Antidepressant Drugs and Breastfeeding: A Review of the Literature

Abstract

The use of antidepressants in breastfeeding mothers is controversial: Manufacters often routinely discourage breastfeeding for the nursing mother despite the well-known positive impact that breastfeeding carries on the health of the nursing infant and on his or her family and society. We conducted a systematic review of drugs commonly used in the treatment of postpartum depression. For every single drug two sets of data were provided: (1) selected pharmacokinetic characteristics such as half-life, milk-to-plasma ratio, protein binding, and oral bioavailability and (2) information about lactational risk, according to some authoritative sources of the literature: Drugs in Pregnancy and Lactation edited by Briggs et al. (Lippincott Williams, Philadelphia, 2008), Medications and Mothers' Milk by Hale (Hale Publishing, Amarillo, TX, 2010), and the LactMed database of TOXNET (www.pubmed.gov; accessed June 2010). Notwithstanding a certain variability of advice, we found that (1) knowledge of pharmacokinetic characteristics are scarcely useful to assess safety and (2) the majority of antidepressants are not usually contraindicated: (a) Selective serotinin reuptake inhibitors and nortryptiline have a better safety profile during lactation, (b) fluoxetine must be used carefully, (c) the tricyclic doxepine and the atypical nefazodone should better be avoided, and (d) lithium, usually considered as contraindicated, has been recently rehabilitated.

Introduction

The broad spectrum of mental disorders affecting new parents (more explicitly, mothers more than fathers) requires close attention for their potential severity.¹ Among them, postpartum depression (PPD) is a serious one with a prevalence ranging from almost 0% to almost 60%.² Such a variability is possibly due to cross-cultural variables, different socioeconomic factors, and differences in research procedures and symptoms definitions.^2,3 With regard to developed countries, as many as 19.2% of women have a depressive episode in the first 3 months postpartum,⁴ supporting the idea that previous reports underestimated the magnitude of a often unaccounted-for problem.⁵

Depressed women experiment anxiety, fatigue, decreased concentration, insomnia, and loss of interest in usual activities. The acknowledgment of feeling unhappy and inadequate just when they usually “expect and are expected to be happiest after childbirth”⁶ could be devastating and represent a reason for embarrassment and delayed call for medical help and diagnosis.

The rapid decline of postpartum hormones combined with stressful life events (including childcare-related stressors), lack of social support, isolation, and an unsatisfactory couple relationship are believed to contribute to the insurgence of PPD,^5,7–12 especially in predisposed individuals with a history of anxiety and antecedents of depression before and during pregnancy.^13,14 In contrast, other risk factors, including low socioeconomic status, obstetric factors, and difficult infant temperament, seem less strongly related to PPD.^8,10

Psychotherapy has been demonstrated to be effective in treating PPD,^15,16 but it may not be available or acceptable or, in addition, may not be a sufficient therapy in severe forms of PPD. Consequently, psychotropic drugs and in particular antidepressants become an important part of the treatment plan during pregnancy and lactation,¹⁷ even if the risk of untreated maternal depressions must be balanced by the risks associated with infant exposure to medication in breastmilk.^18,19

When nursing women treated with psychotropic drugs for PPD face the dilemma of breastfeeding or not, it should be kept in mind that breastfeeding is the norm, which confers to both mother and baby many well-documented short- and long-term benefits.²⁰ The World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months of life and continuation of breastfeeding after weaning²¹ and warns health professionals not to discourage such a healthy behavior, unless well-founded medical reasons are encountered.²²

Given the growing incidence of PPD² and the increase in breastfeeding initiation and duration in the United States²³ as well as Europe,²⁴ maternal use of psychotropic drugs in the nursing woman has recently become a clinical topic and an area of lively scientific interest. Depressed mothers may encounter difficulties in breastfeeding management, need extra support in order to maintain lactation,^25–27 and are particularly prone to sleeplessness, which worsens/triggers depressive symptoms.²⁸

A methodologically correct judgment on the use of antidepressants in the nursing mother is strongly required because untreated depression interferes with mother–child interaction and with the correct maternal perception of a child's behaviors, leading to well-documented negative effects on the child's social and cognitive development.²⁹ The reported association between PPD and negative effects on early infant growth has not been recently confirmed.³⁰

The present review aims to provide the clinician with handy advice on the lactational risk for the commonest antidepressants.

