Pharmacotherapy for depression and bipolar disorder during lactation: A framework to aid decision making

Abstract

Objective

Breastmilk is recommended as the exclusive source of nutrition for infants younger than 6 months due to the numerous health benefits for both infants and mothers. Although many women are prescribed medications during pregnancy and postpartum, limited data are available to assist women in weighing the benefits compared to the risks of peripartum medication use. The goals of this paper are to discuss the importance of breastmilk for the health of both the mother and infant, evaluate the impact of medication use on women’s infant feeding choice, describe the transfer of drugs to breastmilk and infants, and provide a framework for clinicians to support evidence-based counseling for women treated for mood disorders.

Recommendations

We recommend early pregnancy counseling to discuss the benefits and risks of medications during breastfeeding. The Surgeon General’s Call to Action (2011) highlights the short and long-term negative health effects of not providing breastmilk. Integrating recommendations from the pediatric and obstetric teams allows patients to make decisions based on evidence and reach their infant feeding goals. Databases containing summaries of research findings and pharmacologic properties of the drug of interest are an essential resource for clinicians.

Introduction

The importance of breastfeeding for the health of women and infants is well established.^1,2 The American Academy of Pediatrics recommends exclusive breastfeeding for the first six months of life and continued breastfeeding through the first year and beyond as mutually beneficial for mother and child.¹ Similarly, the World Health Organization recommends six months of exclusive breastfeeding and continuation until at least two years of age or beyond.² However, most women do not meet these duration recommendations and many fall short of their own personal breastfeeding goals, often for non-medical reasons.^3–5 However, medical contraindications to breastfeeding are rare. One commonly cited is pharmacotherapy, but medications are rarely an absolute contraindication to breastfeeding. Nonetheless, medication use during and after pregnancy impacts women’s decisions to breastfeed.⁶ Lack of widespread and consistent clinician training in lactation pharmacology results in poorly informed shared decision-making. In this review, we provide a process for physicians to evaluate medication use and breastfeeding that supports shared-decision-making.

Risks of not breastfeeding

The 2011 Surgeon General’s “Call to Action to Support Breastfeeding” identified 20 key actions to improve support for breastfeeding, including providing education and training for all health professionals caring for women and children.⁷ The document urges a shift in the conceptual framework from discussing the benefits of breastfeeding to a focus on the risks of not breastfeeding. Children who are not breastfed have an excess risk of multiple morbidities including: ear infections (100%), eczema (47%), diarrheal illnesses (178%), lower respiratory tract infections (257%), asthma (3567%), childhood obesity (32%), SIDS (56%), and leukemia (1823%).^7–14 The impacts of breastfeeding are broad. Choosing to breastfeed is a key modifiable factor with wide reaching influences on infectious morbidity, health care costs and potentially mortality of infants and children. Preterm infants born before 32 weeks and who are not fed an all human milk diet are at increased risk for developing necrotizing enterocolitis.^1,15,16 Evidence regarding the importance of the microbiome in health is rapidly increasing, and infants fed breastmilk develop a distinct composition of gut flora that differs from those fed formula.¹⁷ Microbiome differences persist after 6 months of age, and some of the differences in gut microbiota have been implicated in altered lipid and vitamin metabolism at 6 months of age or younger.¹⁸

Not only is breastfeeding important for the health of infants and children, it also is an integral component of the reproductive cycle for women. Women who do not breastfeed have increased risk for developing hypertension, type 2 diabetes, and breast and ovarian cancer.^19–23 In a prospectively followed sample, women who did not breastfed were at a 1.5 fold increased risk of developing ovarian cancer when compared to women who breastfed 18 months or more.²⁰ They also retain visceral adiposity, and have elevated serum levels of triglycerides, total cholesterol and low density lipoprotein cholesterol, which confer an increased risk for myocardial infarction.^{21,22,24–26} Overall lifetime duration of lactation is associated with long-term benefit for women’s cardiovascular health.^22,24–26 Investigators deriving models from epidemiologic studies estimate that for every 597 women who optimally breastfeed (defined as exclusively for 6 months with continued breastfeeding for at least one year), one maternal or child death is prevented.¹⁶ In these models, preventable maternal deaths are due to myocardial infarction, breast cancer and diabetes while the causes of infant deaths are Sudden Infant Death Syndrome and necrotizing enterocolitis.^15,16

