Teratology

L3

"Moderately safe": NO STUDIES WITH POSSIBLE RISK OR STUDIES SHOW MINIMAL EFFECTS (There are no controlled studies in breastfeeding women, however the risk of untoward effects to a breastfed infant is possible; or controlled studies show only minimal non-threatening adverse effects. Drugs should be given only if the potential benefit justifies the potential risk to the infant).

L4

"Possibly hazardous." : EVIDENCE OF RISK BUT MAY NEED TO BE TAKEN IN LIFETHREATENING SITUATIONS (There is positive evidence of risk to a breastfed infant or to breastmilk production, but the benefits of use in breastfeeding mothers may be acceptable despite the risk to the infant e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

L2

"Safer": TAKEN LESS OFTEN WITH NO EFFECTS; LITTLE EVIDENCE OF RISK - Drug which has been studied in a limited number of breastfeeding women without an increase in adverse effects in the infant. - And/or, the evidence of a demonstrated risk which is likely to follow use of this medication in a breastfeeding woman is remote.

L1 category

"Safest": OFTEN TAKEN WITH NO EFFECTS; STUDIES OK (Drug which has been taken by a large number of breastfeeding mothers without any observed increase in adverse effects in the infant. - Controlled studies in breastfeeding women fail to demonstrate a risk to the infant and the possibility of harm to the breastfeeding infant is remote; or the product is not orally bioavailable in an infant.)

If teratogen acts in the preimplantation stage, what affects are there likely to be?

"all or none". Lethal to the embryo or no effect.

What were the concerns expressed by the public regarding the new FDA proposal on pregnancy and lactation labeling?

- A few expressed concerns with the verbosity, as well as the difficulty of the reading level and the format and requested keeping the previous categories as a quick reference. - Product manufacturers noted concerns with providing some of the data requested due to exclusion of pregnant women in clinical trials and the cost of establishing post-approval registries. - Others commented on the omission of the considerable risks of not adequately treating chronic conditions and of not breastfeeding.

What signs is Fetal Carbamazepine Syndrome associated with?

- Facial dysmorphism - Fingernail hypoplasia

What teratogenic affects are DES associated with?

- Feminization of male offspring - Vaginal adenosis - Cervical and uterine abnormalities - Infertility - Cancers of breast & reproductive systems of both male & female offspring - Clear cell adenocarcinoma of vagina and cervix

What are the symptoms of transplacental lithium intoxication?

- Fetal and neonatal cardiac arrhythmias - hypoglycemia - Bradycardia - Reversible changes in thyroid function - Diabetes insipidus - Polyhydramnios - Preterm birth - Floppy infant syndrome similar to that seen with benzodiazepine exposure

Symptoms of neonatal lithium toxicity?

- Flaccidity, lethargy, and poor suck

What teratogenic affects are NSAIDs associated with?

- Gastoschisis if embryo is exposed during early gestation - Irreversible closure of the ductus and kidney failure can occur if the fetus is exposed after 32 weeks - Necrotizing enterocolitis

What teratogenic affects is Ribavirin associated with?

- Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted in hamsters, rats and rabbits. - The incidence and severity of teratogenic effects increased with escalation of the ribavirin dose. Survival of fetuses and offspring was reduced.

Why is fetal valproate syndrome?

- Neural tube defects (Usually in lumbar-sacral area) - Facial dysmorphology - Limb and heart defects - Varying degrees of cognitive impairment - Mental development delay - Autism - Asperger's syndrome - Acute neonatal risks - Hepatotoxicity - Coagulopathies - Neonatal hypoglycemia - Withdrawal symptoms (10% die in infancy)

What are the conditions necessary to prove teratogenicity of an agent?

- Proven exposure at critical times during human development - Consistent dysmorphic findings recognized in well conducted epidemiologic studies - Specific defects or syndromes associated consistently with specific teratogens - Rare anatomic defects associated with environmental exposure - Proven teratogenicity in experimental animals

What teratogenic affects is accutane associated with?

- Spontaneous abortions - Craniofacial, cardiac & CNS abormalities (also with high doses of vitamin A) - Thymic agenesis - Microphthalmia - Hydrocephalus - Cleft palate - Deafness - blindness

What long-term affects is fetal nictoine exposure associated with?

- There is a positive association between maternal smoking and sudden infant death syndrome (SIDS). - The connection between nicotine addiction, depression, attention disorders, and learning and behavior problems in humans is not straightforward but nicotine's action on the production and function of neurotransmitters makes it a prime suspect in the pathology of these diseases. - Nicotine accentuates neurotransmitter function in adults but desensitizes these functions in prenatally exposed infants and children. This desensitization causes an abnormal response throughout the lifespan.

