Absorption from GI tract • No accurate way exists to measure level in infant’s bloodstream – Tolerance of chemical to pH of stomach – Enzymatic activity of intestinal tract – Volume of milk consumed • Oral bioavailability of a compound is a major factor of risk
Infant’s ability to Detoxify and Excrete agent • Any drug given to infant by any route has to be evaluated • According to Infant’s ability to detoxify or conjugate chemical in liver and excrete it in urine or stool
Infant’s ability to Detoxify and Excrete agent • The maturity of infant at birth is an extremely important factor during first few months of life – Less mature infant, less well tolerate drugs – Immaturity of organ systems – Difference in body composition • Less mature, greater water content and proportion of extracellular water • Protein is similar for all newborns, binding is less in smaller infant • Amount of body fat is low in less mature infant
Infant’s ability to Detoxify and Excrete agent
Breast milk/plasma ratio for drugs usually not useful • M/P ratio is the concentration of drug in milk versus in maternal plasma at the same time • It presumes that relationship between two concentration remains constant, which it does not • M/P ratio is most valuable if obtained when an infant would be nursed • If the ratio 1:0, it mean only the level are equal
M/P Ratio
Safety for infant • To determine the dose delivered to an infant, the following formula is used: Dose/24 hours = Concentration of drug in milk x Weight kg of infant x Volume of milk per kg ingested in 24 hours Dose/24 hours = Cmilk x Weight x Volume/kg/24 hours
Safety for infant • The relative infant dose (RID) it is also recommended that not more than 10% be acceptable RID = Absolute infant dose mg/kg/day x 100 Maternal dose mg/kg/day
Correlation of drug safety in pregnancy and lactation • Very rarely is valid information • Because pharmaceutical companies usually merely indicate that it should not be taken during pregnancy and lactation • Drugs that are contraindicated in pregnancy may be acceptable during lactation
Oral bioavailability • The dose of drug delivered via milk to infant is significantly affected by oral bioavailability • If compound is poorly absorbed, it is less concern • Most drugs administered by injection only are not orally bioavailable
Food-Drug interaction • Because a breastfed infant receives all maternal medications excreted in milk “with food” • Effect of food may reduce GI absorption or irritation
Mechanisms of food-drug interactions • Physiologic – Changes in gastric emptying – Increase intestinal motility, splanchnic blood flow, bile, acid, enzyme secretion – Induction and inhibition of drug metabolism – Competition in active transport
Mechanisms of food-drug interactions • Physiochemical – Food as a mechanical barrier to absorption – Altered dissolution of drugs – Chelation and adsorption • Pharmacodynamic – Altered enzyme activity – Changes in homeostasis
FDA Prescription drug labeling changes
http://apps.who.int/iris/bitstream/ 10665/62435/1/55732.pdf WHO 2002
Dec 2020
https://www.ncbi.nlm.nih.gov/books/NBK501922/
http://e-lactancia.org/
Antipyretic and analgesic drugs Aspirin Diclofenac Ibuprofen Tramadol Fentanyl Morphine Mefenamic acid (Ponstan) Acetaminophen (Paracetamol)
Antihistamine drugs CPM (<4mg/day) Loratadine Cetirizine
Antibiotic drugs Azithromycin Erythromycin Roxithromycin Ciprofloxacin Norfloxacin Ofloxacin Doxycycline (<1wk) Metronidazole (<2gm/day) Amoxicillin Augmentin Cloxacillin Dicloxacillin Gentamicin Vancomycin
Antifungal drugs Amphotericin B Fluconazole Ketoconazole Nystatin Acyclovir Antiviral drugs Anti-TB drugs Isoniazid Rifampicin Streptomycin
Endocrine drugs PTU (<450mg/day) Thyroxine Methimazole (<30mg/day) Prednisolone (<60mg/day) Metformin
Antihypertensive drugs • ACEIs Captopril Enalapril • Calcium channel blocker Diltiazem Nifedipine Verapamil • Beta blockers Labeterol Propranolol
Anticonvulsant drugs Carbamazepine Phenytoin Valproic acid Lorazepam Midazolam (Dormicum) Sumatriptan Antipsychotic drugs Sertraline Haloperidol Olanzapine
Caffeine • The level in milk is low (1% of level in mother) and infant’s plasma level is also low • If mother drank > 6-8 cups of any containing beverage in a day, infant could accumulate symptomatic amounts of caffeine; wideeyed, active, alert infant, wakefulness, jitteriness • Soft drink often contributed to caffeine build up
Avoid if possible May inhibit Lactation • HCTZ • Amiloride • Furosemide • Ergotamine • Estrogen • Progestin • Pseudoephridine • Dopaminergic agents
Drugs should be avoid • ACEIs • Alcohol • Acebutolol • Amphetamine • Fluoxetine
Contraindicated • Iodides • Lithium • Clozapine • Amiodarone • Ergot alkaloids • Methotrexate • Immunosuppressants • Antineoplastic agents • Radioactive substances
• Favipiravir (T-705) is a synthetic prodrug • Excellent bioavailability (94%) • Protein binding 54% • Low volume of distribution (10-20 l) • Cmax reach within 2 hr • Short half-life 2.5-5 hr • Rapid renal elimination
Is it safe for a mother to breastfeed her infant if she has silicone breast implants? Research is limited; however, there have been no recent reports of clinical problems in infants of mothers with silicone breast implants. Can a mother breastfeed after breast or nipple surgery? Usually. Most mothers who have had breast or nipple surgery are able to produce some milk, but not all of these mothers will be able to produce a full milk supply for their infants.
