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Pharmacy Notes

Comprehensive Guidelines for Medication Use During Pregnancy and Lactation

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An in-depth overview of pharmacokinetic changes, fetal development stages, and safe prescribing practices for pregnant and lactating women to optimize maternal and fetal health.

  • pregnancy
  • breastfeeding
  • safe prescribing
  • fetal development
  • maternal medication

By Dr. Ayesha Fatima

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  1. Slide 1. GENERAL PRESCRIBING GUIDELINES FOR PREGNANCY & LACTATION Presented by Dr. Ayesha Fatima Pharm D Assistant Professor Dept of Pharmacy Practice
  2. Slide 2. ● Medication doses for acute and chronic illnesses are generally the same as those used in non-pregnant adults. ● However, some drugs require dose adjustments or alternative drug selection because pregnancy alters maternal physiology and may affect fetal development. ● The primary goal of drug therapy during pregnancy is to provide benefit to the mother while minimizing risks to the fetus. Drug Use in Pregnancy
  3. Slide 3. Physiology of Pregnancy Fertilization (Fallopian Tube) ↓ Zygote Formation ↓ Cell Division During Transport ↓ Blastocyst (Day 6) ↓ hCG Production Begins ↓ Implantation in Endometrium ↓ Embryo (Weeks 2–8) ↓ (Organogenesis) Fetus (>8 Weeks) ↓ (Growth & Maturation) Term Pregnancy (~40 Weeks LMP) 1. Fertilization ➔ Fertilization occurs in the fallopian tube. ➔ A sperm attaches to the outer layer of the ovum called the zona pellucida. ➔ This attachment prevents other sperm from entering the egg. ➔ The sperm releases enzymes that help it penetrate the zona pellucida. ➔ The sperm membrane and egg membrane fuse together. ➔ A single cell called a zygote is formed. ➔ Maternal and paternal chromosomes combine to form one nucleus and initiate cell division.
  4. Slide 4. 2. Transport to the Uterus Time After Fertilization Event Day 0 Fertilization occurs in fallopian tube Day 2 Fertilized egg reaches uterus while dividing Days 3–5 Continued cell division in uterine cavity Day 6 Cell mass becomes a blastocyst Day 6 onward Implantation begins 3. Blastocyst Formation ➔ By approximately 6 days after fertilization, the developing cell mass is called a blastocyst. ➔ The blastocyst begins producing human chorionic gonadotropin (hCG). ➔ hCG is the hormone detected in pregnancy tests. 4. Implantation ➔ The blastocyst sheds the zona pellucida. ➔ It attaches directly to the uterine lining (endometrium). ➔ The blastocyst grows into the endometrial wall. ➔ By day 10 after fertilization, implantation is complete. ➔ Maternal blood begins supplying nutrients to the developing embryo.
  5. Slide 5. 5. Embryonic and Fetal Periods Embryonic Period ➔ Begins approximately during the 3rd week after fertilization. ➔ The developing organism is called an embryo. ➔ Lasts from 2–8 weeks postfertilization. ➔ Most major organs and body structures form during this period (organogenesis). ➔ This is the period of greatest susceptibility to teratogenic drugs. Fetal Period ➔ Starts after the embryonic period (after 8 weeks postfertilization). ➔ The embryo is now called a fetus. ➔ Growth, maturation, and functional development of organs occur. ➔ Continues until delivery.
  6. Slide 7. Characteristics of Pregnancy Duration of Pregnancy ➔ Pregnancy lasts approximately 280 days from the first day of the last menstrual period (LMP) . ➔ This corresponds to about 38 weeks after fertilization. ➔ This equals: ◆ 40 weeks ◆ 9 months ➔ Pregnancy duration is conventionally calculated from the LMP, even though fertilization usually occurs about 2 weeks later. Gestational Age ➔ Gestational age is the age of the embryo or fetus measured from the first day of the last menstrual period (LMP) . ➔ Since ovulation and fertilization usually occur about 2 weeks after the LMP: ◆ Gestational age is approximately 2 weeks greater than the actual fetal age . Example ➔ LMP: January 1 ➔ Fertilization: January 15 (approximately) ➔ On February 12: ◆ Gestational age = 6 weeks ◆ Actual fetal age = 4 weeks Trimesters of Pregnancy Pregnancy is divided into three trimesters , each lasting approximately 3 calendar months . Trimester Duration First Trimester 0–13 weeks Second Trimester 14–27 weeks Third Trimester 28–40 weeks
  7. Slide 8. Estimated Due Date (EDD) Naegele's Rule: To calculate the expected date of delivery: EDD = First day of LMP + 7 days − 3 months + 1 year Example ● LMP = 10 January 2025 ● Add 7 days = 17 January 2025 ● Subtract 3 months = 17 October 2024 ● Add 1 year = 17 October 2025 Expected Due Date = 17 October 2025 Fetal Movement (Quickening) Definition ● First perception of fetal movement by the mother. Timing ● Usually felt between 14–20 weeks of gestation. Influence of Previous Pregnancies Woman Type Time of Perceiving Fetal Movement Multiparous (previous pregnancies) Earlier Primiparous (first pregnancy) Later
  8. Slide 10. Maternal Pharmacokinetic Changes During Pregnancy Pregnancy produces several physiological changes that alter the absorption, distribution, metabolism, and excretion (ADME) of drugs. These changes can influence drug concentrations, therapeutic response, and toxicity, sometimes requiring dosage adjustments. Pharmacokinetic Process Physiological Change During Pregnancy Effect on Drug Therapy Absorption Gastrointestinal motility ↓ Decreased Slower gastric emptying and intestinal transit; delayed drug absorption Lung function ↑ Increased Greater absorption of inhaled medications Skin blood circulation ↑ Increased Enhanced absorption of transdermal and topical drugs
