Teratogens and Prenatal Health

• Teratology is the study of malformations or serious deviations from the normal type in developing organisms
• Teratogenesis is the process by which congenital malformations are produced in an embryo or fetus
• Teratogen is an exposure in pregnancy that has a harmful effect

Recognized Human Teratogens

• Medicines (antiepileptics, warfarin, methimazole, retinoic acid, etc) are recognized
• Heavy metals (lead, mercury, etc) are known teratogens
• Maternal conditions (DM, hyper-/hypothyroidism, smoking, alcohol, etc) are recognized
• Infections (CMV, Toxoplasmosis, Rubella, Varicella, etc) can act as teratogens
• Medical Procedures (CVS, amniocentesis, ICSI, D&C) are recognized
• Other factors (heat, hypotension, misoprostol, etc) can be teratogens
• Radiation (non-medical x-rays, cancer radiotherapy, etc) are human teratogens

Characteristics of a Human Teratogen

• Increases the frequency of an abnormal fetal effect
• Exhibits a dose-response effect, a threshold exists below which an exposure is harmless
• There is a period (developmental stage) of increased sensitivity through exposure
• Has an established mechanism of action, animal model often required
• The teratogenic effect must make sense biologically
• There might be genetically susceptible populations of both mothers & embryos/fetuses

Possible Fetal Effects of Human Teratogens

• Minor and/or major malformations can occur when exposed to warfarin, phenytoin, or retinoic acid
• Cancer (DES)
• Spontaneous abortion may occur due to maternal diabetes or vasoconstrictive agents
• IUGR (alcohol)
• Stillbirth (nevirapine)
• Abruptio Placentae (cocaine)
• Cognitive and developmental dysfunction may be caused by exposure to retinoic acid, phenobarbital, lead, and PCB
• Altered social behavior occurs(DES)

Possible Teratogenic Effects of Medicines

• 80%-99% of pregnant women use prescribed or OTC medicine
• Certain physiologic changes occur due to pharmacokinetic alterations during pregnancy
• Medicines may be prescribed for the benefit of the mother or fetus
• Limited or no studies during new drug development include pregnant or lactating women, which limits safety, efficacy & dosing schedule data
• Medicines’ labeling is problematic, overly simplistic, perceived as grading, used incorrectly, lacks risk description & mitigation plans, and lacks maternal disease risk

Mechanisms of Medicine-Caused Teratogenesis

• Folate antagonism
• Neural crest cell disruption
• Endocrine disruption
• Oxidative stress
• Vascular disruption
• Specific receptor- or enzyme-mediated teratogenesis

Mechanisms of Fetal Protection

• The placenta
• Fetal hepatic metabolism

Factors Affecting Medicines' Passage Through the Placenta

• Physicochemical properties of the medicine
• Dose reaching the fetus
• Rate of exposure
• Duration of exposure
• Tissue distribution
• Developmental stage
• Concurrent use of medicines, etc

Pharmacokinetic Differences Between Sexes & During Pregnancy - Absorption

• GI transit time in females is less than or equal to males, and it varies with progesterone
• Transit time increases during pregnancy
• Transport and metabolism systems change, including P-glycoprotein (P-gp) activity
• Skin: absorption is less in females than males
• Lungs: proportional to respiratory rate and depth
• Minute ventilation increases during pregnancy due to progesterone
• There are changes during cycle
• Some complain of shortness of breath
• Inhaled insulin

Pharmacokinetic Differences Between Sexes & During Pregnancy - Distribution

• For protein binding, albumin levels are approximately equal between females and males
• Alpha 1 acid glycoprotein is lower in females than males
• Free fraction drugs are higher in females than males
• Protein binding diminishes during pregnancy
• Body composition shows fat content is higher in females than males
• Females have a fat content from 33% to 48% with aging, while males range from 18% to 36% with aging
• Body water and fat increase during pregnancy

Pharmacokinetic Differences Between Sexes & During Pregnancy - Metabolism

• Drug transporters like P-gp show greater presence in males which may lead to a decrease in hepatic metabolism, role in transport and metabolism remains unclear
• Phase I enzymes: Oxidation via CYP3A overlap in substrates with P-gp
• Phase II enzymes: Conjugation, UDP-GTSulfotransferases, Methyltransferases are greater or equal in males
• N-Acetyltransferases are similar between males and females

