1. Describe the mechanisms by which medications pass from maternal blood into breast milk and recognize the factors that influence the milk/plasma ratio and affect the transfer of medications from breast milk to the infant.

2. Effectively use available resources to guide clinical decisions for breastfeeding mothers and identify safe options within various drug classes.

3. Counsel breastfeeding women who use drugs of abuse or recreation.

4. Implement effective therapeutic regimens to treat and manage constipation in children.

5. Recommend appropriate dietary and lifestyle options to minimize constipation.

Balancing Maternal Medication Use and Breastfeeding
Debra L. Bogen, MD, Associate Professor of Pediatrics, University of Pittsburgh School of Medicine, and Children’s Hospital of Pittsburgh, Division of General Academic Pediatrics, Pittsburgh, PA

Background: survey in Ontario, Canada, found 80% of mothers breastfeed, and 80% of these take (and expose infants to) medications

Contraindications to breastfeeding: maternal infections—eg, HIV (in United States), active tuberculosis (can use expressed milk), and herpesvirus on breast (nurse on contralateral side); inborn errors of metabolism—eg, galactosemia, tyrosinemia; maternal exposure to medications and environmental agents—rarely contraindications

Risks and benefits: balance risk from medications in breast milk against those of feeding formula; in general, most medications safe, but most mothers think most medications not safe

Transfer of medications into breast milk

Mechanism: maternal plasma level of orally administered free drug depends on bioavailability and metabolism in liver (cytochrome activity varies in individuals); drugs transfer from maternal plasma to milk by equilibrium-driven diffusion (gradient based on properties of drug); early during breastfeeding, more space exists between alveolar cells, so higher drug concentrations found in colostrum than milk; however, only small amounts of colostrum delivered to infant; later, prolactin causes alveolar cells to swell, intercellular tight junctions close, and transport between cells stops; factors that determine whether drug enters infant’s system include acid levels in infant’s stomach, and oral bioavailability of drug; most studies measure level of drug in breast milk, not in infant; when measured, level in infant often low, relative to level in breast milk

Factors affecting drug transfer: route of administration; half-life (longer the half-life, greater the transfer); dissociation factors; volume of distribution; molecular size (eg, interferon too large to pass into milk); degree of ionization (weakly alkaline drugs have increased transfer); fat solubility (facilitates transfer); and protein binding (free drug transfers more readily)

Predicted milk/plasma (M/P) ratios: M/P defined as concentration of drug in milk divided by concentration in maternal plasma; highly lipid-soluble drugs have M/P of 1; M/P of highly protein-bound drugs <1 (less free drug)

Factors affecting transfer from milk to infant: bioavailability—eg, gentamicin not absorbed from gut, therefore, not available to infant from milk; ability to detoxify and excrete drug—infants’ livers immature and less able to process drugs; gestational and chronologic age—limited data on effects of medications in premature infants; preterm infants have less fat and less protein-binding

Evaluation of risk: M/P >1 suggests accumulation of drug in milk (important to determine M/P at time of peak drug levels in plasma); relative infant dose (RID)—infant’s dose via milk in mg/kg per day divided by mother’s dose in mg/kg per day; theoretic infant dose—highest concentration of drug in milk multiplied by daily volume infant receives (150 mL/kg per day)

Principles of drug use for breastfeeding mothers: use safest possible drugs (eg, drugs approved for infants, least toxic drugs, older or better known drugs within class) and only if necessary; evaluate infant’s risk (ie, age, weight, and duration of treatment); use shorter-acting drugs; most drugs with RID <10% considered safe; schedule dosing to minimize transfer

Resources

Medications and Mother’s Milk—book by Thomas Hale (htttp://neonatal.ttuhsc.edu/lact/); do not assume safety of drugs during pregnancy (pregnancy categories) equivalent to that during lactation; risk categories for lactation—L1 (safest; evidence to support safety); L2 (safer, limited evidence); L3 (moderately safe, but little data available); L4 (possibly hazardous, as suggested by case reports); L5 (contraindicated); National Library of Medicine website—http://toxnet.nlm.nih.gov/cgi-bin/sis/search; classification of lactation safety similar to that of Hale; American Academy of Pediatrics (AAP) policy statements—updated less frequently; others—Academy of Breastfeeding Medicine website (www.bfmed.org); University of Rochester help line (585-275-0088, for professionals only)

Specific medications

Postpartum pain: oxycodone and acetaminophen combination (Percocet)—listed as L3, RID of 3.9%; plan to use for short time, as needed; stop if signs of infant sedation or excessive maternal sedation appear; LactMed provides data on effects in breastfed infants and on lactation (eg, some safe drugs reduce milk supply); other medications—eg, acetaminophen (L1), ibuprofen (L1), naproxen (L3 for acute use, L4 for chronic use), morphine (L3, poorly absorbed from gut)

Antibiotics: those safe for infants and lactating mothers include amoxicillin, penicillin, amoxicillin and clavulanic acid (Augmentin), clindamycin, and erythromycin; rare reactions possible, eg, glucose-6-phosphate dehydrogenase (G6PD)-deficient infants at risk for problems with sulfonamides; idiosyncratic reactions, eg, pseudomembranous colitis