  9. Slide 11. Pharmacokinetic Process Physiological Change During Pregnancy Effect on Drug Therapy Distribution Plasma volume ↑ Increased Dilution of water-soluble drugs, lowering plasma concentrations Total body water ↑ Increased Increased volume of distribution for hydrophilic drugs Plasma proteins (especially albumin) ↓ Decreased Increased free (unbound) fraction of highly protein-bound drugs Fat deposition ↑ Increased Increased storage and distribution of lipophilic drugs Metabolism Liver enzyme activity ↑ or ↓ Variable Some drugs are metabolized faster, others more slowly depending on the enzyme involved Excretion Glomerular filtration rate (GFR) ↑ Increased Faster renal elimination of drugs excreted unchanged in urine
  10. Slide 12. Pharmacokinetic Process Pregnancy Change Clinical Effect Gastric motility ↓ Delayed drug absorption Gastric acidity ↓ Altered absorption of weak acids/bases Pulmonary blood flow ↑ Increased inhalational drug absorption Plasma volume ↑ 30–50% Dilution of drugs Total body water ↑ 8 L Increased Vd of hydrophilic drugs Albumin ↓ Increased free drug fraction Hepatic metabolism Variable (↑ or ↓) Drug-specific dose changes Renal plasma flow ↑ 100% Increased renal clearance GFR ↑ 50–70% Faster elimination of renally excreted drugs
  11. Slide 13. Absorption Factor Change During Pregnancy Effect on Drug Absorption Gastric Emptying & Intestinal Transit Time Increases by 30–40% due to progesterone Delayed absorption and delayed onset of action Gastric Secretions Gastric acid decreases, mucus secretion increases, gastric pH increases Reduced absorption of weak acids; increased absorption of weak bases Morning Sickness Nausea and vomiting increase May reduce absorption of oral medications; parenteral route may be preferred near term for rapid effect Pulmonary Absorption Cardiac output, respiratory volume, pulmonary blood perfusion increase; hyperventilation develops Enhanced absorption of inhalational anesthetics, bronchodilators, volatile drugs, environmental pollutants, and cigarette smoke
  12. Slide 14. Distribution Factor Change During Pregnancy Effect on Drug Distribution Plasma Volume Increases by approximately 30–50% Increased volume of distribution (Vd) and lower plasma drug concentrations Cardiac Output Increases by approximately 30% Enhanced tissue perfusion and drug distribution Total Body Water Increases by about 8 L (60% to placenta, fetus, and amniotic fluid; 40% to maternal tissues) Increased Vd of hydrophilic drugs and reduced plasma concentrations Renal Blood Flow Increases by up to 50% by the end of the first trimester Greater distribution of drugs to the kidneys Uterine Blood Flow Increases throughout pregnancy and peaks at 36–42 L/hour at term Increased drug delivery to the uterus, placenta, and fetus Clinical Consequences Altered drug distribution Some drugs may require larger loading doses and therapeutic drug monitoring
  13. Slide 15. EXAMPLES Change During Pregnancy Effect on Drug Distribution Hydrophilic Drugs Distributed into expanded body water compartment Increased Vd and lower plasma concentrations Lipophilic Drugs Greater distribution into maternal fat stores Potentially prolonged drug half-life
  14. Slide 16. Protein Binding Factor Change During Pregnancy Effect on Protein Binding / Clinical Significance Albumin Decreases due to hemodilution and increased plasma volume Reduced binding of acidic drugs (e.g., phenytoin, salicylates, valproic acid) α1-Acid Glycoprotein Remains relatively unchanged Binding of basic drugs (e.g., β-blockers, opioid analgesics) remains largely unchanged Hormonal Effects Steroid and placental hormones occupy protein-binding sites Further increases free (unbound) drug fraction Free Drug Fraction Increases as protein binding decreases Increased pharmacologically active drug concentration Total Drug Concentration Often decreases Does not necessarily indicate reduced therapeutic effect Clinical Implication Clinical effect depends on free drug concentration Dose escalation is usually not required based solely on reduced total drug levels
  15. Slide 17. EXAMPLES Change During Pregnancy Effect on Protein Binding / Clinical Significance Phenytoin Albumin binding decreases and hepatic metabolism increases Total concentration falls; free phenytoin monitoring is preferred Antiepileptic Drugs Phenytoin, Carbamazepine, and Valproic acid show reduced total concentrations Free fraction increases; therapeutic monitoring may be required
  16. Slide 18. Metabolism Factor Change During Pregnancy Effect on Drug Metabolism / Clinical Significance CYP3A4, CYP2D6, CYP2A6, CYP2C9 Activity increases (↑) Increased drug metabolism, increased clearance, reduced plasma concentrations, may require higher doses UGT1A1, UGT1A4, UGT2B7 Activity increases (↑) Enhanced glucuronidation and faster drug elimination CYP1A2, CYP2C19 Activity decreases (↓) Reduced metabolism, drug accumulation, increased risk of toxicity, dose reduction may be needed Progesterone High circulating levels induce hepatic enzymes Accelerated metabolism of many drugs, especially lipid- soluble drugs Clinical Implication Effects vary among drugs Therapeutic drug monitoring may be required; dose adjustments should be individualized
