Teratogenesis: Principles and Critical Periods

• Teratogenesis is the process by which congenital malformations are produced in an embryo or fetus.
• No medications are 100% safe for all patients.

Principles of Teratogenesis

• Teratogen susceptibility varies.
• Susceptibility is specific to the embryo/fetus stage of development.
• The mechanism of teratogenesis is specific for each teratogen.
• Teratogenesis is dose-dependent.
• Teratogens can cause death, growth retardation, malformation, or functional impairment.

Critical Fetal Period

• The critical fetal period for teratogenesis is 3-16 weeks, because of organogenesis.
• Organogenesis is the formation of organs from the 3 germ layers.
• Most birth defects occur prior to 8 weeks, often before the first prenatal appointment.

Fetotoxicity

• During preimplantation, fetotoxicity can result in spontaneous abortion.
• During the embryonic phase, fetotoxicity can result in spontaneous abortion and structural malformations.
• During the fetal phase (8-40 weeks), fetotoxicity can result in CNS dysfunction, growth restrictions, neurobehavioral effects, fetal demise (intrauterine fetal death), and smaller size.

Prescribing Medication During Potential Pregnancy

• Always check the safety information for every medication before prescribing to pregnant or potentially pregnant women.
• Ask when their last menstrual period (LMP) was.
• Order a urine test to check for pregnancy.

FDA Pregnancy Categories

• The FDA previously used categories A, B, C, D, and X to classify drugs based on risk to the fetus, ranging from no risk to very high risk, but this system is now outdated.
• When prescribing, use medications only when there is strong evidence of need, and prioritize those classified as Category A when possible.

Drug Exposure

• Drugs cross the placenta and expose the fetus.
• A thin placental membrane separates the mother's blood from the fetus's blood in the villi of the placenta.
• Drugs in the mother's blood cross the placental membrane into blood vessels in the villi and pass through the umbilical cord to the fetus.

Thalidomide Tragedy

• Approximately 10,000 children were born with limb reduction or abnormalities due to pregnant mothers taking thalidomide.
• Amelia is the complete absence of limbs.
• Meomelia is the partial absence of limbs.
• Phocomelia is the absence of long bones with upper/lower limbs attached to the trunk.

Kafauver-Harris Drug Amendment Act

• Resulted from the thalidomide tragedy and ensures:
  • Proof of safety & efficacy prior to drug approval.
  • FDA reviews medications within 180 days.
  • Adverse effects must be recorded.

Diethylstilbestrol (DES)

• DES is a potent estrogen previously used to prevent spontaneous abortion, premature labor, and nausea/vomiting in pregnant mothers.
• "DES Mothers" have an increased risk for breast cancer and should be counseled on this risk.
• "DES Mothers" should be encouraged to do self-breast examinations and get regular mammograms.
• "DES Daughters" (females exposed to DES in utero) have an earlier onset risk for vaginal cancer, increased risk for cervical cancer, structural defects in the cervix/uterus/fallopian tubes, and potential infertility or poor pregnancy outcomes.
• "DES Sons" (males exposed to DES in utero) have an increased risk of cysts of the epididymis, microphallus, and cryptorchidism (undescended testicle).
• No increase in infertility nor cancer risk in "DES Sons"

Vitamin A

• Babies born to mothers taking excess Vitamin A are 4 times more likely to develop cleft lip, cleft palate, hydrocephalus, and cardiac deformities.
• Isotretinoin (Accutane) is a Vitamin A isomer currently used for the treatment of cystic acne.
• Isotretinoin is one of the most potent teratogens currently in use.
• Isotretinoin increases the risk of spontaneous abortion and can cause "thalidomide-like" abnormalities.

iPLEDGE Program

• iPLEDGE is a risk management program required for dispensing isotretinoin (Accutane) to reduce prenatal exposure.
• Accutane prescribers must be registered with iPLEDGE.
• Females of childbearing age must use 2 forms of birth control one month prior to Accutane use.
• Females of childbearing age must have 2 negative pregnancy tests before getting the prescription, undergo monthly pregnancy testing while on the medication, and undergo pregnancy testing 1 month post-medication cessation.