Medications are one barrier to breastfeeding

Over the last 40 years, a dramatic increase in the number of medications women used during pregnancy was observed.²⁷ From 1976 to 2008, a 68% increase in first trimester medication use (other than multivitamins and iron) occurred, and the average number of medications rose from 2.5 to 4.2.²⁷ Antidepressant use increased most dramatically, from <1% in 1976 to 7.5% in 2008.^27,28 From 20042008, the most commonly used medications in pregnancy were albuterol, progesterone, ondansetron, amoxicillin and sertraline.²⁷

Given increasing use of medications during pregnancy, it is imperative to consider the same trajectory of use in lactating mothers. Concern about exposure to medications is suggested by the lower rates of breastfeeding initiation and duration among women prescribed specific medications.^6,29 For example, among lactating women who called an information help line for advice on taking a prescribed antibiotic, one in five reported that they either stopped breastfeeding or did not take the prescribed medication even though they were counseled to continue to breastfeed.³⁰ Women with major depressive disorder who take antidepressants during pregnancy are less likely to intend to breastfeed and to initiate it after controlling for variables associated with breastfeeding.^31–33

Prescribers also prioritize avoidance of infant exposure to medications through breast milk. To minimize risk and perhaps liability, health care professionals err on the conservative side and recommend that women avoid medications while breastfeeding or forego breastfeeding to take the medication. The most common reasons prescribers contact a teratogen information service is to discuss use of antidepressants, despite evidence of minimal risk associated with these medications in breastfeeding.³⁴ The delivery of evidence-based information that balances the risks of not breastfeeding with the risks of the medication exposure supports optimal decision making.^35,36

Contraindications to breastfeeding

Situations in which the risks of maternal or childhood disease or medication exposure outweigh the myriad benefits of breastfeeding are rare and strategies often are available to support long-term breastfeeding. Although in the US, Europe and many countries, HIV infection is considered an absolute contraindication to breastfeeding,³⁷ the World Health Organization recommends exclusive breastfeeding for HIV-positive women taking antiretroviral medications in specific parts of the world, such as sub-Saharan Africa.³⁸ Women with active lesions from herpes simplex on the breast may transmit the virus to the infant while breastfeeding from the affected side; however, if the lesions are kept covered, women can breastfeed from the unaffected side.^39,40 Mothers may pump and discard the milk from the affected side to maintain their supply until the lesions have healed. Similarly, women with active tuberculosis should avoid respiratory contact with their infant until the period of contagion has passed.¹ Affected mothers can express their milk and have another person feed the breastmilk to the infant.¹ Infant factors thatpreclude breastfeeding include metabolic disorders such as classic galactosemia and tyrosinemia. In some variants, partial breastfeeding may be possible and should be discussed with the medical geneticist caring for the infant. A common misconception is that women with infections, such as influenza and Hepatitis B and C should not breastfeed.⁴¹ Please refer to the CDC and the AAP Red Book for comprehensive and up to date information about maternal infections and breastfeeding by disease.^40,41

Few medications qualify as absolute contraindications to breastfeeding. Examples include chemotherapy and long-acting radioactive compounds.^42,43 Some drugs require special consideration and monitoring for both baby and mother (Table 1). For a comprehensive updated information on medication use and contraindications to breastfeeding refer to the American Academy of Pediatric Section on Breastfeeding and Use of Human Milk and the online database, LactMed from the National Library of Medicine.^1,44

Table 1 –

Drugs with special considerations in lactation^{1,42,43,45,51,54,77}.

Medications	Potential risk
Antineoplastic medications	Bone-marrow suppression, leukopenia in infant
Iodine or Iodine containing compounds	Interfere with thyroid function
Amiodarone	Long half-life, contains iodine components
Oral Retinoids	Risk significant in pregnancy
Radiopharmaceuticals	Radioactive isotopes
Codeine	Concern for CYP2D6 ultra-rapid metabolizers
More comprehensive information available through the National Library of Medicine and AAP guideline1,44

