TERATOGENS STEPHANIE TUFANO Teratogenesis Cell death Alter normal

TERATOGENS STEPHANIE TUFANO

Teratogenesis • Cell death • Alter normal growth • Interfere with cellular differentiation 4 -6% of birth defects • Fetal loss • Growth restriction • Birth defects • Impaired neuro system

Teratogenesis 1. Genetic susceptibility: genes determine mother and baby’s ability to metabolize teratogens 2. Dose & duration • 3. Example: binge drinking alcohol for 14 days is worse than 1 drink/day for a longer period of time Timing • Exposure in the first 10 -14 days of development – likely death • Organogenesis: fertilization to 10 weeks. All organ systems are susceptible. • Fetal period: nervous system, eyes, genitalia, hematopoietic system. More likely to have growth restriction disorder if exposed during this time.

Fetal Development

Pregnancy Categories

Psychiatric Medications – OB 101 • Cross placenta, found in amniotic fluid & breast milk • Risk of neonatal medication exposure vs. risk of untreated psych illness • • • Poor compliance with PNC Inadequate nutrition Exposure to additional meds, herbals, alcohol, tobacco, drugs Poor mother-infant bonding Family disruption • Shared decision making • Multidisciplinary • Single high dose medication > polypharm • Avoid changing medications • Prefer fewer metabolites, higher protein binding (this decreases placental passage), fewer interactions with other meds

Effects of untreated psychiatric illness

Neonatal Effects of Psychotropics • SSRI: cardiac, anencephaly, omphalocele • TCA: limited, possible limb anomalies • Atypicals (buproprion, venlafaxine, mirtazapine): limited, possible SAB • Anti-epileptics/Mood stabilizers: • Carbamazepine: facial dysmorphism, fingernail hypoplasia • Valproate: NT defects, craniofacial/limb, CV, developmental delay • Lamotrigine: no strong associations, possible cleft palate • Lithium – better safety profile • Early – Ebstein’s Anomaly • Later – hypoglycemia, diabetes insipidus, arrhythmias, floppy baby, reversible thyroid disease polyhydramnios,

Antidepressants

Anti-epileptics/Mood Stabilizers

Surveillance during treatment

Isotretinoin • Cystic Acne • Cell apoptosis • Oral: 50% SAB rate, ear anomalies, CNS malformations, hydrocephalus, cerebellum abnormalities, severe intellectual disability, seizures, optic nerve/retinal abnormalities, conotruncal heart defects, thymic defects, and dysmorphic features (cleft palate, microcephaly, micrognathia) • Pregnancy Prevention Program/i. PLEDGE: contracts between patient & provider that pledge patient’s willingness to take monthly birth control & use 2 forms of birth control • Topical: no significant associations, but use as prescribed

Antibiotics 1. Tetracycline • FDA class D • Calcification • Discoloration of “baby” teeth. No change to permanent teeth. • Reduced bone growth during exposure. Reversible after d/c. 2. Quinolones • FDA class C • Historically associated with arthropathy & interference with development of cartilage – only been shown in animals • Highly unlikely, but insufficient data to say “no risk”

Angiotensin Converting Enzyme Inhibitor (ACE-I) / Angiotensin II Receptor Blocker (ARB) 1. First Trimester – weak evidence • Congenital cardiac (septal defects, PDA), CNS malformations 2. Second/Third Trimester • Growth restriction • Oligo – pulmonary hypoplasia, RDS, skeletal deformations • Anuria – renal failure due to tubular dysgenesis 3. Long Term – renal effects can be reversible, but some studies have shown CKD requiring long term dialysis

RAAS Refresher

ACE-I/ARB • Hypothesized pathogenesis 1. 2. 3. Fetus has relatively low perfusion pressures -> blocked angio II by ACE-I/ARB -> decreased GFR -> oligo/anuria Angio II block -> no feedback to release vasodilatory prostaglandins -> decreased uteroplacental flow -> growth restriction Angio II has role in fetal growth esp. of fetal kidney

Alcohol • There is no “safe” amount • Equally susceptible in all trimesters 1. 1 st tri: facial/major structural anomalies 2. 2 nd tri: SAB 3. 3 rd tri: low birth weight • Fetal Alcohol Spectrum Disorder (FASD): facial features + CNS abnormalities + growth retardation • Fetal alcohol syndrome (FAS) • Partial fetal alcohol syndrome (p. FAS) • Alcohol-related neurodevelopmental disorder (ARND) • Neurobehavioral disorder associated with prenatal alcohol exposure (ND- PAE) • Alcohol-related birth defects (ARBD)

FAS Characteristic Facial Features

Tobacco • No significant increase in structural congenital anomalies. • Possible link to cleft palate, anal atresia, cardiac defects, limb defects • Pregnancy: preterm labor, placental abruption, fetal demise, growth restriction, pre-eclampsia • Long Term: SIDS, T 2 DM, pulmonary function, cognitive function, behavioral problems, schizophrenia

Illicit Drugs Heroin • Congenital anomalies risk similar to general population. 1. • Associated factors are threat: infection, high risk behaviors, mental illness, exposure to violence, poor prenatal care • Pregnancy: preterm labor, placental abruption, fetal demise, growth restriction, meconium, NAS • Methadone/suboxone advantages: oral administration, known dose and purity, safe and steady availability, improved maternal/fetal/neonatal outcomes Cocaine • Pregnancy: vasoconstrictive effects 2. • SAB, fetal demise, abruption, growth restriction, preterm labor • Mimics pre-eclampsia, but DO NOT give labetalol • Long term effects: limited due to confounders • Behavioral, language, memory, attention, executive function, processing

Conclusions • Definitive data can be sparse, but neonatal outcomes described are impacting enough to place significant thought into the use of these substances • Risk vs. benefit • Multidisciplinary approach • Importance of proper surveillance

Teratogen Reference Databases • Organization of Teratology Information Specialists (OTIS) • Teratogen Information System (TERIS) • Mother to Baby

References • https: //www. acog. org/Clinical-Guidance-and-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins- Obstetrics/Use-of-Psychiatric-Medications-During-Pregnancy-and-Lactation#table 2 • https: //www. acog. org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Obstetric- Practice/Opioid-Use-and-Opioid-Use-Disorder-in-Pregnancy • https: //www. uptodate. com/contents/fetal-alcohol-spectrum-disorder-clinical-features-and- diagnosis? topic. Ref=4798&source=related_link#H 191778440 • https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 2835909/ • https: //www. fda. gov/drugs/emergencypreparedness/bioterrorismanddrugpreparedness/ucm 130712. htm • https: //www. uptodate. com/contents/substance-use-by-pregnant- women? search=cocaine%20 pregnancy&source=search_result&selected. Title=1~150&usage_type=default&disp lay_rank=1#H 18 • https: //www. uptodate. com/contents/cigarette-and-tobacco-products-in-pregnancy-impact-on-pregnancy-and- theneonate? section. Name=ADVERSE%20 OUTCOMES&topic. Ref=5010&anchor=H 7&source=see_link#H 383471023 9 • https: //www. uptodate. com/contents/adverse-effects-of-angiotensin-converting-enzyme-inhibitors-and- receptor-blockers-in-pregnancy? topic. Ref=110900&source=related_link#H 6 • https: //mothertobaby. org/fact-sheets-parent/