which has significantly reduced occurrence

What are the only 3 VIRUSES that qualify as teratogens in humans?

Rubella virus Cytomegalovirus Herpes simplex virus

CMV puts children at risk for...

SNHL Cognitive impairment Microcephaly Developmental delay Seizure disorder Cerebral palsy

What does rubella syndrome look like?

SNHL PDA (patent ductus arteriosus)-cardiac defects Cataracts

Syphilis is an acquired ___

STD

When there's a teratogen, it doesn't simply delay the development, it ___ it

STOPS

We refer to these viral and non-viral teratogens as the ___ complex

STORCH: Syphilis Toxoplasmosis Other Rubella Cytomegalovirus Herpes Simplex

Typically within the embryonic period (period of rapid development) but may include later times (during functional maturation)

Sensitive periods

What is Dr. Frances O. Kelsey (US FDA) known for in terms of thalidomide?

She was a medical officer who fought and blocked approval of thalidomide (believed more testing needed to be done), while drug companies maligned her as a bureaucratic nitpicker

Pregnant women metabolize cocaine ___ than other people making them more sensitive to small amounts

Slower

What are some common features of STORCH presented at birth?

Small size for gestational age (SGA) Petechiae or a rash from low platelet count Calcification of the brain on CT scan at birth Microcephaly (small brain)

What are some aminoglycocides that cause intrauterine ototoxicity?

Streptomycin or dihydrostrptomycin Danamycin Gentamicin

2 NON-VIRAL infectious diseases that qualify as teratogens?

Syphilis Taxoplasmosis

Factors that have adverse effects on embryos of fetuses between the time of fertilization and birth (e.g., environmental agents like drugs and viruses)

Teratogens

____ is a well-known nonprescription drug with devastating effects on the unborn It was an OTC sedative available for a short-time in the 1950s and used by women during pregnancy to relieve nausea/morning sickness When ingested during the 1st trimester (while the limbs are differentiating), babies can be born with...

Thalidomide Limb buds - malformed and under-formed limbs

What is the problem with using antivirals as a treatment?

There are a lot of negative side effects Which leads to physicians not wanting to treat babies with these antivirals

What are some reasons why mothers might not know about CMV?

There is no medication for it If there's nothing to sell, pharmaceutical companies are less likely to spend money to spread awareness about it

How is the identification of syphilis made?

Through Venereal Disease Research Lab (VDRL) Or Fluorescent treponemal antibody absorption (FTA) screening

The ___ of maternal infection of rubella is critical to transmission of virus to fetus 1st trimester- the transmission rate is 67-80% Risk of transmission drops at the end of the 2nd trimester to 25%, but increases to >___% int he last trimester After ___ months gestation, low risk of damage

Timing >90% Four months

T/F patients with congenital rubella can have CNS disorders

True

What type of hearing loss is usually associated with congenital syphilis?

Typically SNHL Symmetrical Sudden onset Progression (However, if it's late onset it's a slow progression)

Are there any treatments for CMV?

Vaccines are in the R & D stage Antiviral agents (e.g., Glanciclovir or Valganciclovir) are possible treatments for SNHL -85% of treated infants had either improved hearing or maintained normal hearing, compared to 56% of the untreated group -No progression of HL in subjects treated with glanciclovir

How is syphilis treated?

With penicillin and corticosteroid therapy However penicillin does NOT prevent or retard progression of hearing loss

Is it possible that the only thing we see with CMV children is hearing loss?

Yes Dr. Tharpe has seen children as old as 5 years old who have developed completely normally except for hearing loss

We can't diagnose a child with CMV unless they are tested for CMV within ___ days of birth i.e., to figure out was it congenital CMV or did they contract it after birth?

5-6 days

___% of patients with congenital rubella will have heart abnormalities

50%

With CMV: At least ___% of HL is progressive ___% have late onset (usually onset age of ~2 years, sometimes as late as 5 years) Variable degree and configuration

50% 18% Because of this, we want to see them every 6 months during the first 5 years of age After about 5 years, we are comfortable seeing them once/year

HL from congenital syphilis can occur anytime during the 1st ___ decades of life

7

What are some other drugs known to be ototoxic in adults?

A variety of antibiotics -Some amino-glycosides -Tetracylines Anti-inflammatory agents Chloroquine (antimalarial drug) Chemotherapy drugs Diuretics

What does the ABR look like for cocaine babies?

ABR shows no increased risk of HL but it shows evidence of CNS disorder Waveforms are delayed

What are some symptoms of cocaine in babies?

Abnormal sleep patterns Tremors Poor feeding Hypotonia (low muscle tone, floppy baby) Frantic fist sucking Gaze aversion Difficulty with state control -Short durations of quiet, alert states, difficulty orienting to visible or audible stimuli

The most likely source of CMV maternal infection is from ...

