Teratogenesis: Principles, Timing, and Effects

• Teratogenesis refers to the process by which congenital malformations are produced in an embryo or fetus.
• No medication is 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

• Weeks 3-16 are the most critical period for teratogenesis due to organogenesis impairment.
• Organogenesis is the formation of organs from the three germ layers.
• Most birth defects occur before 8 weeks, often before the first prenatal appointment.

Effects of Fetotoxicity Based on Timing

• Preimplantation: Potential adverse effect is spontaneous abortion (AB).
• Embryonic phase: Potential adverse effects are spontaneous abortion and structural malformations.
• Fetal phase (8-40 weeks): Potential adverse effects include CNS dysfunction, growth restrictions, neurobehavioral effects, fetal demise (intrauterine fetal death), and smaller baby size.

Prescribing Medications During Pregnancy

• Always check safety information for every medication before prescribing to pregnant or potentially pregnant women.
• Ask "When was your last menstrual period (LMP)?" and order a urine pregnancy test.
• FDA Pregnancy Categories are A, B, C, D, and X, ranging from no risk to the fetus to very high risk.
• Only use medications when there is strong evidence of need, prioritizing Category A when possible.

Mechanism of Fetal Drug Exposure

• Drugs cross the placenta, exposing the fetus.
• A thin placental membrane separates maternal and fetal blood.
• 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.
• The Kafauver-Harris Drug Amendment Act was developed as a result, mandating drug testing for adverse side effects on fetal development.

Kafauver-Harris Drug Amendment Act

• Requires proof of safety and efficacy before a drug can be manufactured and sold.
• Grants the FDA 180 days to review medications.
• Mandates adverse effects must be recorded.
• Before the act, medications could be sold six days after application filed with the FDA.

Diethylstilbestrol (DES)

• DES is a potent estrogen formerly used to prevent spontaneous abortion, premature labor, and nausea/vomiting in pregnant mothers.
• "DES Mothers" have an increased risk for breast cancer.
• As a provider, counsel "DES Mothers" on the risk for breast cancer and encourage self-breast exams and regular mammograms.
• Females exposed to DES in utero ("DES Daughters") have an earlier onset risk for vaginal cancer that peaks at age 20, increased risk for cervical cancer, structural defects in the cervix/uterus/fallopian tubes, and potential infertility or poor pregnancy outcomes.
• Males exposed to DES in utero ("DES Sons") have an increased risk of cysts of the epididymis, microphallus, and cryptorchidism but do not experience a decrease in infertility or increased cancer risks as seen in DES Daughters.

Vitamin A

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

iPLEDGE Program

• Requirements for dispensing isotretinoin reduce prenatal exposure.
• Prescribers must be registered with iPLEDGE.
• Females of childbearing age must use two forms of birth control one month prior to Accutane use and have two negative pregnancy tests before prescription, monthly pregnancy testing while on the medication, and a pregnancy test one month post-medication cessation.

ACEs and ARBs

• ACEs (Angiotensin Converting Enzyme Inhibitors) and ARBs (Angiotensin Receptor Blockers) treat hypertension.
• They are not recommended during pregnancy.
• First trimester effects include possible cardiovascular and CNS abnormalities.
• Second and third trimester effects include renal dysfunction, growth retardation, fetal demise, and oligohydramnios.

Oligohydramnios

• Amniotic sac has little fluid and is constricted, causing the baby's 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 immediately when pregnancy is confirmed or suspected.
• Hypertension treatment often begins with ACEs, with medication names ending in -pril.
• A common side effect of ACE Inhibitors is a dry hacking cough.
• Angiotensin Receptor Blockers (ARBs) end in -artan.

SSRIs

• Selective Serotonin Reuptake Inhibitors (SSRIs) treat depression, anxiety, and OCD and are mostly Category C, including Fluoxetine (Prozac®) and Paroxetine (Paxil®).
• In utero SSRI exposure can interfere with cardiac growth processes and leads to increased risk of cardiac defects and craniosynostosis.
• PAXIL (Paroxetine®) exposure increases the risk of anencephaly, atrial septal defects, cardiac defects, gastroschisis, and omphalocele.
• OB-GYNs utilize Risk vs Benefit for pregnant mothers when considering SSRI use.

