Medications and Breastfeeding

3. Medications and Breastfeeding ArmanianAmir Mohammad, MD Neonatologist Assistant Professor of IsfahanFaculty of Medicine

4. The use of a medication by the breastfeeding mothercontinues to be a common reason for unnecessarily stopping breastfeeding. • Usually this occurs because the mother gets incorrect advice as to what drugs are safe for the breastfed infant. • The goal of successful maternal therapy during lactation is to provide the necessary therapeutic compounds to the breastfeeding mother while minimizing the amount of drug passed through the milk to the child, and those amounts that are transferred do not cause any significant changes in the child.

5. Pharmacologic Principles • There are several factors that enhance drug transfer into human milk, including • low molecular weight • high lipid solubility • long half-life • low protein binding • drug metabolites with long half-life • acid-base characteristics that favor the transfer of weak bases.

6. Pharmacologic Principles • Intestinal drug absorption may be unpredictablein the neonate due to lower gastric pH. • The neonate may have : • less protein binding of drugs • greater blood-brain barrier permeability • less body fat to store drugs • The neonate with delayed renal and hepatic clearance of drugs, is exposed to even greater effects when the mother uses medication with active metabolites.

7. Pharmacologic Principles • There are practicesto minimize drug exposureduring breastfeeding. • Because drugs disappear from maternal circulation with a known half-life, it is possible to minimize the amount transferred to the infant by recommending that drug dosing occur just at the conclusion of the feeding. • In some cases, the drug can be substituted with a safer drug, or the therapy can be delayed.

8. Drug Categories Cigarette • Cigarette smoking exposes the infant to nicotine and other compounds, including cyanide and carbon monoxide, directly via milk and indirectly by passive smoking. • Cigarette smoking may effect milk production, impair let-down, and result in behavioral changes in the infant.

9. Cigarette • Pregnancy and lactation are opportune times to counsel the mother on smoking cessation to protect her health as well as her infant's. • Because nicotine appears in milk, there is a slight risk that the breastfed infant may exhibit signs of restlessness, jitteriness, poor feeding, and abnormal sleep patterns. Despite these concerns, breastfeeding should be encouraged because of its protection against respiratory illnesses, which are more common in the infant living in a home with smokers.

10. Alcohol • Ethanol is one prototype of drug demonstrating rapid transport into milk. It is lipid-soluble, is not ionized, and has low molecular weight. Concentrations in milk are very close to maternal plasma concentrations. • There is evidence that the consumption of alcohol by the mother may decrease the amount of milk ingested by the infant. • Chronic drinking of alcoholic beverages may diminish milk production.

12. Caffeine • Caffeine is transferred but the amount in milk is usually less than 1% of the amount ingested by the mother. • Because no caffeine is detected in the infant's urine with maternal consumption of up to 3 cups of coffee a day, it is unlikelythat the infant has measurable exposure to caffeine.

13. Drugs of abuse • Drugs of abuse are contraindicated for breastfeeding mothers.

14. Anticoagulation • Unfractionated and low molecular weightheparin given to the mother are safe for the breastfed infant because they do not cross into milk. • Warfarin is also safe because of its very low concentration in milk due to very high binding of the drug to maternal plasma protein.

15. Asthma Therapy • Steroids are transferred into milk in extremely small quantities, and transfer from oral inhalers is even smaller. The use of steroids to treat asthma in the breastfeeding mother is safe for the infant. • Beta-agonistssuch as albuterol are associated with very small transfer to the breastfed infant and seem to be safe. • Theophyllineis rarely used now for either prophylaxis or treatment of acute asthma and ordinarily will not be an issue for the breastfeeding mother. Irritability in the infant, however, has been reported. • Newer agents such as zileuton inhibit leukotriene formation, and zafirlukast and montelukast block leukotriene action. No information on their concentration in milk is available and there are no reports of effects on the breastfed infant.

16. Maternal depression • Maternal depression, often accompanied by anxiety, carries significant risk for child development. • Antidepressants are thought to alter the concentration of neurotransmitters in the CNS particularly in the interneuronal space. • Older antidepressants, such as the tricyclicsnortriptylineand amitriptyline, have a good safety profilein breastfeeding, including long-term infant developmental follow-up.

17. Maternal depression • serotonin selective reuptake inhibitors (SSRIs), are better tolerated and are widely prescribed during pregnancy and lactation. • The SSRIs generally exhibit low concentrations in human milkusually less than 50%of maternal plasma level.

18. Maternal depression • Many infants, especially older than 4 months, may have no detectable serum levels of the drug after passage through milk. • Infants younger than 4 months may have detectable levels and, in the case of some drugs (fluoxetine),the infant plasma level may be close to the accepted therapeutic range for adults. • There have been a few reports of infants who exhibited restlessness, irritability, colic, poor weight gain, and sleep disorders when their mothers took fluoxetine.