Transfer of medications into breastmilk

Most medications transfer from maternal blood into breastmilk. In general, the exposure of drug via breastmilk is orders of magnitude less than the quantity of medication that reaches the fetus during pregnancy. The quantity of drug that transfers is affected by many factors, including route of administration, age of the infant and drug characteristics such as molecular size, protein binding, fat solubility and oral bioavailability. Tracking the path of the medication from maternal consumption to infant ingestion is useful in conceptualizing infant exposure (Fig. 1). After a mother takes an oral medication, it undergoes absorption from the gut and enters the portal vein to the liver where the hepatic cytochrome system acts upon the drug (first pass metabolism). The active drug and metabolites (if any) reach the circulation. The protein bound and free drug concentrations are valuable indicators of therapeutic efficacy for many agents. Driven by equilibrium forces between maternal plasma and milk, the free (unbound) drug diffuses across the alveolar membrane and passes through capillary walls and both lipid membranes of the alveolar cells. An exception to this is within the first 72 h postpartum, when the drug can pass between alveolar cells due to transient between-cell gaps.^45–47 By the end of the first week postpartum, tight junctions between alveolar cells close under the influence of prolactin, which limits transcellular entry of drugs and proteins into the milk. When an infant ingests the milk, the drug that survives gastric acids undergoes hepatic metabolism in the infant prior to entering the circulation. Infant plasma concentrations, which reflect systemic exposure after the multiple steps in the metabolic pathway, are the most direct measure of drug exposure through breastmilk.

Fig. 1–

Transfer of medications into breastmilk.

Important factors affecting the transfer into breastmilk from maternal plasma are protein binding, molecular size, and lipophilicity. Most medications circulating in the blood are bound to albumin and other proteins. Unbound free drug passes into breastmilk while bound drug does not. For example, the chemical element lithium has no protein binding and is a small molecule that readily diffuses into the breastmilk.^45,48 Breastmilk has a high fat content so lipophilic medications more readily transfer into milk compared to hydrophilic medications. Most medications are in equilibrium between maternal plasma and milk; therefore, as maternal plasma drug concentrations fall, levels in milk also decline. Small molecular weight drugs more easily transfer into breastmilk. For instance, alcohol, with a low molecular weight (~120 dalton), diffuses rapidly into milk whereas heparin, with a large molecular weight (~15,00030,000 dalton) does not enter milk.^47,48 Alcohol demonstrates the important point that breastmilk and maternal plasma are in equilibrium. For example, levels of alcohol in milk typically mirrors maternal blood levels so as alcohol is cleared from maternal plasma, so too is it cleared from milk.^1,48 A typical drink of alcohol (1 glass of wine, one beer, one shot of whiskey) is cleared in 2 to 2.5 h (based on maternal height) from both maternal plasma and breastmilk.^1,48,49 Occasional use of small quantities of alcohol are not associated with short- or long-term negative effects but daily or heavy (more than 2 drinks/day) alcohol use is associated with adverse effects in infants such as altered sleep patterns, sedation and potentially infant growth and motor development.^48,49

In rare cases the chemical properties of the medication are conducive to ion trapping. The pH of human milk pH is mildly acidic (pH 7.07.2) so basic medications can be “trapped”, or prevented from diffusing from the breastmilk back into maternal circulation.⁴⁷ Barbiturates, oxycodone and codeine are weakly basic medications that are prevented from readily diffusing back into maternal circulation.^42,45,47 However, that does not mean that these drugs are contraindicated in breastfeeding because many factors influence the drug levels in milk and infants. Drugs that may become “trapped” in milk warrant monitoring for adverse effects. Rarely, active transport systems on the alveolar cell membrane pump medications into the breastmilk, such as the iodide pump. Iodinated medications should be avoided during breastfeeding.⁴⁷ An additional active transporter, the breast cancer resistance protein (BCRP/ABCG2), is present in the membrane of alveolar cells and can pump specific substrates into breast milk,⁵⁰ which results in a higher M/P ratio. Examples are bupropion (M/P 2.58.6), diazepam (M/P 3.79.5) and sumatriptan (M/P 4.9).⁵⁰

The half-life of the drug is a factor in decision-making because long-half-life drugs and/or their metabolites may accumulate in maternal and infant plasma.⁵¹ For example, sertraline is the most commonly prescribed medication for women with postpartum depression in part because of its relatively short half-life. In contrast, fluoxetine and its active metabolites have very long half-lives and higher levels in maternal milk. It is important to integrate the above factors in decision making. For example, for a woman for whom sertraline was not effective but fluoxetine treatment resulted in remission should be offered fluoxetine to prevent recurrence of depression.⁵² Using resources such as LactMed will assist clinicians in integrating the factors that impact plasma and breastmilk drug concentrations. This information facilitates in the selection of optimal medications for lactating women (Table 2).

