Drugs and lactation A .Hosseini Nouri MD Pediatrician Guilan university of medical science Drug Use During Lactation Almost all medications enter the breast milk, Amount absorbed by the amount in breast milk infant Despite this lack of information, most drugs are considered safe while breastfeeding. Passage of drugs from Maternal Blood to Milk In general, drugs enter breast milk by passive diffusion. The presence and concentration of compounds in breast milk depend on a number of important factors, including the: drug’s molecular weight lipid solubility protein binding in blood amount and composition of the drug’s half-life milk degree of ionization Drugs characteristics that minimize transfer into breast milk Molecular weight >200 daltons Weakly acidic High degree of protein binding Water soluble M/P (Milk to plasma ratio ) M/P =the ratio of concentration of the drug in milk to the drug concentration in maternal plasma. MP<1 No accumulation of drug in milk MP=1 Equal accumulation of drug in milk and plasma MP>1 accumulation of drug in milk>plasma M/P× Maternal plasma drug concentration = milk drug concentration Estimated daily infant dose(mg/kg/day) = Milk drug concentration(mg/ml)×volume breast milk ingested(cc/kg/day) RID (relative infant dose) More accurate tool to estimate infant exposure to a drug RID(%) = estimated daily infant dose (mg/kg/day) ——————————————————— × 100 maternal dose(mg/kg/day) RID >10% CONCERN Antibiotics Most antimicrobial agents appear to be safe for nursing infants. Broad antimicrobial spectra diarrhea or trush no contrandication contraindication in breastfeeding sulfanamides Chloramphenicol?? tetracyclines hyperBilirubinemia Dental staining VLBW/Premature/G6PDD Antibiotics Metronidazole : Is present in breast milk similar to maternal plasma RID : 13.7-22.9% Case reports :Loose stools/oral and perineal candida or trush have ben reported in breastfeeding infants exposed to metronidazole. Compatible with breatfeeding Anticoagulants The use of anticoagulants may be critical to health of a mother with a history of pulmonary embolism, venous thrombosis, or other clotting disorder. synthetic heparin has a much Heparin (MW of ~20,000 daltons) lower MW(3000 daltons) too large for passage into breast milk. does not enter breast milk Oral Anticoagulants warfarine indanedione groups: Bishydroxycoumarine Ethyl biscoumacetate Oral choice Drug Factor X a inhibitor Direct thrombin inhibitor Pass into breast Weak acid apixaban milk High PB Rivaroxaban Anticonvulsants Valproic acid is known to have teratogenic potential when taken during pregnancy, but is thought to be compatible with breastfeeding because of the low levels of drug transferred to milk (RID = 1.4%- 1.7%). platelete Liver test Lamotrigine (RID of 9.2% - 18.3%) and topiramate (RID of 3% -23%), more readily transferred into breast milk, there are minimal reports of adverse effects in the infants. Liver test Breastfeeding while taking any of the above anticonvulsants should be encouraged, with appropriate monitoring of the infant for any signs of toxicity (e.g., apnea, sedation). Anticonvulsants Phenytoin: is found in small amounts in breast milk(compatible with breastfeed). Phenobarbital :safe(but metabolized much more slowly in neonates /monitor for lethargy or poor weight gain). Lithium:contraindicated during lactation(cardiovascular/CNS signs).if mother require lithium,should be permitted to continue to breast feed with close infant monitoring, Check blood lithium concentrations in the infant 1 to 2 w after initiating renal function tests Cbc diff thyroid function tests Feeding /weight gain Antidepressant Postpartum depression affects up to 20% of women. Unfortunately, breastfeeding mothers often discontinue therapy to avoid perceived harm to the infant. Selective serotonin reuptake inhibitors (SSRIs) and serotonin & NE reuptake inhibitors (SNRIs) are the most common antidepressants used in breastfeeding mothers. Fluoxetine (prozac), has a long half-life .Although there are reports of significant fluoxetine plasma levels in infants, but no adverse effects have been identified. Limited reports of inappropriate weight gain irritability Colic.vomiting.diarrhea, sleep disorder.seizure Sertraline or paroxetine are often the drugs of choice and the most well-studied SSRI for nursing mothers; produces very low or undetectable milk and infant plasma levels. Antidepressant In general, SSRIs and SNRIs are considered compatible with breastfeeding, benzodiazepines Lorazepam : safe(short half life/no active metabolites) Clonazepam:not recommended(long half life/apnea/hypotonia) Diazepam:avoid for lactating patients( long half life/high amount of secretion to milk/sedation/poorfeeding/apnea/hypotonia) The primary