19. Maternal depression • Two often-used SSRIs, fluoxetine and sertraline, have active metabolites and half-lives that are on the order of days, and accumulation may occur in the very young infant. • The concern about exposure of the breastfed infant to these compounds is that there are no long-term studies indicating either safety or adverse effects. • For the other SSRIs, no adverse effects have been described.

20. Maternal depression • Long-acting benzodiazepines (diazepam), especially if associated with chronic use, may accumulate in milk and produce symptoms in the infant, such as lethargy, sedation, and poor suck. • Sporadic use of long-acting drugs and the use of short-acting drugs (lorazepam, midazolam, oxazepam) pose less of a risk.

22. Diabetes therapy • Diabetes therapy generally does not present any concerns for breastfeeding. In some cases, breastfeeding may reduce maternal insulin needs. • Insulin does not cross into human milk. • Oral Hypoglycemics • There are little data concerning the use of the oral hypoglycemics and virtually none on newer agents. • Tolbutamide is usually compatible with breastfeeding. Other drugs should be used with caution by mothers who breastfeed.

23. Diabetes therapy • This is based on the experience with their use in pregnancy, which can result insevere and prolonged hypoglycemia in the newborn. The best advice for using these agents during lactation is to avoid them until lactation is well established, the infant is gaining weight satisfactorily, and the parents discuss with the pediatric care professional the need to monitor the infant's blood glucose. • Newer data on glyburideare encouraging. There is poor transplacental transfer of this drug likely due to high protein binding and a short elimination half-life. • For the same reason, there may be limited transfer into milk. • Until safety during lactation is established, however, these agents also should be used with caution.

24. GERD • H2 receptor blocking agents (famotidine, ranitidine, and cimetidine) seem to be safe during lactation. • All of these compounds have been given directly to young infants to treat reflux and in hospitalized children to decrease production of gastric acid and minimize the occurrence of peptic ulcers. • Likewise, the use of the protein pump inhibitor omeprazole also seems to be quite safe during lactation, although concentrations in milk have not been documented.

25. Inflammatory Bowel Disease • The treatment of inflammatory bowel disease (Crohn disease, ulcerative colitis) may require the use of multiple medications. • These include corticosteroids (by enema and orally) and anti-inflammatory drugs such as sulfasalazine, mesalamine, and olsalazine. • This substance is rapidly cleared from the plasma of adults and if it does appear in milk, it is in very low concentrations.

26. Inflammatory Bowel Disease • IBD occasionally may be treated with an antimetabolite drug, such as 6-mercaptopurine or methotrexate. • Previous editions of the AAP policy statement reported that these drugs were contraindicated during breastfeedingbecause of potential cytotoxicity. • However, there exist no data to support this, and the amount transferred may be inconsequential to the baby. • These drugs should not be given to lactating mothers without fully informing the parents about the possible immune suppression and effects on growth, even in small amounts, to the breastfed infant. • If used, the infants should be monitored for neutropenia.

27. Hypertension • The treatment of adult hypertension often involves combinations of drugs. • Currently there are 4 classes of antihypertensive drugs that are used: • 1) diuretics, • 2) beta blocking agents, • 3) angiotensin converting enzyme inhibitors (ACEI) • 4) calcium channel blocking agents.

28. Hypertension • DiureticsSeem to be safe during lactation. Hydrochlorothiazide and chlorothiazide have been used for decades and no problems have been described in the breastfed infant. • Beta-Blocking Agents. The drugs within this class that seem to be safest for useduring pregnancy are propranolol, sotalol, and metoprolol.

29. Hypertension • Atenololand acebutolol may present problems to the breastfed infant. • One case report describes cyanosis and bradycardiain a 5-day-old infant whose mother was receiving atenolol. It is prudent to avoid atenolol and acebutolol in the breastfeeding mother • The infant of any mother who needs to take abeta-blocking agentshould be monitored, especially for heart rate, feeding problems, respiratory pattern, and activity.

30. Hypertension • ACE inhibitors are excreted in limited quantities into milk. There are no reports of problems using these drugs. • Calcium channel blocking agents are the newest of the antihypertensive agents. Little is known about their excretion in milk, but it does seem that nifedipine is excreted in small amounts and is safe during breastfeeding. • These drugs also is probably safe during breastfeeding.

32. Infectious disease • Infectious diseasetreatmentis probably the most frequent cause for the use of drugs in the lactating woman. • Generally, all antibiotics are transferred to milk. Many of them are also used for the treatment of infectious diseases in pediatrics. • The doses received by the breastfed infant always are less than what would be given directly to the infant for therapy.

33. Infectious disease • Sulfonamidesshould not be given to a breastfeeding mother whose infant is jaundiced or in the age group where jaundice may develop. • This is because of the possible displacement of bilirubin from albumin in the infant's plasma by sulfonamides, which may increase the risk of kernicterus. • In addition, there are concerns that these drugs may increase the risk of hemolysisin infants with a deficiency of G6PD.

