teratogens
slide 11 memorize that char
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valproate use
•should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. •Note: folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk of congenital neural tube defects
Pregnancy risk summary labeling must state and include
•the percentage range of live births in the USA with a major birth defect, regardless of drug exposure. •Labeling states the percentage range of pregnancies in the USA that end in miscarriage, regardless of drug exposure. •Risk Summary must summarize the specific developmental outcome, its incidence, and the effects of dose, duration of exposure, and gestational timing of exposure.
Topiramate plus phentermine undergoing REMS Is used when for what, can cause
•treat weight management •first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate)
Goals in managing a patient on a drug identified with a known risk of teratogenicity
•Avoidance of unintended fetal exposure •Prevention of unintended pregnancy •Inform stakeholders (physicians, patient, families) of teratogenic risk and safe use conditions •Some medications require linkage of negative pregnancy test prior to dispensing
Misoprostol use
•Black Box Warning •Can cause birth defects, abortion, and premature birth (uterine contractions) •If physician prescribes misoprostol for NSAID-induced ulcers, the patient must: •Have a negative serum pregnancy test within 2 weeks prior to beginning therapy. •Be capable of complying with effective contraceptive measures. •Receive both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. •Begin only on the second or third day of the next normal menstrual period.
methotrexate and pregnancy
•Black Box Warning •Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. •Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. •Should only be used in the treatment of neoplastic diseases in female pregnant patient only when the potential benefit outweighs the risk to the fetus.
tetracyclines and pregnancy
•Black Box Warning •Tetracycline can make birth control pills less effective. •... CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. IF ANY TETRACYCLINE IS USED DURING PREGNANCY, OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING THESE DRUGS, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. •THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOWISH-GRAY-BROWN).
ACEs and pregnancy
•Black Box Warning to counsel women of child bearing age •Practice safe sex while on medication •If accidentally become pregnant, need to switch anti-hypertensive medications ASAP
other drugs undergoing REMS include
•Bosentan - treat pulmonary arterial hypertension •ambrisentan - treat pulmonary arterial hypertension •Lenalidomide - analogue of thalidomide •Fingolimod - treat relapsing forms of multiple sclerosis •Telavancin - antibacterial •There are no data on VIBATIV use in pregnant women. In 3 animal species, VIBATIV exposure during pregnancy at clinically relevant doses caused reduced fetal weights and increased rates of digit and limb malformations in offspring. •Isotretinoin and thalidomide (previously covered)
When a drug is administered to a pregnant woman it can reach the fetal circulation because the placenta can be permeable barrier to chemicals of
•low molecular weight (MW). •Drugs with MW less than 800-1000 can cross the placenta easily (depending upon their lipid solubility and the degree of ionization) while those with MW exceeding 1000 cross very poorly
human milk contents
•major proteins in human milk are whey (60%-80%) and casein (20%-40%). Human milk also contains growth factors, immune factors, cytokines, and other substances shown to be beneficial to the newborn infant that cannot be replicated in artificial feedings.
Strictly defined, a teratogen causes
•only structural abnormalities. Not to be confused with "hadegen" (agent that interferes with organ maturation and function) or a "trophogen" which alters growth.
The umbilical cord is a mechanical barrier between the maternal and fetal compartments, susceptible to
•partial and total occlusion •Important in the late first and second stages of labor
lithium on the fetus
tricuspid valve malformation/ ebsteins anomaly
New Pregnancy Labeling System includes what 3 categories and each has what subcategories
1. Pregnancy - a risk summary, a registry if exists, clinical considerations, data, developmental outcomes 2. Lactation- a risk summary, clinical considerations, data 3. Females and Males of Repro potential pregan test, contraception, infertility
Mechanism and Criteria for Determining Teratogenicity 6 things
1. The defect has been completely characterized. •done by a geneticist or dysmorphologist 2. The agent must cross the placenta. • transport must be of sufficient quantity to directly influence embryonic or fetal development or to alter maternal or placental metabolism to exert an indirect effect. 3. Exposure must occur during a critical developmental period. 4. A biologically plausible association is "supportive". 5. Epidemiological findings must be consistent. •two or more high-quality epidemiological studies report similar findings. üThe suspected teratogen causes a defect in animal studies. 6. The Teratology Society (2005) however states that establishment of causation in teratology-related litigation requires human data.