  17. Slide 19. Excretion Factor Change During Pregnancy Effect on Drug Excretion / Clinical Significance Renal Plasma Flow Increases by approximately 100% Enhanced renal drug elimination Glomerular Filtration Rate (GFR) Increases by approximately 50% within the first few weeks and may reach 70% above non-pregnant values Increased clearance of renally excreted drugs Clinical Implication Renal drug excretion is significantly increased Lower steady-state plasma concentrations; higher doses or more frequent administration may be required
  18. Slide 20. EXAMPLES Change During Pregnancy Effect on Drug Excretion / Clinical Significance Cardiovascular Drugs Atenolol, Sotalol, Digoxin show increased renal elimination Reduced steady-state drug concentrations Other Drugs Lithium, Dalteparin sodium, Enoxaparin sodium show increased renal elimination Enhanced clearance and possible need for dose adjustment Antibiotics Ampicillin, Cefuroxime, Ceftazidime, Cefazolin, Piperacillin show 20–65% increased renal elimination Lower plasma concentrations; dose adjustment may be required Examples Lithium, Digoxin, Penicillin Increased clearance during pregnancy
  19. Slide 21. Fetal–Placental Drug Transfer ➔ The placenta serves as the interface between maternal and fetal circulation. ➔ The placenta is not an absolute barrier but a selective membrane. ➔ Most drugs administered to the mother can cross the placenta and reach the fetus to some extent. ➔ The extent of drug transfer determines fetal exposure and potential effects. ➔ The degree of transfer depends on the drug's properties, placental characteristics, and fetal factors. ➔ F etal:maternal drug concentration ratio is less than 1 .
  20. Slide 23. Physiochemical properties Physicochemic al Property Change / Characteristic Effect on Placental Transfer Clinical Significance Lipid Solubility Lipophilic (fat-soluble) drugs Cross the placenta readily Achieve higher fetal concentrations Hydrophilic (water- soluble) or highly ionized drugs Cross slowly Lower fetal exposure Molecular Size < 500 Da Crosses readily Significant fetal exposure possible 500–1000 Da Crosses partially Moderate fetal exposure > 1000 Da Minimal transfer Limited fetal exposure Insulin, Heparin Negligible transfer Generally do not reach the fetus in significant amounts
  21. Slide 24. Physicochemic al Property Change / Characteristic Effect on Placental Transfer Clinical Significance Degree of Ionization Non-ionized drugs Cross membranes easily Greater placental transfer Ionized drugs Cross poorly Reduced placental transfer Ion Trapping Fetal blood is slightly more acidic than maternal blood Weak bases become ionized after entering fetal circulation and cannot easily diffuse back Accumulation of weakly basic drugs in the fetus
  22. Slide 25. Placental Factors - Protein binding Change / Characteristic Effect on Placental Transfer Clinical Significance Protein Binding Only the free (unbound) fraction of a drug can cross the placenta Determines the amount of drug reaching the fetus Major determinant of fetal drug exposure Maternal Albumin Decreases gradually during pregnancy Increases free drug fraction in maternal circulation May increase placental transfer of some drugs Fetal Albumin Increases with fetal growth Alters fetal drug binding capacity Fetal and maternal drug concentrations may differ Highly Protein- Bound Drugs Remain largely bound in maternal blood Cross the placenta poorly Lower fetal concentrations Poorly Protein- Bound Drugs Higher free drug fraction Cross the placenta more readily Higher fetal exposure
  23. Slide 26. Placental Factors Change / Characteristic Effect on Placental Transfer Clinical Significance Fetal Protein Binding Differences Ampicillin & Benzylpenicillin: lower fetal affinity; Salicylates: higher fetal affinity Influences fetal drug concentrations May alter fetal drug effects Placental Transporters P-gp, BCRP, and MRP3 act as efflux transporters Pump drugs from fetal circulation back to maternal circulation Reduce fetal drug exposure and accumulation Placental Metabolism Placental enzymes metabolize drugs May detoxify or bioactivate drugs before reaching the fetus Can either protect the fetus or increase fetal toxicity
  24. Slide 27. FETAL FACTORS
  25. Slide 28. Maternal Pharmacodynamic Changes During Pregnancy ➔ Drug exposure during pregnancy can affect the mother, fetus, and neonate . ➔ These effects may be therapeutic , predictable pharmacological effects , or unpredictable (idiosyncratic/teratogenic) effects . ➔ Pharmacological effects are the predictable effects produced by a drug because of its known mechanism of action. ➔ Characteristics 1. Most common type of fetal drug effect. 2. Usually dose-dependent . 3. Generally predictable . 4. Often reversible . 5. Occur much more frequently than teratogenic or idiosyncratic effects.
  26. Slide 33. Drug Therapy in Pregnancy: Dosing, Drug Selection, and Counseling The management of medications during pregnancy requires balancing the benefits to the mother against the potential risks to the fetus . Drug therapy should be individualized, evidence-based, and guided by a careful risk–benefit assessment.