ACEs and ARBs

• ACEs (Angiotensin Converting Enzyme Inhibitors) and ARBs (Angiotensin Receptor Blockers) are medications used to treat hypertension.
• These medications affect the RAAS feedback mechanism that regulates BP by managing fluid and vascular tone.
• ACEs and ARBs are not recommended for use during pregnancy.
• In the first trimester, ACEs and ARBs can cause possible cardiovascular and CNS abnormalities.
• In the second and third trimesters, ACEs and ARBs can cause renal dysfunction, growth retardation, fetal demise, and oligohydramnios.

Oligohydramnios

• Oligohydramnios means little amniotic fluid, which can constrict the amniotic sac and cause the baby to have an inability to urinate (anuria), leading to abnormal limb development.
• Several medications are approved for hypertension in pregnancy, but not ACEs and ARBs.
• Patients should be switched off of ACEs and ARBs immediately upon notification of pregnancy or potential pregnancy.
• Hypertension treatment often begins with ACEs (medication names end in -pril).
• A common side effect of ACE inhibitors is a dry, hacking cough without pain.
• ACEs can be switched out for ARBs, but both classes cannot be taken at same time.
• Angiotensin Receptor Blockers (ARBs) end in -artan.

SSRIs

• Selective Serotonin Reuptake Inhibitors (SSRIs) are used to treat depression, anxiety, and OCD
• Most SSRIs are Category C
• Examples of common SSRIs include Fluoxetine (Prozac) and Paroxetine (Paxil).
• Serotonin interferes with cardiac growth in utero.
• Exposure to SSRIs in utero increases the risk of cardiac defects and craniosynostosis (fusion of the baby's skull in utero).
• Exposure to PAXIL (Paroxetine) in utero can result in anencephaly, atrial septal defects, cardiac defects, gastroschisis, and omphalocele.
• OB-GYNs will utilize Risk vs. Benefit Analysis for pregnant mothers if the use of an SSRI is being considered.

Anticonvulsants

• Anticonvulsants are used to treat seizure disorders and bipolar disorder (BPD).
• Anticonvulsants can cause cleft palate/cleft lip, spina bifida, atrial septal defect, developmental delay, and limb abnormalities in the fetus.

NSAIDs

• Aleve, ibuprofen, Advil, Naproxen, ketoprofen, and celecoxib are all NSAIDs (non-steroidal anti-inflammatories).
• Many women unknowingly take NSAIDs during pregnancy for pain relief.
• NSAID use during pregnancy increases the risk of cardiac ventricular septal disease (VSD) when used in the 1st trimester.
• NSAID use during pregnancy increases the risk of pulmonary hypertension when used in the 3rd trimester.
• NSAIDs use during pregnancy can cause spontaneous abortion.

Warfarin (Coumadin)

• Warfarin is an anticoagulant (blood thinner) used in patients who have DVTs.
• First trimester Warfarin (Coumadin) use is associated with major visual deformities, nasal hypoplasia (small nose, depressed bridge), and stippled epiphyses (ossification of the long bones, resulting in elongated/deformed shaft).

Benzodiazepines

• Benzodiazepines are used to treat generalized anxiety and take effect within 30 minutes.
• Benzodiazepines are medications that end in (-pam) and are highly addictive.
• Examples of Benzodiazepines include Alprazolam (Xanax), Diazepam (Valium), Lorazepam (Ativan), Clonazepam (Klonopin), Temazepam (Restoril), and Oxazepam (Serax).
• Benzodiazepine use can cause neonatal withdrawal, cyanosis (baby can appear blue due to low O2), and hypotonia (low muscle tone; baby can appear "floppy-like") in newborns.