Pharmacokinetic Differences Between Sexes

• Bioavailability differs
• Oral bioavailability tends to be greater in females compared to males
• Transdermal bioavailability is similar between males and females
• Bronchical bioavailability is greater in males vs females
• Distribution volume is different
• Water soluble is greater in females compared to males
• Lipid-soluble is greater in females than males
• Alpha 1 acid gp is greater in males as compared to females
• Renal function differences
• GFR, Tubular Secretion, and Tubular Reabsorption are greater in males
• CYPs - Hepatic and others
• CYP3A activity is greater in females compared to males
• CYP2D activity is greater in males cpmpared to females
• Conjugation shows mixed activity
• Glucur, Methyl activity is greater in males compared to females
• Acetyl activity is similar between males and females

Congenital Malformations & Medicines

• 3-5% of all live births globally have congenital defects
• 1-2% of live births in Europe have congenital defects
• An estimated <10% of congenital defects are due to medicine use during pregnancy

Pregnancy Labeling For Prescription Medicines

• The FDA pregnancy category system ranged from Category A representing controlled studies that showed no risk, to Category X defined as contraindicated in pregnancy
• Pregnancy labeling is a communication tool to ensure safe & effective use of medicines & biologics
• Labeling is owned by the manufacturer but reviewed & approved by Medicines Agencies
• Labeling must be unbiased, in line with regulations by the FDA
• New drug labeling was introduced in June 2016, marketed since 2001, fully implemented by 2020
• Drug labels need a section dedicated to safety in pregnancy, lactation and effects on fertility

Pristiq (desvenlafaxine)

• Pregnancy exposure registry monitors pregnancy outcomes for antidepressant.
• No studies on Pristiq, studies using venlafaxine have no clear association with adverse development but risks associated with SNRIs/SSRIs when treating depression during pregnancy.
• Animal studies showed no evidence of teratogenicity in plasma, but fetotoxicity was observed in one study using rats.
• All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. the risk of birth defects is 2-4% and miscarriage is 15-20%.
• Discontinuing antidepressant medication leads to relapses. If the exposure is mid to late, the risk for preeclampsia increases, and there is also risk for postpartum hemorrhage.
• Exposure to SNRIs or SSRIs leads to increased risk for neonatal complications such as prolonged hospitalization, respiratory support, and tube feeding
• Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or postpartum hemorrhage
• The use of Pristiq caused respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

Fetal Warfarin Syndrome

• Occurs in >6% of exposed pregnancies
• Limits vitamin K activation & inhibition of osteocalcin, incorrect protein folding, limited production of blood & bone growth factors
• Low birth weight, slower growth
• Microcephaly
• Mental retardation (>31%), microphthalmia
• Bone/cartilage/joint malformations
• Deafness, nasal hypoplasia
• Spontaneous abortion/stillbirth
• Congenital heart defects (>8%)
• Fetal anemia, acidosis

Fetal Retinoid Syndrome - Isotretinoin (13-cis-Retinoic Acid)

• Impaired neural crest cell migration
• Pre- & postnatal growth retardation, miscarriage, premature delivery
• Craniofacial malformations occur (microtia, hypertelorism, oral clefts, midface hypoplasia, etc)
• CNS malformations can develop (hydrocephalus, endocranial cysts, holoprosencephaly), mental retardation, learning disabilities
• Heart malformations such as transposition of the great vessels, hypoplastic left heart syndrome, ventricular septal defects, tetralogy of Fallot are associated with it
• Thymus gland abnormalities and skeletal abnormalities such as syndactyly are observed

Fetal Alcohol Syndrome

• Is a dose-related effect
• Results in pre- & postnatal growth retardation, miscarriage, intellectual impairment, and abnormal behavior
• Leads to increased irritability, increased sensitivity to sounds (hyperacusis) and abnormal muscle tone & fine motor dysfunction
• Causes brain malformations such as corpus callosum agenesia and cerebellar hypoplasia
• Results in facial abnormalities like palpebral fissures, epicanthal folds, which presents as a short, upturned nose with a broad nasal bridge, long philtrum, micrognathia, and midfacial hypoplasia

Misoprostol

• Can cause severe uterine contractions, hypoxia, and tissue damage
• Results in 3-fold increase of fetal malformations
• Results in limb malformations, arthrogryposis, amniotic bands
• Cranial nerve abnormalities can occur