  27. Slide 36. FDA Pregnancy Risk Categories (Historical Classification) Cate gory Definition Examples Risk/Recommendation A Controlled human studies show no fetal risk . Multivitamins (recommended doses), Magnesium sulfate Safest category B Animal studies show no fetal risk , but adequate human studies are lacking. Amoxicillin, Paracetamol (Acetaminophen) Generally considered safe C No adequate human studies; animal studies show adverse effects or data are lacking. Morphine, Atropine Use only if benefits outweigh risks D Positive evidence of fetal risk exists, but benefits may justify use in serious conditions. Aspirin (especially high doses), Phenytoin Use when clearly indicated X Proven fetal abnormalities; risks clearly outweigh any possible benefit. Thalidomide, Estrogens (historical classification), Isotretinoin Contraindicated in pregnancy
  28. Slide 39. Stage Duration Developmental Characteristics Possible Drug Effects Key Clinical Point 1. Pre- implantation Stage (Blastocyst Stage) Conception to implantation (0–16 days after fertilization) Rapid cell division; cells are undifferentiated All-or-None Phenomenon: (a) Embryonic death/spontaneous abortion or (b) No lasting effect with normal development No teratogenesis occurs during this stage 2. Organogenesis Period 17–56 days after fertilization (≈ 3–8 weeks gestation) Formation of major organs (heart, brain, limbs, eyes, ears, kidneys) No measurable effect, abortion, gross anatomical defects (limb defects, cardiac defects, neural tube defects), or permanent functional/metabolic defects Period of maximum teratogenic risk Stages of Pregnancy and Drug Effects
  29. Slide 40. Stage Duration Developmental Characteristics Possible Drug Effects Key Clinical Point 3. Second and Third Trimesters After organogenesis until birth Growth and functional maturation of organs Growth retardation (IUGR, low birth weight), brain development abnormalities, behavioral defects, premature labor, neonatal toxicity, delayed postnatal effects (e.g., cancer, reproductive abnormalities) Functional development is most vulnerable during this period 4. Labour and Delivery Stage During labor and immediately before birth Continued placental drug transfer; immature neonatal liver and kidneys Respiratory depression, CNS depression, poor feeding, neonatal toxicity, withdrawal syndrome (opioids, benzodiazepines, antidepressants) Neonatal toxicity is the major concern
  30. Slide 41. Drug Prescribing During Pregnancy Drugs may be prescribed during pregnancy for: 1. Treatment of common minor ailments 2. Treatment of pre-existing or pregnancy-aggravated medical illnesses The guiding principle is to use the safest effective drug at the lowest effective dose while balancing maternal benefits against fetal risks.
  31. Slide 42. 1. Treatment of common minor ailments Condition Preferred/Safe Drugs Important Notes Pain & Fever (Analgesics/Antipyretics) Paracetamol (Acetaminophen) Drug of choice; safe at recommended doses throughout pregnancy Aspirin May decrease neonatal platelet adhesiveness and increase maternal intrapartum blood loss Nausea & Vomiting Meclizine, Cyclizine Generally considered safe Promethazine Possible association with congenital dislocation of the hip Metoclopramide Useful for severe nausea and vomiting; can be used during labor and anesthesia Heartburn & Dyspepsia Aluminum hydroxide, Magnesium trisilicate Preferred non-absorbable antacids Sucralfate, H₂-receptor blockers, Bismuth subsalicylate Considered safe options
  32. Slide 43. Condition Preferred/Safe Drugs Important Notes Constipation Bran, Isapghula (Psyllium), Methylcellulose Bulk-forming laxatives are preferred Stimulant laxatives Avoid; may cause uterotonic effects and uterine contractions Common Cold Loratadine, Fexofenadine, Cetirizine Non-sedating antihistamines Chlorpheniramine, Diphenhydramine Sedating antihistamines Phenylephrine, Pseudoephedrine Oral decongestants Cough Guaifenesin, Ipecac, Terpin hydrate Expectorants Codeine, Dextromethorphan Antitussives
  33. Slide 44. 2. Treatment of pre-existing or pregnancy-aggravated medical illnesses Condition Preferred/Safe Drugs Important Notes Bronchial Asthma Salbutamol, Terbutaline May cause maternal/fetal tachycardia; maternal hyperglycemia; fetal hypoglycemia Salmeterol Long-acting β₂ agonist Beclomethasone, Budesonide Preferred inhaled corticosteroids Nedocromil Minimal systemic adverse effects Oral corticosteroids May increase risk of pre-eclampsia
  34. Slide 45. Condition Preferred/Safe Drugs Important Notes Hypertension Methyldopa Drug of choice; safe throughout pregnancy Hypertensive Emergency Hydralazine IV, Labetalol IV Used for severe hypertension Atrial Flutter/Fibrillation Digoxin Drug of choice Arrhythmias Quinidine Relatively safe in late pregnancy Anticoagulation Heparin Does not cross placenta Thrombolysis Streptokinase, Urokinase, t-PA Generally acceptable when indicated Use with Caution Atenolol, Acebutolol, Labetalol Traditionally avoided during first 28 weeks
  35. Slide 46. Condition Preferred/Safe Drugs Important Notes Epilepsy Phenobarbital, Phenytoin, Carbamazepine Use lowest effective dose Valproate - Contraindicated Neural tube defects and major congenital malformations Folic Acid Supplementation 5 mg/day Recommended for all women with epilepsy Anxiety/Panic Disorders Diazepam, Lorazepam, Midazolam, Alprazolam Chronic use may cause neonatal withdrawal Depression Fluoxetine, Sertraline SSRIs generally safe Antipsychotic Therapy Chlorpromazine No increased malformation risk Use with Caution Lithium Risk of neonatal goiter, floppy baby syndrome, Ebstein anomaly