Children

What does cocaine do to the unborn in terms of delivering nutrients and oxygen?

Cocaine can cross placental barrier Causes vasoconstriction of blood vessels delivering nutrients and oxygen to fetus

What does nicotine do to the unborn?

Constricts placental blood flow depriving fetal brain of oxygen Increases risk for abortion, still-births, cleft palate, mental retardation, hyperactivity

What are some ear abnormalities caused by isotretinoin?

Enlargement of saccule and utricle Shortening of cochlea Malformation of external ear Conductive and SNHL reported because of maternal use during gestation ***Impact on all aspects of the ear (as opposed to just impacting the inner ear) Because of this, we can see conductive as well as SNHL

The effects of cocaine are not always evidence in newborn nursery Cocaine can be found in urine of exposed infants for up to ___ days after birth

10

Toxoplasmosis associated with HL is present in ~___% of cases What also might toxoplasmosis be associated with?

10% -Hydrocephalus -Intracranial calcifications -Pulmonary lesions

Why is there little point in testing children with hearing loss for CMV after 6 months?

10-40% of normally-developing infants in the US acquire CMV between 2-6 months So we couldn't tell congenital vs. acquired

____% of infants with HSV-2 present with widespread infection, localized infection, or encephalitis during 1st 3 weeks of life Severe neurological sequelae is common

100%

The likelihood of HL due to CMV depends on whether babies were in-apparently affected vs. obviously affected Likelihood of those with HL Inapparently affected: ___% Obviously affected: ___%

15-25% inapparently affected 60% obviously affected Those obviously affected at birth have a much higher incidence of HL NOTE: Dr. Tharpe hesitates with these percentages because there's a lot we don't know about CMV and hearing loss These figures might change considerably when we are able to define what is congenital CMV

Almost all congenitally-infected infants are excreting the virus at __ years of age >50% are excreting at __ years ~30% STILL excrete at __ years

2 4 8 The likelihood of children who are in Mama Leere still excreting the virus is very high

Between ___ and ___% of pregnant women who test negative (while trying to get pregnant) become infected during pregnancy

2-7%

____ is by far the most frequent exposure to unborn babies ~5,500 annually (over FAS, down syndrome, spinal bifida, and HIV/AIDS)

Cytomegalovirus (CMV)

Despite the fact that CMV puts children at the most risk, mothers are the least aware of it What is the percentage of women who heard of CMV?

22% On the other hand, HIV/AIDS is way less frequent yet 98% of mothers know about it

The prevalence of tissue cysts in meat used for human consumption varies in the US from ___-___% for pigs and ___-___% for sheep

23-42% 4-22% THIS IS WHY PREGNANT WOMEN ARE TOLD NOT TO EAT RAW UNDERCOOKED MEAT

___-___% (who become infected with CMV during pregnancy) transmit the infection to their fetuses

24-45%

Between ___-___% of children with symptomatic congenital syphilis have HL No causes of congenital HL have been reported with asymptomatic congenital syphilis Those with ___ syphilis can also have HL

25-38% Acquired

___-___% of women who test positive for CMV (while trying to get pregnant) transmit CMV to their fetuses

3-4%

Which of the 5 teratogens making up the STORCH complex is of most concern to audiologists?

Cytomegalovirus (it is the highest causative factor of acquired congenital hearing loss in children)

Children born to mothers who have antibodies during pregnancy have __ the risk of developing hearing loss by age 7

Double

1/2 of those with congenital rubella infection will have ___ onset hearing loss

Early SNHL Cookie-bite configuration Progressive

___% of child-bearing-age women have never been infected

30-50%

If the toxoplasmosis infection is contracted for the 1st time by mother during pregnancy, transmission rate to fetus in utero is ___%

33%

___% of patients with congenital rubella will have abnormalities of the eyes

40% Cataracts Retinopathy Glaucoma Nystagmus

Most studies of aminoglycocides have been retrospective in nature without control of ...

Additional factors

What led to the marked decline of syphilis in the 1950s through the mid 1980s

Advent or prenatal Serology and Penicillin

Patients with toxoplasmosis are usually asymptomatic if acquired ___

After birth

Some ___ are toxic to both the auditory and vestibular systems They can cross the placenta causing SNHL and labyrinthine damage in the fetus Fetal ototoxicity can occur even in the ABSENCE of maternal ototoxicity

Aminoglycosides

90% of newborns with toxoplasmosis are ___ with subclinical infections

Asymptomatic

What are some effects of thalidomide on the auditory system?

Atresia of external auditory meatus Cochlear malformations Absent acoustic and vestibular nerves

How is congenital toxoplasmosis transmitted?

By intracellular protozoan parasite Acquired by adults from accident ingestion of oocysts

What is the leading cause of congenital infection?

CMV

___ is the leading cause of non-hereditary childhood hearing loss

CMV