34. Infectious disease • Tetracycline.There are numerous statements in reviews of drugs in milk cautioning against the use of tetracycline during breastfeeding. • The amount of tetracycline that might appear in milk is extremely low, and there are no reports of adverse effects on the infant's GI tract or on calcified tissues, such as bone and teeth. • Tetracyclinesare not commonly used because they have been replaced by more effective and safer antibiotics.

35. Infectious disease • Metronidazole • Metronidazole is an antibiotic that is occasionally used in infants for the treatment of Giardiaand some anaerobic infections, and is used in pregnancy. • Metronidazole seems to be safe for the breastfed infant.

36. Infectious disease • Quinolone(nalidixic acid) andfluoroquinolone(ciprofloxacin, ofloxacin)antibiotics have reasonably long half-lives, which allow once-or twice-a-day dosing. • They are well absorbed from the GI tract, permitting the early switch from intravenous to oral therapyand hence dischargefrom the hospital and increased compliance.

37. Infectious disease • Some of these drugs may interfere with cartilage formation in juvenile mammals. • This has resulted in a warning label that they are not to be used in anyone younger than 18 years. • However, some pediatric studies involving long-term use in patients with cystic fibrosis have not shown any cartilage damage as measured by serial MRI of joints.

38. Infectious disease • Furthermore, ciprofloxacinis approved for limited use in childrenand the oldest quinolone, nalidixic acid, has been labeled for pediatric use for more than 30 years, although it is now rarely used in the pediatric population. • There have been no reported adverse effects of this drug on growth. • The amount that would be transferred into human milk is extremely low and if there is no other choice for maternal therapy, a short (1-to 2-week) exposure to quinolones may be acceptable for the breastfed infant.

39. Infectious disease • Antifungal agents currently given orally, including fluconazole, are safe for the infant and have been used for direct infant therapy.

41. Migraine headache • Treatment in adults is divided into prophylaxis of attacks and treatment of the acute episode. • The initial therapy for acute migraine headache may range from nonpharmacologic measures, such as rest,darkened room, and a wet cloth to the forehead, to some of the newest drugs.

42. Migraine headache • The use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) is acceptable during lactation because most are weak acids and highly protein bound. • The NSAIDs include ibuprofen, naproxen, and ketoprofen. There are products that contain a combination of acetaminophen with caffeine. • All of these compounds are safe during lactation. • The amount of acetaminophen and/or ibuprofen that might be transferred during lactation is only a small fraction of the dose given to infants for fever and pain.

43. Migraine headache • The Triptan family contains the following compounds: sumatriptan, naratriptan, rizatriptan, and zolmitriptan. The only one for which data exist is sumatriptan, and the excretion in milk is extremely low and has not caused adverse effects in the breastfed infant.

44. Migraine headache • The Ergot family : • The intravenous (IV) form of ergotamine is dihydroergotamine, which has a very long half-life. • An oral ergot is methysergide. Ergotaminesmay inhibit prolactin release and thus interfere with lactation. Because alternatives exist with the triptan family, it is prudent not to use drugs in the ergotamine family during lactation.

45. Pain management • Pain management Can be achieved by appropriate doses of either acetaminophen or NSAIDs such as ibuprofen and naproxen. • More severe pain, such as that occurring immediately after birth or after surgery, is best managed with the use of appropriate doses of morphine because morphine has primarily inactive metabolites.

46. Seizure Management • Phenobarbitalhas low protein binding, and sedation has been reported in breastfed infants exposed to the drug through milk. • Most adults receive carbamazepine or valproic acid as single drug agents with the addition of lamotrigine or tiagabine for complex seizure disorders.

47. Seizure Management • There are single case reports that indicate infant problems. • Cholestasis with carbamazepinehas been reported, and thrombocytopenia and anemia with valproic acid. • An older publication has described methemoglobinemia in the infant of a mother taking phenytoin. • Lamotrigine taken by the breastfeeding mother may be associated with therapeutic levels in the infant.

48. Seizure Management • Regardless of which drug or drugs the mother needs for the control of her epilepsy, it would be prudent not only to clinically observe the baby, but also to measure drug concentrations in the infant's plasma on a regular basis, especially in very young infants in the first 2 months of life.

49. Thyroid hormone • (levothyroxine) is transmitted into milk in extremely small quantities and will not change the thyroid function of the infant. • Women with hyperthyroidism have a choice of 2 drugs for therapy: propylthiouracil and methimazole. • Propylthiouracil is the preferred drug because about 75% of it is bound to maternal plasma protein in contrast to methimazole, which has almost no protein binding. • Thus the amount of propylthiouracil secreted is quite small. • usually less than 1% of the therapeutic dose goes to the infant.