What is Thalidomide currently used for?

- Treatment of painful symptoms of erythema nodosum leprosum - Inflammatory diseases - HIV (treat ulcers in mouth & throat, might also help treat Kaposi's Sarcoma) - Cancer

What teratogenic affects are lithium associated with?

- a rare cardiac malformation, Ebstein's Anomaly - Exposure late in pregnancy may cause transplacental lithium intoxication

What is teratogenesis dependent on?

- drug - dose - Frequency - Route of administration - Absorption of the drug - Maternal serum levels - Maternal and placental clearance system - time of administration during gestation

What teratogenic affects are POPS associated with?

- low birth weight & changes in the functioning of T-lymphocytes, which may have negative effects on the functioning of the immune system - neurotoxic (mechanism unknown): Decreased motor development, intelligence & developmental delays

What is Fetal Hydantoin Syndrome?

- mental & developmental delay - IUGR - microcephaly - shortened neck - Cardiac defects - flattened nose - Strabismus (crossed eyes) - Hypoplastic nails - cleft lip &palate - syndactyly

What are the associated effects of Fetal Warfarin Syndrome?

- mental & developmental delay - growth restriction - Stippled bone epiphyses - Nasal hypoplasia with depressed nose bridge - microcephaly - cataracts & blindness - bleeding disorders - Seizures - Scoliosis - Deafness - Congenital heart disease

What teratogenic affects are ACE inhibitors associated with?

- renal damage - oligohydramnios - lack of cranial ossification - IUGR - Cardiovascular: atrial septal defects, pulmonic stenosis, atrial & ventricular defects) - CNS: microcephaly, eye anomaly, spina bifida, coloboma

What are the physicals signs of FASD?

1. Skin folds at the corner of the eye 2. Low nasal bridge 3. Short nose 4. Indistinct philtrum - groove between nose and upper lip 5. small head circumference 6. Small eye opening 7. Small midface 8. Thin upper lip

What is the risk of FASD in a mother who drinks 2-4 drinks/ day?

10%

For how long might congenital anomalies occur after discontinuation of etretinate?

18mo

When does organogenesis occur?

2-8 weeks post-conception

How many drinks / day will result in FASD?

4-6 drinks/day,

How long has etretinate been detected in the sera of patients after cessation of use?

7 years

What amount of caffeine is associated with increased risk of miscarriage?

> 200 mg caffeine daily or the equivalent of 2 cups of coffee.

What is the difference between teratogenic and fetotoxic?

A teratogen is a chemical or physical agent that can cause abnormalities in an embryo or fetus. In general this term is restricted to birth defects, structural aberration etc. and usually is related to effects during the period of organogenesis (i.e. in general prior to about 10 weeks gestation). In contrast, while a fetotoxin may cause adverse effects at any time in pregnancy, this term usually refers to effects that arise following the period of organogenesis.

What substances might result in oligohydramnios?

ACE inhibitors

What substances might result in spina bifida?

ACE inhibitors

FDA Pregnancy Category C

ANIMAL STUDIES NOT OK AND NO WOMEN STUDIES OR NO ANIMAL OR WOMEN STUDIES: ONLY TAKE IF BENEFITS OUTWEIGH RISKS (Either studies in animals have revealed adverse effects on the fetus teratogenic or embryocidal or other)and there are no controlled studies in women OR Studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus)

FDA Pregnancy Category B

ANIMAL STUDIES OK AND NO WOMEN STUDIES OR ANIMAL STUDIES NOT OK BUT WOMEN STUDIES OK: (Either animal- reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women OR - animal-reproduction studies have shown an adverse effect other than decrease in fertility that was not confirmed in controlled studies in women in the first trimester and there is no evidence of risk in later trimesters.)

What are teratogens?

Agents that act to irreversibly alter growth, structure, or function of the developing embryo or fetus

What are the stimulants?

Amphetamines, Cocaine (crack), Dexatrim (PPA), Nicotine, Caffeine, Ecstasy (member of the amphetamine class of drugs)

What teratogenic affects is Paxil associated with?

Atrial and ventricular septal defects - Exposure to SSRIs late in pregnancy has been associated with transient neonatal complications & admission to a neonatal ICU • Jitteriness • Mild respiratory distress • Transient tachypnea of the newborn • Weak cry • Poor tone • In 2006, the FDA issued a public health advisory which highlighted concerns about the risk of an unconfirmed association of newborn persistent pulmonary hypertension with SSRI use

What herbs are considered abortifacients?

Blue & black cohosh and pennyroyal

Most drugs on the market are which category?