Table 2 –

International resources for pharmacotherapy in lactation.

Source	Accessibility
National Library of Medicine (LactMed)	Internet  https://www.ncbi.nlm.nih.gov/books/NBK501922/
Breastfeeding Practice Interest Network for Pharmacists	Internet  https://www.pharmacists.ca/education-practice-resources/patient-care/breastfeeding-resources/
Organization of Teratology Information Specialists	www.mothertobaby.org/  1–866–626–6847  Texting program also available  See patient handouts
Thomas Hale, PhD (new edition ∼ 2 years)	Print  Texas Tech website: http://www.infantrisk.com/  App for iPhone or Android (for purchase)
Academy of Breastfeeding Medicine (ABM)	Internet  http://www.bfmed.org  See free protocols in multiple languages
Department of Health of Western Australia  Obstetric Drug Information Service at the Women and Newborn Health Service	+61 93,402,723  https://www.tga.gov.au/obstetric-drug-information-services
Australian Breastfeeding Association	1–800–686–268  https://www.breastfeeding.asn.au/
UK Drugs in Lactation Advisory Service (UKDILAS)	0116 258 6491  Ukdilas.enquiries@nhs.net

Factors specific to the infant also influence the amount of drug ultimately absorbed. An infant’s stomach pH is lower than that of older children and adults, and more acidic stomach fluid may denature some medications.^47,53 Medications ionize differently in the higher acidity of the infant stomach, which may impair absorption.⁴⁷ A classic example is the commonly used antibiotic gentamicin, which is given parenterally due to lack of oral bioavailability.^47,51 When mothers receive this medication intravenously, it can be measured in her breastmilk but not in the infant’s plasma because it is not absorbed from the infant gut. Some medications, like tetracyclines, are poorly absorbed when taken with calcium-rich foods such as human breastmilk.⁴⁵ Drugs like omeprazole, which are formulated as enteric coated because they are degraded in the acidic stomach, also will not be absorbed from breastmilk.⁴²

Genetic variability in drug metabolism is increasingly recognized as an important factor to consider for medication choice and dosing and is beginning to be included in the literature on medication use during lactation. An example is in the management of pain in the postpartum period with codeine. Mothers with the specific genotype of Cytochrome P450 (CYP) 2D6 associated with ultra-rapid metabolism have elevated conversion of codeine to morphine, which results in elevated maternal serum concentrations which transfer into milk.⁵⁴ Their breastfed infants, who may also have inherited this rapid metabolizing genotype, are at risk for developing toxic and potentially fatal levels, as in one tragic case.⁵⁴ Pain treatment in lactating women has shifted from codeine to other treatments such as nonsteroidal anti-inflammatory drugs and non-codeine containing opioids.⁵⁵

Infant age and maturity are important considerations. Metabolism and elimination of medications change with age in parallel with the maturation of the cytochrome P450 system, renal clearance, body composition, gut microbiome and food diversity.^56,57 Newborns are most vulnerable to adverse drug effects due to their relatively slow drug elimination and the clinical challenge in discerning drug effects. Commonly cited infant effects are lethargy and sedation, which can be challenging for nonmedical individuals to assess in newborns, who typically sleep 1820 h per day. By a few months of age, many of the CYP enzyme activities have increased and by 6 months the infant diet includes food in addition to breastmilk, which reduces the potential for adverse effects of medications from breastmilk.⁵⁸

Preterm neonates are at the greatest potential risk for adverse effects of medication exposure from breastmilk because they have less total body fat and protein for binding along with an increase in body water content compared to term infants. Premature infants also have decreased overall energy metabolism, often with diminished glucose storage from lower glycogen and fat storages. The immaturity of the CYP450 system influences the preterm infant’s ability to detoxify and excrete drug. Lastly, the blood-brain barrier is not fully developed; therefore, the risk for toxicity of neuroactive medications is increased. However, due to the importance of human milk for the health of premature infants in the neonatal intensive care unit, it is unusual for these infants not to be fed their mother’s own milk if it is available regardless of maternal medication use, with some exceptions such as active illicit drug use or iodine containing drugs. Despite the increased potential for adverse effects in this population, there are very few case reports in the literature related to medication exposures in preterm infants, perhaps because many are not exclusively fed their mother’s own milk, especially early in their NICU stay.