Other Known Teratogenic Medicines/Environmental Factors

• ACE (angiotensin-converting enzyme) inhibitors
• Smoking
• Illicit drugs
• Androgens
• Tetracycline, doxycycline, streptomycin, fluconazole
• Anticonvulsants (phenytoin, valproic acid, etc)
• Lithium
• Antimetabolites (methotrexate)
• Antithyroid medicines
• Thalidomide
• Diethylstilbestrol
• NSAIDs/paracetamol

Lactation Facts

• Infants who are not breastfed face higher risk for developing infectious & chronic diseases
• Mothers who do not breastfeed face higher risk for cancer & metabolic diseases
• Most medications can be safely used during lactation

Milk Synthesis Regulation

• Milk synthesis is regulated by Hypothalamus release of Prolactin Inibiting Factor (PIF or Dopamine): it induces anterior pituitary to release Prolactin, which stimulates milk secretion.
• Progesterone also blocks milk synthesis

How Medicines Get Into Milk

• Drug entry related to dosing and administration is transferred through the maternal plasma which is cleared into breast milk and then orally ingested by the infant, finally clearing into the infant's plasma
• Molecular weight, ionization, solubility, protein binding, and transport mechanism facilitate this process
• Maternal drug metabolism, child age, gestational age, and concurrent illness also affect this process

Stage One of Drug Process

• Maternal drug dose
• Drug concentration in mothers blood
• Bio-availability, and excretion

Stage Two of Drug Process

• Drug concentration in mothers' milk
• Molecule size, plasma protein binding, fat solubility, acid base conditions all affect the drug

Stage Three of Drug Process

• Drug concentration in the infant's digestive tract
• Ingested volume of mother's milk affects concentration

Stage Four of Drug Process

• Drug concentration in the infant's blood
• Bioavailability, distribution, metabolism and excretion affect the drug

Stage Five of Drug Process

• The infant's health condition and pharmacodynamic factors affect the drug's effect

Factors Affecting Medicines' Presence in Milk

• An average percentage of less than 1% of the medicine an average mom takes makes its way to the milk
• Lower long half-life drug use
• Most drugs transfer via simple diffusion through milk and plasma

Additional Factors Affecting Medicines' Presence in Milk

• Infant gestational age
• Care through preterm newborns
• Infant chronological age
• 1st 4 days postpartum due to large gaps between alveolar cells
• Amount of milk consumed
• Pharmacogenomics

Pharmacogenomics - Codeine

• Codeine use case reports show in their breastfed newborns maternal postpartum pain led to respiratory failure due to ultrarapid metabolizers of cytochrome P450 2D6 causing new born exposure to morphine toxic doses
• Symptoms of this are excessive sleepiness, feeding and respiratory difficulties
• Incidence of ultrarapid metabolizers in the general population is between 1/100 to 28/100, requiring the need for anticipatory guidance

Absolute Contraindication for Lactation

• Most chemotherapeutics and radioactive lodine prohibits it

Pregnancy Registries

• It is the most common type of study issued as a post-marketing requirement in pregnant women
• Registries are a prospective observational study
• They collect information on drug exposure during pregnancy and associated pregnancy outcomes
• Enrollment is based on known drug exposure but occurs before pregnancy outcome is known
• Active collection of information from the woman and the healthcare provider

2018 New Drug Approvals With a Pregnancy Study

• Orilissa (elagolix) is used for treating endometriosis
• Aimovig (erenumab), Ajovy (fremanezumab), Emgality (galcanezumab) are used for migraine prevention
• Ilumya (tildrakizumab), Cimzia (certolizumab) are used for new psoriasis indication
• Onpattro (patisiran), Tegsedi (inotersen) are used to treat polyneuropathy in hereditary transthyretin-mediated amyloidosis
• Palynziq (pegvaliase) treats phenylketonuria
• Cryvita (burosumab) treats X-linked hypophosphatemia
• Galafold (migalostat) is used to treat Fabry disease

Better Pregnancy & Lactation Safety Data Collection

• Integrate pregnant & lactating women in the clinical research agenda
• Increase the quantity, quality & timeliness of research on therapeutic modalities used by pregnant & lactating women
• Remove regulatory barriers as well as create public awareness campaigns to include pregnant & lactating women in research studies
• Develop and implement evidence-based communication strategies with healthcare providers to improve pregnancy protocols
• Develop programs to increase data on off-label use during pregnancy & lactation
• Reduce liability to facilitate research on women who are or may become pregnant or are lactating
• Develop research protocols & study designs that include pregnant & lactating women
• Encourage discovery and development of new medicines to treat conditions occurring in pregnancy & lactation