DRUG THERAPY OF THE LACTATING WOMAN • Is drug therapy really necessary? If drugs are required, consultation between the pediatrician and the mother's physician can be most useful in determining what options to choose. • The safest drug should be chosen, for example, acetaminophen rather than aspirin for analgesia. • If there is a possibility that a drug may present a risk to the infant, consideration should be given to measurement of blood concentrations in the nursing infant. • Drug exposure to the nursing infant may be minimized by having the mother take the medication just after she has breastfed the infant or just before the infant is due to have a lengthy sleep period.
Minimizing effect of maternal medication 1. Do not use the long-acting form of drug 2. Schedule doses so the least amount possible gets into the milk 3. Watch the infant for any unusual signs or symptoms 4. When possible, choose the drug that produces the least amount in the milk
กรณีทราบแน่ชัดว่ายาที่มารดาได้รับมีผลต่อทารก หรือเป็นยาที่ห้ามใช้ในหญิงให้นมบุตร • งดให้นมบุตรระหว่างรับประทานยา • บีบนมทิ้งเพื่อกระตุ้นการหลั่งน้ำนม • หลังจากหยุดยา ควรเว้นระยะ 4-5 เท่าของค่าครึ่ง ชีวิตของยาก่อนจะเริ่มให้นมบุตรอีกครั้ง
References • Lawrence, Ruth A., Breastfeeding: a guide for the medical profession-8th edition, 2015 • Martin, Richard J., Fanaroff, Avroy A., Walsh Michele C., Fanaroff and Martin’s neonatalperinatal medicine: disease of the fetus and infant-10th edition, 2015 • The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics, Committee on Drugs, Pediatrics, September 2013 • Breastfeeding and maternal medication, Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs, WHO, 2003
10/04/62 1 Jaundice associated with breast feeding Premsak Lao-yoo-khong, MD. Division of Neonatology Queen Sirikit National Institute of Child Health Bilirubin Metabolism Bilirubin metabolism Bilirubin production Bilirubin clearance and excretion • Transport • Hepatic uptake • Conjugation • Excretion Bilirubin production is derived primarily from the breakdown of senescent circulating erythrocytes Extrahepatic bilirubin is bound to serum albumin and delivered to the liver Hepatocellular uptake Uridine diphosphate glucuronyl transferase (UDPG-T) enzyme conjugate/direct bilirubin Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residua of intact pigments are excreted in the feces, with some reabsorbtion and re-excretion into bile Physiologic VS Pathologic
10/04/62 2 Physiologic Pathologic Onset DOL 2-3 Within first 24 hours Duration 1 week (Term) 2 weeks (Preterm) 2 weeks Not exclusive breast fed Sign & Symptom normal Hemolysis / Cholestasis Bilirubin indirect Indirect Direct : > 1.5-2 mg/dL > 20% of TB Rate of rising of IDB < 5 mg/dL/day > 0.2 mg/dL/hr or > 5 mg/dL/day Bilirubin Encephalopathy Bilirubin Encephalopathy Acute Bilirubin Encephalopathy • Acute manifestation of bilirubin toxicity seen in the 1st week after birth Chronic Bilirubin Encephalopathy ( Kernicterus ) • The chronic and permanent clinical sequalae of bilirubin toxicity Increase free bilirubin Diminished plasma albumin Free bilirubin deposit at basal ganglia & brain stem nuclei Drug & chemical displace bilirubin from albumin Risk factors of Bilirubin Encephalopathy Increase free bilirubin concentration • Isoimmune hemolytic anemia • G6PD deficiency • Hypoalbuminemia Brain immaturity • Prematurity Damage blood brain barrier • Hypoxia Alteration blood brain barrier permeability • Sepsis • Hyperosmolarity • Acidosis
10/04/62 3 Initial phase (1st few days) • Slight stupor • Slight hypotonia • Poor sucking • Seizure • High-pitched cry Intermediate (middle of 1st weeks) • Moderate stupor • Irritability • Hypertonia involved extensor muscle • Neck : Retrocollis • Trunk : Opisthotonos • Fever • High-pitched cry Advance phase (after 1st weeks) • Deep stupor – coma • Increase tone • Shrill cry • Refuse to feed • Apnea • Fever • Seizure • Death Chronic Bilirubin Encephalopathy ( Kernicterus ) Manifestation (1st year age) • Hypotonia • Increase deep tendon reflex • Delayed motor skill • Obligatory tonic neck reflex Chronic Bilirubin Encephalopathy ( Kernicterus ) Feature Manifestation after 1st year Extrapyramidal Choreoathetosis Auditory Sensory neural hearing loss Visual Upward gaze paralysis Dental Dental enamel dysplasia Intellectual (minor) Mental retardation Duration of Hyperbilirubinemia Duration of Exposure with TSB > 20 mg /dl Incidence of Neurologic Abnormalities < 6 hr 2.3 % 6 -11 hr 18.7 % ≥ 12 hr 26 % Avery’s Neonatology Pathophysiology and Management of the Newborn : 7 edition ; 2016 Breast milk & Breast feeding jaundice Enterohepatic circulation