Methods to estimate medication transfer into breastmilk and infants

The following measures serve as estimates of infant exposure to medication via breastmilk: milk to plasma ratio (M/P ratio), theoretic infant dose (TID) and relative infant dose (RID) (Fig. 2).

Fig. 2–

Measures to estimate medication transfer.

The M/P ratio is the most frequently available measure as it does not require blood testing of the infant. The M/P ratio is the concentration of the drug in the milk divided by the concentration of the drug in maternal plasma. If the M/P ratio is greater than 1, the drug accumulates in milk. However, most case reports include data from single samples, often at peak concentration following medication dosing. This situation represents a worst-case estimate of the amount of drug in the milk. M/P ratio is useful as a tool to compare medications. A low M/P ratio is an indication that the exposure to the infant will be low while an M/P ratio greater than 1 warrants further consideration.^51,59

TID is an estimate of the expected total daily medication dose an infant would ingest from maternal drug in breastmilk. To determine the TID, at least one measured concentration of drug in breastmilk and the estimated volume of daily breastmilk (estimated as 150 mL/kg daily after about two weeks of life) is required. In many case reports, the calculated TID is a worst-case scenario value, specifically when it is based on single measurement of drug in breastmilk taken at the peak maternal plasma concentration. The single medication concentration in breastmilk is assumed to be the same across the entire day although the drug concentration in milk falls as it is cleared from the maternal plasma. To obtain a more accurate estimate, breastmilk samples across the entire dosing interval must be obtained to determine the pharmacokinetics (area under the curve) and calculate a mean concentration over time. Unfortunately, this procedure is rarely done.

The RID is used to estimate infant exposure that is commonly misunderstood. RID is the ratio of the infant and maternal daily weight adjusted dosages. It is calculated by dividing the Theoretic Infant Dose (mg/kg/day) by the mother’s weight adjusted dose (mg/kg/day) and multiplying by 100. The RID is often misinterpreted as the percent of the mother’s total dose. For example, in a case in which the mother takes a medication at 100 mg/day and the RID is reported as 5%, a misinterpretation would be that the baby receives 5 mg of the drug each day when in fact the infant receives orders of magnitude less. Over the years, the convention has developed that medications with a RID less than 10% are considered relatively safe and acceptable to use in breastfeeding, while a RID in the 1025% range dictated a recommendation for caution with consideration given to alternative medications. A RID greater than 25% was considered potentially toxic. However, less than 3% of all medications fall in this high range. These ranges are arbitrary and should be interpreted based on the potential adverse effects of the drug to the infant. For example, lithium (discussed later) can have a RID above 25%, yet many infants have been breastfed during maternal treatment with lithium.^60,61

Infant exposure is most accurately determined by measuring the drug concentration in infant plasma; however, this is rarely done because of discomfort to the infant and the challenge of obtaining blood samples. The most common way to obtain serum is through heel stick sampling, where capillary blood can be used for infant drug levels. When available, the ratio of the concentration of the drug in the infant to maternal plasma can be useful. This ratio allows comparison of maternal therapeutic plasma concentrations of the drug and corresponding infant serum levels.

The limitation of the currently available data affects decision making. Most data come from case reports of women taking a single medication; however, many women take more than one medication and drug-drug interactions are possible. Cases with adverse outcomes are more likely to receive medical attention and are likely to be over-represented in the medical literature due to selection bias. Nearly all case reports come from women feeding full term, generally healthy infants, with rare data on preterm infants.

General rules to be applied when considering maternal drug treatment during breastfeeding are to use as few medications as possible and consider alternatives based on drug characteristics and estimates of medication transfer. Older medications tend to have more information available. Drug characteristics such as low toxicity and short half-life and a low RID are optimal first-line choices. Drugs that are prescribed for infants directly (e.g. acetaminophen, amoxicillin), are preferable to prescribe to a breastfeeding woman.

What is the role of the health-care practitioner?