Drugs of abuse or recreation

Smoking: AAP policy now supports breastfeeding for smoking mothers; nicotine replacement therapy also considered safe; if mother smokes, recommend smoking only after breastfeeding to minimize nicotine levels; nicotine transdermal system—21-mg patch delivers equivalent of 1 pack of cigarettes per day in breast milk; 14- and 7-mg patches deliver less nicotine than single pack per day; caution—study demonstrated babies slept less when mothers smoked; nicotine gum—useful for infrequent smokers

Alcohol: diffuses freely into and out of milk and reaches concentration identical to that in mother’s blood; relatively safe in small amounts; mother should wait until neurologic effects of alcohol dissipate before breastfeeding; breastfeeding not recommended for chronic heavy drinkers

Methadone maintenance therapy: no longer contraindicated for breastfeeding, regardless of therapeutic dose; usually undetectable in infant’s serum; infant has less exposure during breastfeeding (<3% passed into breast milk) than during pregnancy (50% to 75% crosses placenta); may protect infant from effects of withdrawal; consider checking with drug treatment program to determine whether mother continues to use drugs of abuse; ≈90% of women on methadone also smoke, so discuss both issues with patients

Buprenorphine: newer treatment for addiction to opiates; not approved for use in pregnancy; current evidence suggests not contraindicated for breastfeeding

Drugs of abuse: breastfeeding contraindicated in users of heroin, cocaine, and methamphetamine; marijuana enters breast milk in low doses; no documented ill effects in babies; easily detected in urine toxicology screen

Antidepressants: risk-benefit decision should take into account effects of maternal depression on infant; data suggest maternal use of antidepressants has little risk for harm to infants >3 mo of age in whom hepatic enzymes have matured; published data exist for full-term but not preterm infants

Selective serotonin reuptake inhibitors (SSRIs): study measured transport of serotonin (5-hydroxytryptamine [5HT]) into platelets (transporter encoded by same gene on platelet as on neurons); found decrease in maternal but not infant whole blood 5HT levels

Other SSRI antidepressants: very low levels of sertraline and active metabolite found in infants 3 to 141 wk of age; also, very low levels of paroxetine found in infants; fluoxetine—long-acting SSRI with multiple active metabolites; found in higher levels in infants, but acceptable if no other SSRI works for mother

Nortriptyline: also found in low levels in infants

Adverse effects: reported for doxepin and fluoxetine in babies; recommends using drug with shorter half-life because no longitudinal data currently available

Contraceptives: Academy of Breastfeeding Medicine (www.bfmed.org) Protocol 13 lists effects of all methods on breastfeeding; barrier methods (none); copper intrauterine device (IUD; none); levonorgestrel (Mirena; progestin IUD that can decrease milk supply; not recommended before infant 6 wk of age); pills or rings containing progestin only (can decrease milk supply if started before breastfeeding fully established; if stopped within 2-3 days, milk supply returns to normal, but not after 2-3 wk); combination pills (avoid until after weaning because of decrease in milk supply)

Constipation Pearls
J. Fernando del Rosario, MD, Assistant Professor of Pediatrics, Jefferson Medical College, Chief, Division of Gastroenterology, and Director, Pediatric Gastroenterology Fellowship Program, Alfred I. duPont Hospital for Children/ Nemours Children’s Clinic, Wilmington, DE

Background: constipation defined as <3 stools/wk or difficulty passing stool; may cause abdominal pain, development of fissures or hemorrhoids, decreased appetite, rectal prolapse, and fecal impaction with fecal soiling (encopresis); usually results from inadequate intake of fluids and fiber; other causes—illness; metabolic conditions (eg, hypothyroidism); celiac disease (can cause constipation as well as diarrhea); neurologic conditions (eg, tethered spinal cord); anatomic variations (eg, anteriorly displaced anus); medications (eg, analgesics, anticholinergics, and anticonvulsants)

Treatment

Initial cleanout: recommended regimens by age; 3 to 5 yr of age—4 capfuls of polyethylene glycol (Miralax) in 20 oz Gatorade (or other uncarbonated liquid) plus 5 mg bisacodyl (Dulcolax) before and 1 hr after finishing Miralax; consume Miralax over 2 to 3 hr; 6 to 11 yr of age—increase Miralax to 6 capfuls in 32 oz liquid and 5 mg Dulcolax before and after; 12 yr of age—increase Miralax to 10 capfuls in 32 oz and Dulcolax to 10 mg; repeat regimen over ≈24 hr until stool becomes liquid and clear

Maintenance: young children—give 0.5 to 1 capful Miralax up to twice daily; older children—1 to 2 capfuls; increase dose if needed; little risk for intoxication, significant side effects, dependence, or electrolyte abnormalities

Other treatments: may perform x-ray examination to document whether clean-out successful and repeat clean-out if necessary; enemas—avoid in younger children if possible; diet—increase fiber intake (bran, whole-grain, fruits, and vegetables) to 20 to 25 g daily in children; limit intake of dairy; increase intake of fluids; lifestyle—increase exercise, and encourage regular stooling schedule

Treatment pitfalls: failure to achieve adequate clean-out; poor compliance with maintenance regimen and with dietary and lifestyle modifications; failure to diagnose underlying illness, eg, test for hypothyroidism, comprehensive metabolic panel (CMP) to rule out calcium and magnesium abnormalities, MRI of spinal cord to rule out tethering, celiac panel

Frequently asked questions: normal frequency—averages 2 stools/day by 4 mo of age; 1 to 2 per day at >1 yr of age; daily bowel movement does not rule out constipation; need for abdominal x-rays—not always necessary if results of physical examination adequate