Pregnancy and Lactation Lecture Notes PDF

Pregnancy & Lactation Chrysanthi Sardeli Obstetrician-Gynecologist Assoc. Professor of Pharmacology & Clinical Pharmacology Department of Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, AUTh...

Pregnancy & Lactation Chrysanthi Sardeli Obstetrician-Gynecologist Assoc. Professor of Pharmacology & Clinical Pharmacology Department of Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, AUTh E-mail: [email protected] Teratology-Teratogenesis-Teratogen The study of malformations or serious deviations from the normal type in developing organisms (Definition of Teratology) The process by which congenital malformations are produced in an embryo or fetus (Definition of Teratogenesis) An exposure in pregnancy that has a harmful effect (Definition of Teratogen) Recognized Human Teratogens Medicines (antiepileptics, warfarin, methimazole, retinoic acid, etc.) Heavy Metals (lead, mercury, etc.) Radiation (non-medical x-rays, cancer radiotherapy, etc.) Maternal Conditions (DM, hyper-/hypothyroidism, smoking, alcohol, etc.) Infections (CMV, Toxoplasmosis, Rubella, Varicella, etc.) Medical Procedures (CVS, amniocentesis, ICSI, D&C) Other (heat, hypotension, misoprostol, etc.) 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 to the exposure There is an established mechanism of action (an animal model is 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 (warfarin, phenytoin, retinoic acid) Cancer (DES) Spontaneous Abortion (maternal diabetes, vasoconstrictive agents) IUGR (alcohol) Stillbirth (nevirapine) Abruptio Placentae (cocaine) Cognitive and Developmental Dysfunction (retinoic acid, phenobarbital, lead, PCB) Altered Social Behavior (DES) Possible Teratogenic Effects of Medicines It has been estimated that about 80%-99% of pregnant women have used a prescribed or OTC medicine (Peters & Schaefer, 2001 & Lacroix I et al, 2000) Certain physiologic changes occurring in pregnancy alter significantly pharmacokinetics, differing among pregnancy trimesters Medicines may be prescribed for the benefit of the mother or for the benefit of the fetus Limited or no studies performed during new drug development include pregnant or lactating women, limited safety, efficacy & dosing schedule data Medicines’ labeling is problematic, overly simplistic, perceived as grading, used incorrectly by physicians, lacks risk description & mitigation plans, lacks data regarding maternal disease risk (up to 2016) Mechanisms by which medicines cause 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 Intervillus space Placental septum Fetal hepatic metabolism Chorionic villus Chorion Endometrial arteries Umbilical arteries and veins Umbilical vein Amnion Factors affecting medicines’ passage through the placenta Physicochemical properties 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 F≤ M, vary with Progesterone Transit time increased in pregnancy Transport and metabolism systems, P glycoprotein (P-gp)? Skin: F=M Lungs: proportional to respiratory rate and depth F minute ventilation < M Changes during cycle Pregnant F minute ventilation > M (Progesterone) Complain of feeling “short of breath” Inhaled insulin Pharmacokinetic Differences between sexes & during Pregnancy Distribution Protein Binding Albumin F≈M Alpha 1 acid glycoprotein FM Diminished during pregnancy Body Composition Fat content F>M F from 33% to 48% with aging M from 18% to 36% with aging Body water, fat increase during pregnancy Pharmacokinetic Differences between sexes & during Pregnancy Metabolism (Data – limited/conflicting) Drug Transporters P-gp M>F, may decrease hepatic metabolism Role in transport and metabolism remains unclear Phase I Enzymes Oxidation CYP3A, overlap in substrates with P-gp Phase II Enzymes Conjugation M≥F, UDP-GT, Sulfotransferases, Methyltransferases M=F, N-Acetyltransferases Pharmacokinetic Differences between sexes Bioavailability Renal Oral F>M GFR M>F Transdermal M=F Tubular Secretion M>F Bronchial Tubular Reabsorption M>F M>F CYPs – Hepatic and others Distribution Volume CYP3A F>M Water Sol CYP2D M>F M>F Lipid Sol F>M Conjugation Glucur, Methyl M>F Protein Binding Acetyl F=M Albumen F=M Alpha 1 acid gp M>F Congenital Malformations & Medicines 3-5% of all live births 1-2% in Europe An estimated 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) 60% of exposed pregnancies