Prescribers in all clinical specialties will encounter women who are breastfeeding. Most training programs in medicine, pharmacy, and nursing do not include pharmacologic principles of lactation. Furthermore, clinicians may not appreciate the impact they have on women’s decision making. Only 8% of obstetric physicians felt their advice on breastfeeding duration was important to patients.⁶² On the other hand, women who perceive their physician had a neutral attitude regarding breastfeeding are less likely to breastfeed beyond 6 weeks.⁶³ Among those who perceived that their physician favored breastfeeding, the proportion of mothers intending to breastfeed for a longer duration was much higher.⁶³ Lack of recognition of the importance of the physician’s role in promoting breastfeeding highlights a missed opportunity to improve maternal-infant health. Additionally, pediatricians, family physicians and obstetricians report that they do not feel prepared or confident to counsel mothers on breastfeeding, a deficiency that has not changed over the last two decades.^64,65 Physicians also cite time constraint as an impairment to their ability to provide adequate lactation consultation.³⁵

Comprehensive resources are available with up-to-date information for breastfeeding and medication exposure (Table 2). Easy access to the current literature is critical to encouraging lactation goals with patients. Clinicians can use a mnemonic we proposed to identify key considerations for counseling breastfeeding women: SAFEDLCT (Supply-Alternatives-Formula-Effectiveness-Duration-Levels-Characteristics, Table 3)

Table 3 –

Acronym with topics to consider when counseling about medication use in lactation.

S	Supply: Does the drug impact maternal milk supply?
A	Alternatives: consider if alternate medications are available with more data?
F	Formula: consider potential risks to baby and maternal health of not breastfeeding
E	Effectiveness of the drug for mother’s condition
D	Duration of maternal treatment anticipated
L	Levels (in milk and infant): consider drug concentrations in milk and infant plasma
C	Child characteristics such as gestational age in the neonate (term/preterm), chronologic age, exposure in pregnancy or proximal to delivery, underlying health of child, special health conditions such as impaired renal clearance or liver functions
T	Talk with mother/parents to assess concerns; many women assume they cannot breastfeed due to medication use. Have an explicit conversation about all medication use during lactation.

Medication decision making for women taking psychotropic medications

The prescribing rate for antidepressants for pregnant women is increasing.²⁷ These drugs are first-line agents for anxiety and depressive disorders, which are highly prevalent in women of childbearing age. Maternal suicide has become one of the leading causes of mortality in the first 12 months after birth in many countries, which underscores the importance of identification and treatment of depression.^66,67 Perinatal depression is associated with adverse effects on infant and childhood development and behavior.^68–70 For these reasons, we focus on psychotropic medications for mood disorders.

A growing body of research demonstrates negligible risk in infants exposed to the majority of antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs).⁷¹ Plasma drawn from infants exposed to breast milk containing antidepressants has revealed undetectable or clinically insignificant concentrations of most SSRIs.^45,48,71 Platelets and neurons utilize the same serotonin receptor, which allows investigators to examine central nervous function through peripheral blood. When investigators evaluated infants exposure to SSRIs in breast milk, their platelet serotonin concentrations were not affected as evidenced by minimal or no decrease.⁷² Compared to the other SSRIs, fluoxetine transfers into the breast milk at higher levels due to the long half-live and active metabolite, norfluoxetine, that can accumulate in breastmilk.⁵² However, in the case of a patient who was benefiting from fluoxetine throughout pregnancy, continuation of the medication would be recommended with infant monitoring, especially during early infancy.⁵²

Medication decision making for women with bipolar disorder

Rarely are prospective studies conducted to evaluate the impact of drug exposure on child growth and development, which makes counseling about long-term outcomes challenging. However, the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study provides a template for such studies. In this prospective longitudinal observation study, a cohort of mothers and infants exposed to antiepileptic drugs (AED) monotherapy (carbamazepine, lamotrigine, phenytoin or valproate) during pregnancy were followed.⁷³ The study demonstrated no adverse effect of continued exposure to AED through breastmilk on cognitive function in children at 3 years of age as compared to unexposed formula-fed infants.⁷⁴ Importantly, the mean Intelligence Quotient at age 6 was significantly higher for those who were breastfed compared to those who received infant formula.⁷⁵ Studies similar to this for other medications used to treat bipolar disorder are not available.