concern in using benzodiazepines in lactating women is withdrawal in infants Tricyclic antidepressant (TCA) Nortriptyline : is preferable drug Doxepine : is generally not prescribed to lactating women long Half life Respiratory depression high accumulation hypotonia sedation poorfeeding vomiting hypnotics A review of studies that examined secretion of zaleplon , zolpidem and zopiclone into breast milk and adverse effects in infants concluded that theses hypnotics are compatible with breastfeeding Antipsychotics The exacerbation of psychotic disorders is also very common in the postpartum period, and is often treated with a newer class of drugs, the atypical antipsychotics. olanzapine Quetiapine (RID 1.2 %) RID (0.07%-0.1%) Clozapine (contraindicated) (Agranolocytosis/seizure /speech delay) few reported adverse effects risperidone RID 2.8%-9.1 %) dependent on maternal dose, so it is recommended that the lowest effective dose be used and that the infant be monitored closely for signs of toxicity such as somnolence or lethargy. Antipsychotics Pediatricians should assess : Infant behavior Feeding Alertness Sleep disturbances Irritability Agitation Excessive crying Poor weight gain Extrapyramidal symptoms Bs level.cpk.stifness Antihypertensives β-Blockers most are compatible with breastfeeding. Metoprolol inderal Labetalol ok Atenolol Acebutolol No Cyanosis-hypotension-bradycardia Antihypertensives Angiotensin-converting enzyme inhibitors: ACEIs Captopril have a RID of 0.002% Enalapril have a RID 0.175%, and neither has been associated with adverse effects in exposed infant ARBs Angiotensin receptor blockers: Limited data –should avoided if possible Ca nifedipine, verapamil, and diltiazem, all are considered compatible with channel- breastfeeding. blocker Compatible with breastfeeding –note dehydration risk and decrease milk Diuretic production. Oral Contraceptives Contraceptives with high concentration of estrogen and progestin may depress lactation. Previously, it was believed that progestin-only contraception would decrease the risk of lactation suppression, but more recent data suggest no difference between minipill or combined oral contraceptives with regard to successful breastfeeding and milk production. Thus ,any of OCP ,which contain low maternal hormones doses ,are compatible with breastfeeding Pain Medications SAFE NSAIDs, such as ibuprofen(RID 0.0008%), are acidic drugs with low lipid solubility and high protein binding; thus, transfer into breast milk is not favored. SAFE Acetaminophen, the RID is higher (8.81%), Opioid: concern for sedation or lethargy in infant Morphine codeine RID of (9.1 %). sedation’’ tramadol Warning (FDA) choice death’’ Hydrocodone oxycodone RID (0.2%-9%). Reflux Medications H2 blockers : Famotidine and ranitidine have relatively low RIDs (1.9% and 1.3%- 4.6%,) and are considered safe. Cimetidine should be avoided during lactation ,much higher RID (up to 32.6%) Proton pump inhibitors (omeprazole, lansoprazole) are also a safer alternative to cimetidine, as there is minimal drug transfer into breast milk and any drug that is present is not well absorbed by the infant. ANTIDIABETIC AGENTS Insulin does not transfer into the milk ,so is safe. first generation oral hypoglycemic agents are less used nowadays. Second generation like glyburide, glipizide and gliclazide cause less exposure for infant so their use in diabetes type II breastfeed mothers should be encouraged. Metformin = probably safe Thyroid drugs Levothyroxin : safe(No change in infant TFT) PTU :(high protein bindig /less transfer to milk/hepatic injury in infant) Methimazol : more transfer to milk than PTU / CHOICE Iodide : affects infant’s TFT (prolonged consumption is not recommended) Dopamine agonist Bromocriptin Rheumatic disease medication Hydroxychloroquine : compatible with breastfeeding Sulfasalazine: compatible with breastfeeding but avoid breastfeeding premature infants or hyperbilirubinemia or G6PDD ASA: low dose(80 mg) :compatible with breastfeeding AZT ,6MP : compatible with breastfeeding Cholchicine : compatible with breastfeeding NSAIDS: ibuprofen is preferred Glucocorticoids: compatible with breastfeeding(discarding breast milk 4 hours after ingestion of a dose of >20 mg) IVIG : compatible with breastfeeding Rheumatic disease medication Cyclosporine /tacrolimus :most evidence suggests that can be taken. Cyclophosphamide : contraindicated Methotrexate :contraindicated Mycophenolate : no data (should be avoided) Leflunomide : contraindicated Biologic agents : limited data NON Theraputic agents in breast milk Caffeine: ingestion of 1 cup of coffee 1.5 mg caffeine /ml milk 1hour Consistent consume /large quantity infant wakefulness / jitteriness Nicotine : Nicotine from