Anticonvulsants

• Anticonvulsants treat seizure disorders and bipolar disorder, and can cause cleft palate/lip, spina bifida, atrial septal defect, developmental delay, and limb abnormalities in utero.

NSAIDs

• NSAIDs (non-steroidal anti-inflammatories) include Aleve, ibuprofen, Advil, Naproxen, ketoprofen, and celecoxib, and many women unknowingly take them during pregnancy for pain relief.
• NSAID use during pregnancy increases the risk of cardiac ventricular septal disease (VSD) when used in the first trimester, and pulmonary hypertension, and possible spontaneous abortion.
• THIRD TRIMESTER NSAID increases the risk of pulmonary hypertension in newborns.
• FIRST TRIMESTER NSAID increases the risk of cardiac ventricular septal disease (VSD) in newborns.

Warfarin (Coumadin®)

• Warfarin (Coumadin®) is an anticoagulant (blood thinner) used in patients with DVTs.
• FIRST TRIMESTER Warfarin (Coumadin) use can cause major visual deformities, nasal hypoplasia, and stippled epiphyses in newborns.

Benzodiazepines

• Treat generalized anxiety, take effect within 30 minutes, and are highly addictive.
• Medications end in -pam, e.g., Alprazolam (Xanax®), Diazepam (Valium®), Lorazepam (Ativan®) - 2nd most addictive drug after opioids.
• Benzodiazepine use can cause neonatal withdrawal, cyanosis, and hypotonia in newborns.

Acetaminophen (Tylenol)

• Recent studies have linked Tylenol use to an increased risk of autism development.

Fetal Alcohol Syndrom Disorder (FASD)

• Results from fetal developmental disabilities due to alcohol consumption at any gestational stage.
• Teratogenic effects of alcohol during pregnancy depend on the quantity of alcohol consumed and the pattern of drinking behavior.
• Mothers with Alcohol Use Disorder (AUD) typically consume > 8-10 drinks/day and are more likely to see FASD in their newborn.
• Dysmorphisms of FASD individuals include a smooth/flat philtrum, epicanthal folds, small eye openings and head, underdeveloped jaw, "railroad track" ears, and "hockey stick" palmar crease.
• Deformities of FAS include growth retardation, atrial/ventricular defects, renal dysplasia/aplasia, skeletal abnormalities, vision abnormalities, and hearing loss.

Nicotine

• Nicotine-induced vasospasm impairs fetal oxygen delivery.
• Placental changes due to smoking reduce gas exchange between mother and fetus.
• Carbon monoxide (CO) exposure reduces oxygen transport in fetal tissues.
• Tobacco use during pregnancy can lead to placenta previa, preterm premature rupture of membranes (PPROM), and placental abruption.
• Tobacco use during pregnancy, especially with genetic predispositions, significantly increases the risk of cleft lip/palate, anal atresia, gastroschisis, and other defects of the heart, kidneys, digits, and limbs.

Cocaine

• Maternal effects of cocaine use include vasoconstriction and hypertension, leading to MI, aortic rupture, and CVA.
• Suspect cocaine use in young adults presenting to the ED with an MI and no PMH of CV problems.
• Cocaine use can cause spontaneous abortion, fetal demise, and intrauterine growth retardation.
• Newborns may develop neurobehavioral issues like high-pitched crying, irritability, apnea, and tachypnea.
• Long-term effects include behavioral issues with aggression and attention span.

Opioids

• Opioids include heroin, codeine, fentanyl, opium, methadone, oxycodone, meperidine, hydrocodone, hydromorphone, and buprenorphine.
• Heroin is the most rapid-acting and most likely to produce dependence.
• Codeine increases the risk of congenital heart disease.
• Chronic heroin use increases the risk of abruptio placenta, preterm labor, and intrauterine passage of meconium.
• Opioid use during pregnancy can lead to neonatal abstinence syndrome (NAS), with newborns born addicted and weaned off with morphine.

Methamphetamine

• Methamphetamine infant effects include low birth weight, lethargy, and neurotoxicity.
• Methamphetamine maternal effects include gestational hypertension, placental abruption, and increased mortality rate.

Explore the principles of teratogenesis, which is the process by which congenital malformations are produced in an embryo or fetus. Learn about susceptibility, mechanisms, dose-dependency, and potential outcomes. Understand the critical fetal period and the effects of fetotoxicity based on timing of exposure.