susceptibility to teratogenic affects by age of embryo/fetus
1. in the first week/blostocyst generation peroid its an all or nothing affect- fetal loss or resistant to effects or teratogen 2. Embryonic period = weeks 3-8 is MAXIMUM SUSCEPTIBILITY TO TERATOGENS- this is period of organ morphogenesis 3. Fetal period= 9 weeks + and is assoc w lower sus functional dereangement
factors that affect the placental transfer of drugs 7
1.Molecular size of drug •MW > 1000 cross the placenta poorly!! 2.Physicochemical properties of drug •Lipophilic drugs diffuse readily •Highly ionized drugs with MW > 500-1000 cross the placenta slowly and poorly 3.Degree of protein binding •Drugs highly protein bound cross the placenta slowly 4.Placental blood flow 5.Stage of placental development •Passage seems easier during 3rd trimester!! 6.Placental drug metabolism •Placenta is site of metabolism of some drugs (e.g. ethanol) 7.Activity of the of P-glycoprotein that is present in placental vessels and can put some compounds back into maternal blood.
Assume enzyme inhibitors are teratogenic so this includes what drugs
ACEi, coumarin (warfarin) (interacts with vit K0 reductase enzyme), Lithium (IP3 second messenger cascade
FDA Letter Categories for Drugs and Medications (1979-2015) Category C means
Benefit outweighs 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.
assume all antiseizure meds are
BBW teratogenic carbamazepine, phenytoin, phenobarbital, valproate, topiramate
Fetal warfarin syndrome
Facial asymmetry and hypoplasia Blind/absent external ear canal, ear tags Cleft lip/palate Hypoplastic vertebrae nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image.
Pregnancy - Data explain if human or animal what to do/ labeling says what
Human Data •Labeling describe adverse developmental outcomes, adverse reactions, and other adverse effects and, to the extent applicable, the types of studies or reports, number of subjects and duration of each study, exposure information, and limitations of the data. Requires that both positive and negative study findings be included. Animal Data •Labeling describe the types of studies, animal species, dose, duration and timing of exposure, and adds the requirement that the labeling also describe study findings, presence or absence of maternal toxicity, and limitations of the data. Adds the requirement that the description of maternal and offspring findings must include information on the dose-response and severity of adverse developmental outcomes. Requires that animal doses or exposures be described in terms of human dose or exposure equivalents and that the basis for those calculations must be included
FDA Letter Categories for Drugs and Medications (1979-2015) Category X means
RISK DEF OUTWEIGHS benefits 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. The drug is contraindicated in women who are or may become pregnant.
Fetal hydantoin syndrome
Maternal use of phenytoin Growth deficiencies, underdeveloped fingertoenails, mild dev delays, some cleft palate, small head, finger toe malformations
Drug Transfer into Milk mostly occurs how the most important factors in order include:
Mostly by passive diffusion •Most important factors (in order) •Amount of medication in the mother's serum •Bioavailability •Molecular weight, protein binding, pKa, and lipid solubility
FDA Letter Categories for Drugs and Medications (1979-2015) Category B means
SAFE 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 a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
FDA Letter Categories for Drugs and Medications (1979-2015) Category A means
SAFEST Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in late trimesters), and the possibility of fetal harm appears remote.
rubella caused a characteristic form of
•congenital cataracts in infants born to mothers with rubella during pregnancy. •Development of vaccine and vaccination program --> elimination of rubella/congenital rubella syndrome in US.
fetal alcohol syndrome (FAS)
a group of alcohol-related birth defects that include physical and mental problems short palpebral fissures, epicanthal folds, flat midface, hypoplastic philtrum, and thin upper vermilion border
Pregnancy - Adverse Developmental Outcomes defined as
as structural abnormalities, embryo-fetal and/or infant mortality, functional impairment, and alterations to growth.