C

L5

CONTRAINDICATED (Studies in breastfeeding mothers have demonstrated that there is significant and documented risk to the infant based on human experience OR it is a medication that has a high risk of causing significant damage to an infant, the risk of using the drug in breastfeeding women clearly outweighs any possible benefit from breastfeeding, and the drug is contraindicated in women who are breastfeeding an infant).

FDA Pregnancy Category X

CONTRAINDICATED! (Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit.)

What birth defects is etretinate been associated with?

Case reports link the use of this agent to birth defects similar to those observed with isotretinoin (Accutane)

What teratogenic affects is mercury associated with?

Developmental delay & mild neurologic abnormalities to microcephaly and severe brain damage

FDA Pregnancy Category D

EVIDENCE OF HUMAN FETAL RISK: ONLY USE FOR LIFETHREATENING SITUATIONS (There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk e.g., if the drug is needed in a lifethreatening situation or a serious disease for which safer drugs cannot be used or are ineffective).

What teratogenic affects are NSAIDs associated with during early gestation?

Gastoschisis (infant's intestines stick out of the body through a defect on one side of the umbilical cord)

What teratogenic affects are Streptomycin & Kanamycin associated with?

Hearing loss due to eight cranial nerve damage.

If teratogen acts between 6.5-8w, what organ is most likely to be affected?

Heart

If an embryo survives exposure to a teratogen in the preimplantation stage, what will happen to affected cells?

If the embryo survives the exposure, repair or replacement of affected cells will occur, allowing normal development.

What is the New FDA Proposed Rule on Pregnancy and Lactation Labeling?

In 2008, proposed that the pregnancy and lactation subsections of labeling include a risk summary, which summarizes the risks of the medicine to the developing baby (fetus) or breast-feeding infant, and a discussion of the data supporting that summary. The labeling would also include relevant clinical information useful for counseling pregnant or lactating women about medications, and prescribing and managing use of those medications. This would replace the categories. the proposed rule would enhance well informed decision making. Still has not passed.

What teratogenic affects are NSAIDs associated with after 32w?

Irreversible closure of the ductus and kidney failure

What are the hallucinogens

LSD, phencyclidine (PCP)

What drug is Ebstein's Anomaly associated with?

Lithium

What substances might result in polyhydramnios?

Lithum

What are the depressants?

Marijuana, Barbiturates, Heroin (opiates), Methadone, Alcohol

How long might neonatal lithium toxicity last?

May persist for more than 7 days

If teratogen acts in the fetal stage, what affects are there likely to be?

Metabolic and/or developmental

What substances might result in gastoschisis?

NSAIDs

What teratogenic affects is aspartme associated with?

None

Were longterm neurobehavioral sequelae documented with neonatal lithium toxicity?

Not in a 5 year follow up of 60 school-aged children exposed to lithium during gestation

What teratogenic affects is radiation associated with?

Only in high doses: microcephaly, mental delay & leukemia

What are POPS?

Persistent Organic Pollutants (POPS). Compounds such as dioxins, polychlorinated biphenyls (PCBs banned in US in 1977), & pentachlorophenol (PCP)

How is the rate at which caffeine is cleared affected in pregnancy?

Prolonged in pregnancy

With what is nictoine exposure associated during pregnancy?

Spontaneous abortion Fetal death associated with placental abruption, preterm birth, & PROM doubles the risk of low birth weight

What teratogenic affects is warfarin (coumadin) associated with?

Stillbirth -Prematurity - Hemorrhage - CNS defects - Neonatal death - Fetal Warfarin Syndrome: oral anticoagulant therapy (Coumadin).

What teratogenic affects are androgenic agents associated with?

Testosterone & anabolic steroids cause masculinization & premature sexual differentiation of the fetus.

What are Polybrominated Diphenyl ethers (PBDE)?

Used as flame retardants in textiles, home goods & construction materials

What are the facial attributes associated with fetal hydantoin syndrome?

V-shaped eyebrows Low set ears High arched palate Irregular dentition

FDA Pregnancy Category A

WOMEN STUDIES OK AND FETAL HARM SEEMS REMOTE: (Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester and there is no evidence of risk in later trimesters, and the possibility of fetal harm appears remote.)

What category is rivabarin?

X

What SSRI is preferred in pregnancy?

Zoloft, but it is not risk-free

What is the incidence of congenital abnormality?

about 3-4%.