  36. Slide 47. Condition Preferred/Safe Drugs Important Notes Diabetes Mellitus Insulin Preferred treatment Diet modification First-line management Hyperthyroidis m Propylthiouracil (PTU) Preferred due to less placental transfer Alternative Methimazole/Carbimazole May be used when PTU toxicity is a concern Contraindicated Radioactive iodine, Stable iodine Fetal thyroid damage
  37. Slide 48. Category Drugs Notes Safe Penicillins, Amoxicillin Widely used Safe Cephalosporins Short half-life, safe Safe Aztreonam Safe Safe Erythromycin base Preferred macrolide Avoid Erythromycin estolate Hepatotoxicity Contraindicated Chloramphenicol Gray baby syndrome Contraindicated Tetracyclines Teeth and bone toxicity Avoid Co-trimoxazole Folate antagonism, kernicterus Avoid Quinolones Generally avoided Use if Necessary Gentamicin, Tobramycin Preferred aminoglycosides
  38. Slide 49. Category Notes Rifampicin Safe Isoniazid Give with pyridoxine Ethambutol Safe Streptomycin Avoid (ototoxicity) Condition Drugs Candidiasis/Moniliasis Nystatin, Miconazole, Clotrimazole Condition Drugs Herpes/Varicella Acyclovir HIV Infection Zidovudine Category Drugs Notes Safe Chloroquine Preferred Resistant Malaria Quinine Acceptable Avoid Primaquine Hemolysis in G6PD deficiency Condition Drugs Scabies/Lice Lindane Amoebiasis Metronidazole, Diodoquin, Diloxanide
  39. Slide 50. Category Notes General Anesthetics No currently used agent is a proven teratogen Local Anesthetics Accidental fetal exposure may cause neonatal seizures Vitamin Effect Folic Acid Prevents neural tube defects High-dose Vitamin K May cause hemolysis, jaundice, hepatotoxicity High-dose Vitamin A Teratogenic; causes renal, CNS, and neural tube defects
  40. Slide 52. Teratogens and Fetotoxic Drugs in Pregnancy T eratogenicity is the ability of a drug, chemical, infection, radiation, or environmental agent to cause congenital malformations (birth defects) or abnormal fetal development when exposure occurs during pregnancy. A substance that causes such abnormalities is called a teratogen . A teratogen is any drug, chemical, infectious agent, physical factor, or environmental exposure that can cause permanent structural, functional, behavioral, or developmental abnormalities in the embryo or fetus when exposure occurs during pregnancy. Even without exposure to any known teratogen, the risk of congenital abnormalities in pregnancy is approximately 3% . Criteria for a Substance to be Considered Teratogenic A substance should: 1. Produce a Characteristic Pattern of Fetal Defects Example: Thalidomide → limb reduction defects 2. Act During a Specific Developmental Stage Usually during organogenesis (3–8 weeks gestation). 3. Demonstrate Dose Dependence Higher exposure leads to greater risk and severity.
  41. Slide 53. Wilson's Six Principles of Teratology (1959) These principles remain the foundation of modern teratology. 1. Genetic Susceptibility: Susceptibility to teratogenesis depends on: ➔ Genotype of the embryo/fetus ➔ Interaction with environmental factors 2. Timing of Exposure: Teratogenic effects vary according to the developmental stage at exposure. 3. Specific Mechanism of Action: Teratogens act through specific mechanisms on developing tissues and cells. 4. Access to Developing Tissues: The ability of a teratogen to reach fetal tissues influences its effect. 5. Types of Developmental Outcomes: Teratogens may cause: 1. Death 2. Malformation 3. Growth retardation 4. Functional impairment 6. Dose-Response Relationship: The frequency and severity of abnormalities increase with increasing dose.
  42. Slide 54. Major Teratogenic and Potentially Toxic Drugs Drug/Class Major Fetal Effect Vitamin A derivatives (Isotretinoin) Craniofacial, cardiac, CNS defects ACE inhibitors Fetal renal failure, oligohydramnios Warfarin Fetal warfarin syndrome Estrogens and Androgens Sexual differentiation abnormalities Alcohol Fetal alcohol syndrome Lithium Ebstein anomaly, neonatal toxicity Anticonvulsants Neural tube defects and congenital malformations Antineoplastics Multiple congenital anomalies Finasteride Abnormal male genital development Tetracyclines Tooth discoloration and bone growth inhibition https://app.milanote.co m/1WvxjM1Y0C5Fbs/t eratogens
  43. Slide 55. Important Drug-Specific Teratogenic Effects Drug/Class Teratogenic Effect Major Manifestations Thalidomide Phocomelia Severe limb reduction defects ("seal limb" deformity) Androgens & Progestins Virilization of female fetus Ambiguous genitalia, masculinization Tetracyclines Dental and skeletal toxicity Permanent tooth discoloration, enamel hypoplasia, retarded bone growth Alcohol Fetal Alcohol Syndrome (FAS) Low IQ, cognitive impairment, behavioral abnormalities, growth retardation Antithyroid Drugs Thyroid dysfunction Fetal goiter, congenital hypothyroidism Isotretinoin (Retinoids) Multiple congenital malformations Craniofacial abnormalities, congenital heart defects, CNS abnormalities
  44. Slide 56. Drug/Class Teratogenic Effect Major Manifestations Warfarin Fetal Warfarin Syndrome Depressed nasal bridge, eye abnormalities, hand defects, growth retardation Phenytoin Fetal Hydantoin Syndrome Hypoplastic distal phalanges, cleft lip/palate, microcephaly, growth retardation Carbamazepine Neural tube and craniofacial defects Neural tube defects, craniofacial abnormalities, other congenital malformations
  45. Slide 57. Mechanisms of Teratogenesis ➔ Teratogenic drugs produce congenital abnormalities by interfering with normal embryonic and fetal development. ➔ Six major mechanisms have been identified that explain how medications cause teratogenic effects.