Impaired neural crest cell migration Pre- & postnatal growth retardation, miscarriage, premature delivery Craniofacial malformations (microtia, hypertelorism, oral clefts, midface hypoplasia, etc) CNS malformations (hydrocephalus, endocranial cysts, holoprosencephaly), mental retardation, learning disabilities Heart malformations (transposition of the great vessels, hypoplastic left heart syndrome, ventricular septal defects, tetralogy of Fallot Thymus gland abnormalities, skeletal abnormalities (syndactyly) Fetal Alcohol Syndrome Dose related effect Pre- & postnatal growth retardation, miscarriage, intellectual impairment, abnormal behavior Increased irritability, increased sensitivity to sounds (hyperacusis), abnormal muscle tone & fine motor dysfunction (tremulousness, weak grasp, poor hand-eye coordination) Brain malformations (corpus callosum agenesia, cerebellar hypoplasia) Facial abnormalities (palpebral fissures, epicanthal folds, short, upturned nose with a broad nasal bridge, thin upper lip, long philtrum, micrognathia, midfacial hypoplasia) Misoprostol Severe uterine contractions, hypoxia, tissue damage 3-fold increase of fetal malformations Limb malformations, arthrogryposis, amniotic bands Cranial nerve abnormalities Misoprostol Other known Teratogenic Medicines/Environmental Factors ACE (angiotensin converting enzyme) inhibitors Smoking Illicit drugs Androgens Tetracyclin, doxycyxlin, streptomycin, fluconazole Anticonvulsants (phenytoin, valproic acid, etc) Lithium Antimetabollites (methotrexate) Antithyroid medicines Thalidomide Diethylstilbestrol NSAIDs/paracetamol Lactation Infants who do not breastfeed 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 PK during pregnancy is not the same as during lactation How do medicines get into milk? Factors affecting medicines’ presence in milk Average % of drug that will find its way into mother's milk < 1% Bioavailablilty how much medications reaches the plasma Caught in liver, destroyed in gut, no absorbed in the small intestine. Choose drugs with low bioavailability Half life Long half life drugs problematic if taken over a long period accumulate in infant 5 half lives is rule of thumb for drug elimination Most drugs transfer via simple diffusion milk/plasma ratio Factors affecting medicines’ presence in milk Lipid soluble drugs the more lipid soluble the higher the drug in milk Molecular size of medication the larger the molecular size the less likely it is to enter milk compartment Protein binding the more a drug binds to plasma albumin the less available in the plasma Dose rapid or sustained release timing e.g. night Route (inhaled, topical and ophthalmic preparations not in plasma) Other factors Infant gestational age Care with preterm newborns Infant chronological age 1st 4 days postpartum due to large gaps between alveolar cells Amount of milk consumed Pharmacogenomics Pharmacogenomics - Codeine Case reports of maternal use of codeine for postpartum pain and neonatal respiratory failure in their breastfed newborn Both mothers were found to be ultrarapid metabolizers of cytochrome P450 2D6, leading the newborn to be exposed to toxic doses of morphine Incidence of ultrarapid metabolizers in the general population is between 1/100 to 28/100 Symptoms include excessive sleepiness, feeding and respiratory difficulties Need for anticipatory guidance Absolute contraindication for lactation Most chemotherapeutics Radioactive Iodine Collecting Safety Data regarding Medicines Use in Pregnancy Case reports Case series Pregnancy registries Epidemiological studies (Scandinavian patient registries) (RTCs) Pregnancy Registries Better Pregnancy & Lactation Safety Data Collection Include & 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 Create public awareness campaigns aimed to the public & clinicians regarding the need to include pregnant & lactating women in research studies Develop & implement EB communication strategies with healthcare providers on information related to research in pregnancy & lactation Better Pregnancy & Lactation Safety Data Collection 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 Remember to develop research protocols & study designs that include pregnant & lactating women Encourage discovery & development of new medicines specifically aimed to treat conditions occurring in pregnancy & lactation