Methods

In our study, antidepressants drugs were defined according to the International Anatomical Therapeutic Chemical Classification System (code: N06A) by the WHO Collaborating Centre for Drug Statistics Methodology.³¹ We also decided to include in our review two antipsychotic drugs (code: N05A), lithium (a mood stabilizer for bipolar disorders) and quetiapine (an atypical antipsychotic), considering their current use to treat symptoms in depressed patients.

Initially, we collected available advice on the use of antidepressants while breastfeeding from the most clinically recognized, authoritative sources on the topic: The Committee on Drugs of the American Academy of Pediatrics,³² WHO/UNICEF,³³ Hale and Hartman's Textbook of Human Lactation,³⁴ the British National Formulary,³⁵ Drugs in Pregnancy and Lactation edited by Briggs et al.,³⁶ Hale's Medications and Mothers' Milk,³⁷ and the LactMed database,³⁸ commonly considered the most up-to-date resource on the issue.³⁹

Later, we decided to omit the information from the accredited American Academy of Pediatrics and WHO/UNICEF, which had been published before the last 5 years and therefore was evaluated as being outdated. Moreover, data retrievable from the British National Formulary (BNF) 59³⁵ were judged as poorly useful as this source systematically warns against the use of antidepressant drugs, on the basis of the stereotypically cautious indication by the manufacturers.

As a consequence, analysis was limited to three main sources: the 2008 textbook by Briggs et al.,³⁶ Hale's 2010 textbook,³⁷ and the LactMed database³⁸ (accessed in June 2010). On June 17, 2010, to complete the previous analysis, we performed a search in the MEDLINE database (www.pubmed.com) on available literature published in English in the last 5 years, limited to humans, using the key words “breastfeeding AND antidepressant drugs.” As a result of this search, we identified 74 references, among which were 17 reviews, nine case reports, and four practice guidelines. All references were then analyzed. Any relevant information was added to that derived from Briggs et al.,³⁶ Hale,³⁷ and LactMed.³⁸

In the present study, antidepressant drugs were classified into different categories: selective serotonin reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tryciclic, tetracyclic, monoamine oxidase inhibitors, or atypical.

The information on the lactational risk of antidepressants was included into synoptic tables for quick and easy use. For every single drug two sets of data were provided: (1) some selected pharmacokinetic characteristics and (2) information about lactational risk, according to the above-cited three authoritative sources of the literature. Among the pharmacokinetic characteristics we considered were the half-life (adult half-life of the drug), the time interval from administration of the drug until it reaches the highest level in the mother's plasma, the milk-to-plasma (M/P) ratio, the percentage of maternal protein binding, and oral bioavailability (percentage of a drug that reaches the systemic circulation after oral administration).

Results

Selected pharmacokinetic items of different antidepressants drugs are reported in Table 1.³⁷

Table 1.

Summary of Basic Pharmacokinetic Parameters of Antidepressant Drugs During Breastfeeding ³⁷