What substances might result in thymus agenesis?

accutane/etretinate

What substances might result in behavioral disorders/delays/issues?

alcohol

What substances might result in mental disorders/delays/issues?

alcohol anti-convulsants (fetal hydantoin and valproate) warfarin high doses of radiation POPs

What substances might result in developmental disorders/delays/issues?

alcohol anti-convulsants (fetal hydantoin and valproate) warfarin mercury POPs

What substances might result in microcephaly?

alcohol anti-convulsants (in fetal hydantoin) warfarin ACE inhibitors radiation

What substances might result in growth disorders/delays/issues?

alcohol warfarin

What drug is Fetal Carbamazepine Syndrome associated with?

anti-convulsants

What drugs is fetal valproate syndrome associated with?

anti-convulsants

What type of drug is associated with fetal hydantoin syndrome?

anti-convulsants

What substances might result in microcephaly, a shortened neck, a flattened nose, crossed eyes, and cleft lip/palate?

anti-convulsants (in fetal hydantoin)

What substances might result in syndactyly?

anti-convulsants (in fetal hydantoin)

What substances might result in IUGR?

anti-convulsants (in fetal hydantoin) ACE inhibitors

What substances might result in cleft palate?

anti-convulsants (in fetal hydantoin) accutane/etretinate lamictal

What substances might result in autism/asperger's?

anti-convulsants (in fetal valproate)

What substances might result in coagulopathies?

anti-convulsants (in fetal valproate)

What substances might result in cognitive disorders/delays/issues?

anti-convulsants (in fetal valproate)

What substances might result in neural tube defects?

anti-convulsants (in fetal valproate)

Why might garlic and willow bark be a problem in pregnancy?

anticoagulant properties

What is Lamictal (lamotrigine) used to treat?

anticonvulsant, but used in bipolar

Is ethanol fetotoxic or teratogenic?

both a teratogen and fetotoxic: can cause major malformations and alcohol-related neurodevelopmental disorder (ARND).

Why might pennyroyal be a problem in pregnancy?

can cause liver damage, renal failure DIC & maternal death

How do the hallucinogens affect the fetus?

change concentrations of neurotransmitters that will alter normal brain development & function

What teratogenic affects is Lamictal (lamotrigine)associated with?

cleft lip & palate

What teratogenic affects are tertacyclines associated with?

complexes with calcium in bones and teeth causing discoloration and malformation

Why might black cohosh be a problem in pregnancy?

contains a chemical that acts like estrogen

How do the depressants affect the fetus?

decrease respiration and blood pressure that may decrease blood flow (oxygen & nutrients) to the fetus.

How do smoked drugs affect the fetus?

decreased oxygenation of the fetus in addition to the other effects

How does nicotine affect neurotransmitter function in prenatally exposed children?

desensitizes these functions in prenatally exposed infants and children. This desensitization causes an abnormal response throughout the lifespan.

Is Nicotine fetotoxic or teratogenic?

fetotoxic: does not cause malformations but can cause IUGR.

What is ribavarin used for?

for the treatment of chronic hepatitis C (HCV).

What adverse fetal affects is echinacea associated with?

fragmentation of hamster sperm at high concentrations

Why might real licorice be a problem in pregnancy?

has hypertensive & potassium-wasting effects

What is the alternative to coumadin?

heparin

Why might valerian be a problem in pregnancy?

intensifies the effects of prescription sleep aids

Why might ginseng be a problem in pregnancy?

interferes with monoamine oxydase inhibitors

What is the metabolism rate of caffeine in fetus?

low, due to low levels of enzymes.

What is phocomelia?

malformation of the limbs

How does hypertension affect the fetus?

may rupture the immature placental & fetal blood vessels

What are the long-term affects of fetal alcohol spectrum disorders?

mental & developmental delay, physical growth delay, behavioral abnormalities, microcephaly, flattened nose, renal & cardiac defects.

What is amelia?

missing limbs

Fetal stage

ninth week-term

What is etretinate?

oral agent used to treat psoriasis - Currently not available in the U.S

How does vasoconstriction affect the fetus?

reduces blood flow to the fetus; therefore reduces oxygen & nutrients

Embryonic stage

second through ninth week

What kind of congenital abnormalities are possible?

skeletal, soft tissue, metabolic or developmental

What is teratology?

study of chemically induced congenital abnormalities.

If a woman stops smoking during the last 4 months of pregnancy, what is the risk of LBW?

the risk of giving birth to an infant with lowered birth weight becomes similar to that of a nonsmoker

What teratogenic affects are PBDE associated with in rodent studies?

thyroid function Spontaneous motor function Learning Memory Can increase liver & kidney weight

How do stimulants affect the mother?

vasoconstriction & hypertension

What substances might result in stillbirth?

warfarin

What is polysyndactyly?

webbing and the presence of an extra number of fingers or toes.

What is syndactyly?

webbing of 2 or more fingers or toes which usually only involves a skin connection between the two, but may rarely also include fusion of bones in the affected digits.