When human data is available but not sufficient to reasonably determine the drug's effects on fetal developmental abnormalities, this will require the labeling to
characterize the likelihood that the drug increases the risk of developmental abnormalities as low, moderate, or high.
isotretinoin birth defects
cleft palate hydrocephaly thymus abnormailties
in the mom the drug dose may need to be higher in pregancy which means
higher toxicity, fetal tissues are more sensitive to toxic drug effects
assume all meds interfering w DNA synth are tertogenic
methotrexate (anti-folate), isotretinoin (alters DNA transcription),
FDA Letter Categories for Drugs and Medications (1979-2015) Category D means
need to do pro con There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, 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).
Drugs are passed from the maternal compartment, via the
placenta (a partial barrier), to the fetal compartment
Cocaine use during pregnancy
placental abruptiion, fetal loss, low birth weight, microcephaly, limb and urinary tract malforms, poor neurodevelopment
Diethylstilbestrol (DES)
risk of clear cell adenocarcinoma and vaginal adenosis. The glands in the lamina propria lined by tubo-endometrial type of epithelium are partly replaced by metaplastic squamous epithelium.
When use of the drug is contraindicated during pregnancy, it must be stated first in the "Risk Summary." •Risk summary must be presented in the following order:
•1) Based on human data. •2) based on animal data. •3) based on pharmacology.
what is a preg registry and hows it work
•A pregnancy exposure registry is an observational study that collects health information from women who take prescription drugs or vaccines when they are pregnant. The FDA does not conduct pregnancy exposure registries but may recommend or require that a drug company implement a pregnancy registry based on certain criteria. The FDA's Office of Women's Health keeps a list of registries, posted on FDA's website. There are registries for a number of drug products, for example drugs for cancer, epilepsy, arthritis, diabetes and psychiatric conditions. •There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to (name of drug) during pregnancy. •A pregnancy exposure registry is a study that collects health information from women who take medicines and vaccines when they are pregnant and breastfeeding. Information is also collected on the newborn baby. This information is compared to women who have not taken medicine during pregnancy.
Drugs with a recognized use during labor and delivery u need to ask / think about what things in regards to the drugs use
•Does a drug have a recognized use during labor or delivery? •Is the use is stated as an indication in the labeling? •Is expected to affect labor or delivery? • Requires the inclusion of available information about •The effect of the drug on the mother •The effect of the drug on the fetus/neonate •The duration of labor and delivery •The possibility of complications, including interventions, if any, that may be needed •The later growth, development, and functional maturation of the child.
Contras to breast feeding
•HIV •Illicit drug use •Galactosemia in the infant •Herpes simplex virus lesion on the breast •Active tuberculosis •Human T-cell lymphocytic virus infection •Radioactive isotopes/radioactive material •Antimetabolite or other chemotherapy use
When human data are sufficient to reasonably determine the likelihood that the drug increases the risk of fetal developmental abnormalities or specific developmental abnormalities, it will require the labeling to contain one of two risk conclusions =
•Human data does not indicate that (name of drug) increases the risk of (type of developmental abnormality or specific developmental abnormality) •Human data indicates that (name of drug) increases the risk of (type of developmental abnormality or specific developmental abnormality).
"Pump and Dump"
•If a short course of medication is required a mother can use a pump to collect her milk to continue to stimulate the milk production, alleviate symptoms of engorgement, and then discard the milk rather than feed it to her infant
The preganancy risk summary must Require that when the data on which the risk conclusion is based is animal data, the fetal risk summary characterizes the likelihood that the drug increases the risk of developmental abnormalities using one of the following risk conclusions:
•Not predicted to increase the risk •Low likelihood of increased risk •Moderate likelihood of increased risk •High likelihood of increased risk •Insufficient animal data on which to assess the likelihood of increased risk.
phenytoin use
•Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
Lactation risk summary subheadings are
•Presence of drug in human milk •must state the concentration of the drug and/or its active metabolites in human milk and the actual or estimated daily dose for an infant fed exclusively with human milk •Effects of drug on the breast-fed child •Effects of drug on milk production.