	Half-life	T_max	M/P	PB	Oral bioavailability
SSRI
Citalopram	36 hours	2–4 hours	1.16–3	80%	80%
Escitalopram	27–32 hours	5 hours	2.2	56%	80%
Fluoxetine	2–3 days	1.5–12 hours	0.28–0.67	94.5%	100%
Fluvoxamine	15.6 hours	3–8 hours	1.34	80%	53%
Paroxetine	21 hours	5–8 hours	0.056–1.3	95%	Complete
Sertraline	26 hours	7–8 hours	0.89	98%	Complete
NRI
Reboxetine	NR	NR	NR	NR	NR
SNRI
Venlafaxine	5 hours	2.25 hours	2.75	27%	92%
Duloxetine	12 hours	6 hours	0.267–1.29	>90%	>70%
Tricyclic antidepressant
Amitriptyline	31–46 hours	2–4 hours	1	94.8%	Complete
Nortriptyline	16–90 hours	7–8.5 hours	0.87–3.71	92%	51 %
Clomipramine	19–37 hours	—	0.84–1.62	96%	Complete
Desipramine	7–60 hours	4–6 hours	0.4–0.9	82%	90%
Imipramine	8–16 hours	1–2 hours	0.5–1.5	90%	90%
Dothiepin	14.4–23.4 hours	3 hours	0.3	—	30%
Doxepine	8–24 hours	2 hours	1.08–1.66	80–85%	Complete
Protriptyline	NR	NR	NR	NR	NR
Trimipramine	NR	NR	NR	NR	NR
Tetracyclic antidepressant
Amoxapine	8 hours	2 hours	0.21	15–25%	18–54%
Maprotiline	27–58 hours	12 hours	1.5	88%	100%
Mianserine	NR	NR	NR	NR	NR
MAOIs	NR	NR	NR	NR	NR
Atypical
Bupropion	8–24 hours	2 hours	2.51–8.58	75–88%	85%
St. John's wort	26.5 hours	5.9 hours	NR	NR	NR
Nefazodone	1–4 hours	1 hour	0.1–0.27	>99%	20%
Mirtazapine	20–40 hours	2 hours	0.76	85%	50%
Quetiapine^a	6 hours	1.5 hours	0.29	83%	100%
Trazodone	4–9 hours	1–2 hours	0.142	85–95%	65%
Lithium^a	17–24 hours	2–4 hours	0.24–0.66	0%	Complete

Not strictly an antidepressant drug.

Half-life, adult half-life of the medication; MAOI, monoamine oxidase inhibitor; M/P, milk/plasma ratio; NR, not reviewed; NRI, norepinephrine reuptake inhibitor; PB, protein binding in maternal serum; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; T_max, time to reach a peak concentration in maternal plasma.

The lactational risk according to the literature for the most common antidepressants has been reviewed in Table 2.^40–103

Table 2.