Acetaminophen (Tylenol)

• Acetaminophen (Tylenol) was until recently deemed safe for pain-relief during pregnancy.
• Recent studies have linked Tylenol use to an increased risk of autism development.

Fetal Alcohol Spectrum Disorder (FASD)

• FASD is the result of fetal developmental disabilities due to alcohol consumption at any gestational stage.
• The teratogenic effects of alcohol during pregnancy depend on the quantity of alcohol consumed and the pattern of drinking behavior.
• Mothers who suffer from an Alcohol Use Disorder (AUD) typically consume >8-10+ drinks/day and are more likely to see FASD in their newborn.

FASD Dysmorphisms

• FASD dysmorphisms include a smooth/flat philtrum, epicanthal folds, small eye openings, small head/underdeveloped jaw, "railroad track" ears, and "hockey stick" palmar crease.
• In order fo a patient to be confirmed with FASD, they need to be diagnosed with 3 of the dysmorphisms.
• Not all individuals with FASD show facial dysmorphisms.

FASD Deformaties

• Deformities of FAS include growth retardation, atrial/ventricular defects, renal dysplasia/aplasia, skeletal abnormalities, vision abnormalities, and hearing loss.
• Renal Dysplasia is conneced kidney vs Aplasia is without kidney.

Nicotine-Induced Vasospasm

• Nicotine-induced vasospasm impairs fetal oxygen delivery.
• Placental changes due to smoking reduce gas exchange between mother and fetus.
• Carbon monoxide (CO) binds to hemoglobin, reducing its capacity to carry oxygen, which diminishes the oxygen available to fetal tissues, impairing oxygenation.
• Tobacco use during pregnancy can lead to placenta previa (placenta blocks the cervical opening), preterm premature rupture of membranes (PPROM, rupture of the amniotic sac before the onset of labor), and placental abruption (placenta pulls away from its blood supply causing hemorrhaging).
• Tobacco use during pregnancy, especially combined with certain genetic predispositions, significantly increases the risk of certain congenital malformations of the ENT (cleft lip/palate), GI Tract (anal atresia, gastroschisis), heart, kidneys, digits, and limbs.

Cocaine Use

• Cocaine use causes Vasoconstriction and Hypertension leading to conditions s/a MI, Aortic rupture, & CVA.
• If a young adult presents to the ED with an MI and no PMH of CV problems, consider the possibility of cocaine usage.
• Effects of cocaine on the fetus in utero include spontaneous abortion, fetal demise, and intrauterine growth retardation.
• Effects of cocaine on the newborn after birth include neurobehavioral issues evidenced by high-pitched crying, irritability, apnea, and tachypnea.
• Long-term effects of cocaine exposure can include aggression and attention deficiencies.
• The effects of cocaine on a baby include long-term behavioral issues with aggression and attention span.

Opioids

• Heroin, codeine, fentanyl, opium, methadone, oxycodone, meperidine, hydrocodone, hydromorphone, and buprenorphine are all opioids.
• Heroin is the most rapid-acting opioid and most likely to produce dependence.
• Codeine increases the risk of congenital heart disease.
• Chronic use of heroin increases the risk of abruptio placenta, preterm labor, and intrauterine passage of meconium.
• Addiction in newborn due to opioid use during pregnancy causes neonatal abstinence syndrome (NAS), which includes a withdrawal syndrome in newborns caused by prenatal drug exposure.
• In NAS the baby is born addicted, switched to morphine, and is weaned off slowly.

Methamphetamine

• Effects of methamphetamine use during pregnancy on the infant include low birth weight, lethargy at birth, and possible neurotoxicity at birth
• Effects of methamphetamine use during pregnancy on the mother include gestational hypertension, placental abruption, and increased mortality rate.

Explore the principles of teratogenesis, the process of congenital malformations in embryos or fetuses. Learn about factors influencing teratogen susceptibility, the critical fetal period (3-16 weeks), and the potential for fetotoxicity leading to structural malformations or spontaneous abortion.