Lactation - Clinical Considerations
•Require that the labeling include information concerning ways to minimize exposure to the drug and/or its active metabolite(s) in the breast-fed child in situations where the following conditions are present: •The drug and/or its active metabolite(s) are present in human milk in clinically relevant concentrations •Do not have an established safety profile in infants •Used either intermittently, in single doses, or for short courses of therapy. •Describe ways to minimize a breast-fed child's oral intake of topical drugs applied to the breast or nipple skin •Monitoring for adverse reactions
Lactation risk summary must include what
•Requires the inclusion of a risk and benefit statement, unless breastfeeding is contraindicated •Requires that when use of a drug is contraindicated during breastfeeding, this information must be stated first in the "Risk Summary."
Role of United States Food and Drug Administration
•Since 1962, embryo-fetal toxicity and teratogenesis studies in animals have been required by the FDA before starting clinical testing of any drug. Such studies were necessary but not sufficient in order to establish that a drug cannot damage the human fetus. •From 2000-2010 studies of drugs approved by FDA it was found that the teratogenic risk in human pregnancy was "undetermined" for 98 % of the drugs approved for human use.
Pregnancy - Clinical Considerations include what
•Subcategory for Clinical Considerations •Disease associated maternal and/or embryo/fetal risk •Information related to prescribing decisions for pregnant women, including the risk, if known, to the pregnant woman and the fetus from the disease or condition the drug is indicated to treat and the potential influence of drug treatment on that risk •Dose adjustments during pregnancy and the postpartum period •Maternal adverse reactions •Fetal/Neonatal adverse reactions (a description of the complication, the severity and reversibility of the complication) •Labor or delivery
Warfarin (Coumadin) in pregnancy
•Teratogenicity addressed by labeling •Discuss pregnancy planning with patient for duration of therapy •If patient becomes pregnant while taking product, patient should be apprised of the potential risks to the fetus
Carbamazepine
•Warning for women of childbearing age •Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine
Females and Males of Reproductive Potential Subheading considers what things when
•When pregnancy testing and/or contraception is required or recommended before, during, or after drug therapy and/or when there are human and/or animal data that suggest drug-associated fertility effects •Pregnancy Testing •Contraception •Infertility
A teratogen is
•any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. •It may be a medication or other chemical substance. •A physical or environmental factor (heat or radiation). •A maternal metabolite (e.g. diabetes or phenylketonuria). •An infection such as cytomegalovirus. •Obesity ??
Isotretinoin can be used when and how
•approved with restricted use •Women must agree in writing to two specific forms of birth control •Negative Pregnancy tests before dispensing medication, every 30 days while on medication, and 30 days after discontinuing medication •Special dispensing program iPledge -Prescriber and Pharmacy registration •Half-life 21 hours
Sample Medications undergoing REMS (Risk Evaluation and Mitigation Strategies) are medications that
•cause harm to embryo and fetus, therefore special care must be given to avoid pregnancy in women of childbearing age •Pregnancy tests before, during (usually monthly), and after medication use •Counseling patient of risks if accidental pregnancy occurs •Enroll in Pregnancy Registry
Mycophenolate - undergoing REMS is what, used when, can cause
•prophylaxis for organ transplant rejection •Use of mycophenolate during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous system •Patients must use acceptable birth control during entire therapy and for 6 weeks after stopping •Pregnancy test before administration, 8-10 days later, and routinely while on therapy
The milk:plasma ratio, what is it, what do values mean
•ratio is the concentration of drug in the mother's milk divided by the amount in the mother's plasma. •M:P ratio < 1 indicates minimal levels of a medication are transferred into milk •M:P ratio 1 to 5 indicates that a medication may be sequestered in milk •Doxazosin has a M:P ratio of 20 indicating it is concentrated in milk, which leads to the human recommendation to use extreme caution if breastfeeding
Thalidomide can be used with
•restricted distribution system •Prescriber and pharmacy registration •Documentation of safe use (pregnancy tests, birth control during therapy) •Pregnancy registry (REMS)
lithium use
•risk versus benefit similar to antiseizure medications •If this drug is used in women of childbearing potential, or during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. •Lithium birth registries