  46. Slide 59. Fetotoxic Drug Effects Fetotoxicity refers to harmful pharmacological effects on the developing fetus that do not necessarily produce structural malformations.
  47. Slide 60. Fetotoxic Effects Fetotoxic Effect Drugs/Substances Involved Major Manifestations/Consequences Fetal CNS Depression Barbiturates, Tranquilizers, Antidepressants, Narcotic analgesics, General anesthetics Reduced fetal activity, neonatal respiratory depression, poor feeding Neonatal Bleeding NSAIDs, Anticoagulants Prolonged bleeding, hemorrhagic complications Neonatal Withdrawal Syndrome Barbiturates, Opioids, Benzodiazepines, Alcohol Irritability, tremors, jitteriness, feeding difficulties, seizures Reduced Birth Weight Cigarette smoking, Alcohol, Illicit drug abuse Low birth weight, impaired fetal growth, increased neonatal morbidity
  48. Slide 61. Mechanisms by Which Drugs Affect the Fetus Drugs may affect fetal development through: 1. Direct Action on the Embryo/Fetus ● Lethal effects ● Toxic effects ● Teratogenic effects 2. Alteration of Placental Function ● Reduced nutrient transfer ● Reduced oxygen transfer 3. Changes in Myometrial Activity ● Premature uterine contractions ● Preterm labor 4. Alteration of Maternal Physiology ● Maternal hypotension ● Maternal hypoxia ● Metabolic disturbances
  49. Slide 62. Substance Use During Pregnancy and Fetal Effects Substance Placental Transfer / Exposure Major Fetal & Neonatal Effects Alcohol Crosses placenta freely; fetal alcohol levels may approach maternal levels due to immature fetal metabolism Fetal Alcohol Syndrome (FAS) , growth restriction, low birth weight, poor postnatal growth, intellectual disability, learning difficulties, behavioral disorders Smoking (Cigarettes) Nicotine and other toxic substances cross the placenta Low birth weight, intrauterine growth restriction (IUGR), preterm birth, respiratory problems, increased neonatal mortality, cerebral palsy, learning and behavioral disorders
  50. Slide 63. Illicit drugs/ Recreational drugs Placental Transfer / Exposure Major Fetal & Neonatal Effects Marijuana Crosses placenta Low birth weight, developmental delay, behavioral problems Cocaine Crosses placenta readily Low birth weight, congenital abnormalities, developmental and behavioral disorders Heroin Crosses placenta readily Neonatal withdrawal syndrome, low birth weight, developmental problems Amphetamin es Cross placenta Growth restriction, congenital abnormalities, behavioral disorders Ecstasy (MDMA) Crosses placenta Low birth weight, developmental delay, behavioral abnormalities
  51. Slide 64. Drug Use in Lactation (Breastfeeding) ➔ Breast milk is the best source of nutrition for infants. ➔ Provides all essential nutrients and energy for the first 6 months of life . ➔ Recommended exclusively for 6 months by: World Health Organization (WHO) and United Nations Children's Fund (UNICEF) ➔ Protects infants against: ◆ Gastrointestinal infections ◆ Respiratory tract infections ◆ Urinary tract infections ➔ Reduces the risk of: Obesity later in life ➔ Supplies protective antibodies: IgA, IgM ➔ These immunoglobulins help protect against gastroenteritis and infections .