Lithium is the gold standard drug for the treatment of bipolar disorder, and it is a first-line choice for management of postpartum psychosis.⁷⁶ Both the American Academy of Pediatrics and the National Library of Medicine (LactMed) provide guidelines for lithium use during breastfeeding.^61,77 With close and consistent clinical monitoring of the infant for sedation, restlessness, changes in growth and development, and attention to adequate infant hydration, lithium can be continued during lactation.^{60,61,77–79} In a systematic review that included 12 studies pertaining to lithium in breastmilk, few adverse effects were documented.⁶⁰ Infants with adverse outcomes were exposed to factors such as additional drug exposures and in utero exposure to lithium.⁶⁰ In addition, the authors discuss that literature prior to 1990 found a more significant proportion (20%) of infants with life-threatening events.⁶⁰ However, among cases reported after 1990, transient lab abnormalities and hypotonia were reported and these more recent cases had fewer confounding factors.⁶⁰

Lamotrigine is another commonly used mood stabilizer with an FDA indication for maintenance treatment of bipolar disorder. Infant serum concentrations are significantly higher in the neonate compared to other AEDs; however, few adverse events have been reported. Lamotrigine was included as one of the medications evaluated in the NEAD study referenced earlier.^80–83 Clinical monitoring of the infant for drowsiness, poor sucking as well as apnea is recommended,⁸¹ particularly in the first month of infancy.

Atypical antipsychotics are also commonly used to treat bipolar disorder and for augmentation of antidepressants in patients with unipolar depression. Atypical antipsychotics have limited maternal, breastmilk and infant serum data.^84–86 Commonly prescribed atypical antipsychotics for bipolar depression, mania or maintenance include olanzapine, quetiapine, risperidone and aripiprazole. A recent comparative systematic review included a total of 206 breastfed infants exposed to atypical antipsychotics.⁸⁴ The data set included olanzapine (n = 170 infants) and 26 treated with quetiapine, risperidone or aripiprazole.⁸⁴ No olanzapine was detected in nearly all infant sera samples, and the average RID was 1.6%.⁸⁴ Quetiapine was not detected in breastmilk for those mothers taking doses of 75 mg or lower.⁸⁷ In relation to olanzapine and quetiapine, risperidone is excreted into breastmilk at relatively higher levels, however no adverse events have been reported.^84,88 Data on aripiprazole are limited; however, it has been associated with decreased serum prolactin levels and impaired maternal milk supply.^84,89,90 As most antipsychotics are sedating for adults, LactMed recommends monitoring for sedation in the neonate as limited cases have been reported.⁴⁴ In adults, clozapine’s known side-effect of agranulocytosis requires careful monitoring. Infants exposed through breastmilk also warrant careful monitoring given one case report of agranulocytosis in an infant exposed to clozapine through the breastmilk.⁹¹

Sleep and lactation

While women with bipolar disorder are particularly vulnerable to mood destabilization from sleep deprivation, sleep is important for all new mothers.^91,92 If a person to help with night feedings is available, breastmilk can be collected. The mother can feed the baby at bedtime and finish by emptying both breasts with a pump. Freshly expressed, non-refrigerated milk can be used for up to four hours to feed to the baby for the subsequent feeding while the mother sleeps.⁹⁴ The helper can feed the infant the pumped milk while the mother sleeps. The mother can provide the next feeding and pump afterward for the helper’s next feeding. The mother and her helper each get two periods of about 4 h of uninterrupted sleep. For all new mothers, encourage them to nap while their baby naps and allow friends and family assist with noninfant care, such as shopping, preparing meals and laundry.

Practice points.

• The short- and long-term health benefits of breastfeeding for the mother and infant are well established

• The multiple adverse effects of not breastfeeding are important considerations

• The physician’s knowledge, experience and support are important to women’s decision to initiate and continue breastfeeding.

• Access to up-to-date information about medication use in lactating women is readily available (Table 2).

• Clinicians should consider factors outlined in the SAFEDLCT acronym when counseling and prescribing medications for lactating women (Table 3).

• Chose better studied and older medications when possible but also chose medications that are effective to treat the mother’s condition.

• Communication and collaboration with the pediatric health care providers caring for infants is important and good clinical practice.