  52. Slide 65. Flow of Drug Transfer Maternal Drug Administration ↓ Drug enters maternal blood ↓ Free (unbound) drug available ↓ Passive diffusion across mammary alveolar cells ↓ Drug enters breast milk ↓ Infant exposure during breastfeeding ➔ Almost all drugs can enter breast milk. ➔ The main mechanism is passive diffusion . ➔ Only the un-ionized (non-charged) and unbound (free) form of the drug crosses easily. ➔ Drugs pass through the lipid membranes of mammary alveolar cells . ➔ Drug transfer follows the pH partitioning theory . The amount of drug reaching the infant depends on: Maternal Dose + Maternal Plasma Concentration + Drug Properties + Duration of Breastfeeding Infant Drug Exposure
  53. Slide 66. Drug Characteristics Associated with Minimal Milk Transfer Acidic drugs Highly protein-bound drugs Low to moderate lipophilicity Example: Most NSAIDs, warfarin Drug Characteristics Associated with High Milk Transfer Weakly basic drugs Low protein binding Highly lipophilic drugs Example: Sotalol, erythromycin
  54. Slide 67. Factors Affecting Drug Transfer into Breast Milk Factor Effect on Drug Transfer into Milk Examples / Notes Milk pH (7.2) vs Plasma pH (7.4) Milk is slightly more acidic, causing ion trapping of weak bases Weak bases (e.g., erythromycin ) accumulate in milk; weak acids (e.g., penicillins ) remain in plasma pKa (Degree of Ionization) Drugs that are more ionized cross less readily Drugs with higher pKa values generally have higher milk/plasma ratios Protein Binding Only free (unbound) drug enters milk Highly protein-bound drugs have low milk concentrations Lipophilicity Lipid-soluble drugs cross milk more easily Many CNS-active drugs enter milk readily Molecular Weight Smaller molecules cross more readily <200 Da: readily cross; >6000 Da (e.g., insulin, heparin): virtually excluded https://whimsical.com/ayesha964/plac ental-drug-transfer- DD27i7GvGmAR3LNEcriXEs
  55. Slide 68. Factor Effect on Drug Transfer into Milk Examples / Notes Maternal Plasma Concentration Higher maternal blood levels increase milk concentrations Drug transfer is proportional to maternal concentration Stage of Lactation Drug transfer is greater in colostrum than mature milk Colostrum contains more protein and less fat Alveolar Cell Gaps (First Week Postpartum) Increased permeability allows more drug passage Gaps close by the end of the first week under prolactin influence Milk Composition Variations in fat and protein content can alter transfer End-of-feed milk contains more fat than beginning-of-feed milk Active Transport (Pumping Systems) Some drugs are actively secreted into milk Iodides can achieve high concentrations in breast milk
  56. Slide 69. Milk-to-Plasma Ratio (M/P Ratio) Definition The Milk-to-Plasma Ratio (M/P Ratio) is the ratio of: Interpretation M/P Ratio Interpretation < 1 Lower concentration in milk than plasma = 1 Equal concentration in milk and plasma > 1 Higher concentration in milk than plasma High M/P ratio Greater transfer of drug into breast milk
  57. Slide 70. A high M/P ratio does not necessarily mean toxicity because infant exposure also depends on: 1. Oral Bioavailability of the Drug ➔ Some drugs may be present in high concentrations in milk. ➔ However, they are poorly absorbed from the infant's gastrointestinal tract. ➔ Therefore, actual infant exposure remains low. 2. Infant Drug Clearance ➔ Premature infants and newborns have: ◆ Immature liver function ◆ Reduced renal function ◆ Slower drug elimination ➔ Even small amounts of drug may accumulate and cause toxicity. 3. Drug Elimination Rate ➔ Drugs with rapid clearance are removed quickly from the infant. ➔ Thus, exposure may remain low despite a high M/P ratio.
  58. Slide 71. Potential Risks Despite Low Exposure Although pharmacological toxicity is uncommon, some infants may develop: 1. Idiosyncratic Reactions : Unpredictable, Rare, Not dose dependent 2. Increased Sensitivity: Some infants may be unusually sensitive to very small drug amounts, especially: a. Premature infants b. Neonates c. Infants with hepatic impairment d. Infants with renal impairment
  59. Slide 72. Medication Timing in Breastfeeding Mothers If a nursing mother must take a medication that is considered relatively safe: Take the medication 30–60 minutes after breastfeeding AND Take it 3–4 hours before the next feeding This strategy helps to: ● Reduce the drug concentration in breast milk during the next feed. ● Minimize infant exposure to the medication. ● Maintain breastfeeding while ensuring maternal treatment. Breastfeed Baby ↓ Take Medication (30–60 min later) ↓ Drug level gradually falls ↓ Next Feed after 3–4 hours ↓ Lower drug exposure to infant
  60. Slide 73. Drugs That Suppress or Inhibit Lactation Drug/Class Effect on Lactation Bromocriptine Suppresses prolactin secretion → inhibits milk production Estradiol (Estrogens) Reduces milk supply High-dose Oral Contraceptives Decrease breast milk production Levodopa Suppresses prolactin release and lactation Trazodone May reduce milk production Bendroflumethiazide Can suppress lactation, especially at higher doses
  61. Slide 74. Assessing the Risk to the Breastfed Infant ➔ Focuses on how much harm the drug may cause to the infant ➔ Infant risk during breastfeeding depends on the drug's toxicity, amount transferred into milk, oral bioavailability, presence of active metabolites, half-life, infant maturity, maternal dosing regimen, and route of administration. ➔ Premature infants and those receiving exposure to long-term maternal therapy are at the greatest risk of adverse drug effects.
  62. Slide 75. Factors Affecting Infant Risk from Maternal Drug Therapy Factor Significance / Effect on Infant Risk Examples / Notes Drug Adverse Reaction Profile Inherent toxicity of the drug is a major determinant of infant safety. Antineoplastic drugs, radionuclides, iodine-containing compounds are high-risk. Relative Infant Dose (RID) Estimates the amount of maternal drug received by the infant through breast milk. Lower RID generally indicates lower risk. Commonly used to assess breastfeeding safety. Oral Bioavailability Drugs poorly absorbed from the infant's gastrointestinal tract produce less systemic exposure. Drug may be present in milk but not significantly absorbed. Active Metabolites Active metabolites can prolong infant exposure and increase accumulation. Diazepam → Desmethyldiazepam. Drug Half-Life Long half-life drugs remain in the infant longer and may accumulate. Fluoxetine.
  63. Slide 76. Factor Significance / Effect on Infant Risk Examples / Notes Infant Maturity / Gestational Age Premature infants have immature hepatic and renal function, resulting in slower drug elimination. A 30-week gestation infant has ~10% of maternal drug clearance. Maternal Drug Regimen Chronic therapy and multiple drugs increase infant exposure and toxicity risk. Psychotropics and anticonvulsants may have additive effects. Route of Maternal Administration Determines maternal plasma concentration and therefore breast milk concentration. Topical/Inhalational < Oral < Systemic therapy. Single vs Chronic Therapy Single doses or short courses are usually low risk; chronic therapy increases accumulation risk. Long-term treatment requires closer monitoring. Multiple Maternal Medications Simultaneous use of several drugs increases the risk of adverse effects in the infant. Psychotropic drugs, anticonvulsants. Pharmacogenetic Factors Genetic differences in drug metabolism may alter infant susceptibility to adverse effects. Variability in drug clearance and toxicity.
  64. Slide 77. Infant Drug Clearance Infant Status Drug Clearance Capacity Clinical Implication Premature infant (~30 weeks gestation) ~10% of maternal clearance Highest risk of drug accumulation and toxicity Full-term infant Higher than premature infant Lower risk but still reduced compared with adults Infant aged 6–7 months Approaches adult values Drug elimination becomes more efficient
  65. Slide 79. Drug/Class Safety in Breastfeeding Important Notes / Infant Effects Ibuprofen Safe Preferred analgesic during lactation. Indomethacin Generally safe Low transfer into milk; seizures have been reported rarely. Aspirin Short-term use acceptable Theoretical risk of Reye's syndrome; prolonged use should be avoided. Paracetamol (Acetaminophen) Safe Very little excreted into breast milk; well tolerated by infants. Morphine Safe Low oral bioavailability in the infant. Fentanyl Safe Low oral availability; minimal infant exposure. Meperidine (Pethidine) Avoid if possible May cause seizures and CNS effects in the infant. Codeine Use cautiously Rarely causes infant sedation; monitor infant. Individual Drugs During Lactation
  66. Slide 80. Drug/Class Safety in Breastfeeding Important Notes / Infant Effects Heparin Safe Large molecular weight; negligible transfer into milk. Warfarin Safe Highly protein bound; infant observation recommended. Corticosteroids Caution with high doses/long-term use May suppress infant growth and endogenous steroid production. Penicillins Safe May occasionally cause loose stools in the infant. Cephalosporins Safe Generally well tolerated. Erythromycin Safe Compatible with breastfeeding. Aminoglycosides Generally safe Poorly absorbed from infant gut; minimal systemic exposure. Sulfonamides Use cautiously Avoid if infant has G6PD deficiency or hyperbilirubinemia. Sulfisoxazole Preferred sulfonamide Lowest excretion into breast milk.
  67. Slide 81. Drug/Class Safety in Breastfeeding Important Notes / Infant Effects Tetracyclines Short-term use acceptable Safe up to 10 days; long-term use may stain teeth and affect enamel. Chloramphenicol Contraindicated Risk of serious toxicity in the infant. Chloroquine Avoid if possible Potential risk of retinal damage in the infant. Metronidazole Special precautions required If 2 g single dose is given, suspend breastfeeding for 24 hours and discard expressed milk. Ketoconazole Safe Highly protein bound; low milk transfer. Acyclovir Safe Minimal infant exposure; considered compatible with breastfeeding.
  68. Slide 82. Drug/Class Potential Effect on Breastfed Infant Safer Alternative / Recommendation Anticancer drugs Serious toxicity to infant Contraindicated Radiopharmaceuticals Radiation exposure to infant Contraindicated Ergot derivatives (Ergotamine, Methysergide) Adverse infant effects; suppress lactation Contraindicated Chloramphenicol Risk of serious toxicity (Gray baby syndrome) Contraindicated Phenylbutazone Serious adverse effects Contraindicated Thiouracil Thyroid suppression in infant Contraindicated Iodides Thyroid dysfunction in infant Contraindicated Mercurials Neurotoxicity Contraindicated Drugs to Be Avoided During Lactation
  69. Slide 83. Drug Adverse Effects in Infant Preferred Alternative / Advice Acebutolol Hypotension, tachypnea Avoid Atenolol Hypotension, cyanosis Propranolol preferred Clemastine Drowsiness, feeding problems, neck stiffness Cetirizine, Loratadine Amiodarone Thyroid and cardiovascular toxicity Monitor infant thyroid and cardiac function if used long-term Chlorpromazine Sedation, reduced developmental score Avoid if possible Haloperidol Reduced developmental score Use cautiously Diazepam Infant sedation and accumulation Midazolam preferred Lamotrigine Significant infant exposure Monitor infant plasma levels Drugs with Documented Adverse Effects During Breastfeeding
  70. Slide 84. Drug Adverse Effects in Infant Preferred Alternative / Advice Acebutolol Hypotension, tachypnea Avoid Atenolol Hypotension, cyanosis Propranolol preferred Clofazimine Red discoloration and skin pigmentation Avoid if possible Ephedrine Irritability Avoid Aminophylline (>200 mg every 6 hrs) Irritability Use cautiously Combined Oral Contraceptives (Estrogen + Progesterone) Reduced milk production Progestin-only pills or barrier methods

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