Safety Assessment of Antidepressant Drugs During Breastfeeding

	Reference
Drug	Briggs et al. ³⁶ (2008) ^a	Hale ³⁷ (2010) ^b	LactMed ³⁸ (2010)
SSRI^40–47
Citalopram^48–51	L-PT	L2	Agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. The breastfed infant should be monitored for behavioral side effects such as sedation or fussiness.
Escitalopram⁵²	N-PT	L2	Escitalopram would not be expected to cause any adverse effects during breastfeeding. Monitor the infant for drowsiness if the infant is older than 2 months, exclusively breastfed infants, and when using combinations of psychotropic drugs.
Fluoxetine^53–60	L-PT	L2	Agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. The breastfed infant should be monitored for behavioral side effects such as colic, fussiness, or sedation and for adequate weight gain.
Fluvoxamine^61–64	L-PT	L2	Maternal fluvoxamine doses of up to 300 mg daily produce low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
Paroxetine^62,65–66	L-PT	L2	Paroxetine has not been detected in the serum of most infants tested and should be considered one of the preferred antidepressants during breastfeeding.
Sertraline^62,67–70	L-PT	L2	Sertraline is usually not detected in the serum of the infant and should be considered one of the preferred antidepressants during breastfeeding.
NRI
Reboxetine	NR	NR	NR
SNRI
Venlafaxine^71,72	L-PT	L3	Breastfed infants, especially newborn or preterm infants, should be monitored for excessive sedation and adequate weight gain. Include measurement of serum desvenlafaxine to rule out toxicity. Newborn infants of mothers who took the drug during pregnancy may experience poor neonatal adaptation syndrome; it has been proposed the use of venlafaxine during breastfeeding as a method of mitigating infant venlafaxine withdrawal symptoms.
Duloxetine⁷³	N-PT	L3	An alternate drug that has been better studied may be preferred, especially while nursing a newborn or preterm infant. Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of psychotropic drugs.
Tricyclic antidepressant
Amitriptyline	L-PT	L2	Amitriptyline use during breastfeeding would usually not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Other agents with fewer active metabolites may be preferred when large doses are required or while nursing a newborn or preterm infant.
Nortriptyline	L-PT	L2	Most authoritative reviewers consider nortriptyline one of the preferred antidepressants during breastfeeding.
Clomipramine^74,75	L-PT	L2	The use of clomipramine during breastfeeding is acceptable but may be less desirable than other tricyclic antidepressants that have been studied more thoroughly.
Desipramine	L-PT	L2	Desipramine use during breastfeeding would usually not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
Imipramine	L-PT	L2	Imipramine use during breastfeeding would usually not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Other agents may be preferred when large doses are required or while nursing a newborn or preterm infant.
Dothiepin^{76, 77}	L-PT	L2	NR
Doxepin⁷⁸	L-PT	L5	Doxepin is a poor choice, and other agents may be preferred, especially while nursing a newborn or preterm infant. If doxepin is required by the mother of an older infant, the infant should be monitored carefully for excessive sedation and adequate weight gain.
Protriptyline	N-PT	NR	There is no published experience with protriptyline during breastfeeding so other agents may be preferred, especially while nursing a newborn or preterm infant.
Trimipramine	N-PT	NR	Because of the lack of data on use during breastfeeding, other antidepressants are preferred during breastfeeding, especially while nursing a newborn or preterm infant.
Tetracyclic antidepressant
Amoxapine⁷⁹	L-PT	L2	Because no information is available on the use of amoxapine during breastfeeding, another drug may be preferred, especially while nursing a newborn or preterm infant. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels.
Maprotiline⁸⁰	L-PT	L3	Because there is little published experience with maprotiline during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
Mianserine⁸¹	NR	NR	NR
MAOIs
Fenelzine	NR	NR	NR
Moclobemide⁸²	NR	L3	NR
Tranylcypromine	N-PT	NR	Because of the lack of data on use during breastfeeding, other antidepressants are preferred during breastfeeding.
Atypical
Bupropion^83–87	L-PT	L3	Another drug may be preferred, especially while nursing a newborn or preterm infant. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels.
St. John's wort^88–92	L-PT	L2	NR
Nefazodone⁹³	L-PT	L4	Nefazodone produce low but variable levels in milk that would not be expected to cause adverse effects in a breastfed infant, especially if the infant is older than 2 months. Until more data become available, other drugs may be preferred, especially while nursing a newborn or preterm infant.
Mirtazapine^94–97	L-PT	L3	Maternal doses of up to 120 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Exclusively breastfed infants should be monitored for behavioral side effects and adequate growth if this drug is used during lactation.
Quetiapine^72,98–100^c	L-PT	L2	Limited information indicates that maternal quetiapine oral doses of up to 400 mg daily produce low levels in milk. Other agents may be preferred, especially while nursing a newborn or preterm infant.
Trazodone¹⁰¹	L-PT	L2	Trazodone would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months or when doses of 100 mg or less are used at bedtime for sleep.
Lithium^102,103^c	L-PT	L3	Limited data suggest that lithium in milk can adversely affect the infant when its elimination is impaired, as in dehydration or in newborn or premature infants.

Breastfeeding recommendations for Briggs et al.³⁶ are defined as follows: L-PT, limited human data—potential toxicity; N-PT, no human data—potential toxicity; L-PC, limited human data—probably compatible; N-PC, no human data—probably compatible; P, drugs associated with significant side effects on some nursing infant and should be given with caution; C, usually compatible with breastfeeding.

Lactation risk categories according to Hale³⁷ are as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.

Not strictly an antidepressant drug.

As antidepressants represent a class of drugs with long or intermediate half-life, they are usually suspected to accumulate in the nursing infant. Plasma peaks are usually reached between 1 hour (nefazodone, trazodone) and 12 hours (fluoxetine, maprotiline) after oral intake, depending on the particular antidepressant. Nevertheless, antidepressant drugs are highly protein bound (usually >80%) and cannot easily exit the plasma compartment. Exceptions are represented by escitalopram and especially by venlafaxine, bound to plasma proteins at percentages of 56% and 27%, respectively, but such a low level of binding is not enough reason to contraindicate these two medications in the nursing mother.

While some antidepressants show an M/P of 1 or less (e.g., fluoxetine and desimipramine), indicating that the drug is not concentrated in human milk, others such as citalopram, escitalopram, nortryptiline, and bupropion show an M/P even greater than 2, indicating that the drug is concentrated in breastmilk. Yet, an M/P ratio of 2 or more cannot be interpreted per se as unsafe and rarely provides useful information on infant exposure risk assessment.¹⁰⁴ Better than M/P, the concentration of a drug in milk is the determinant of infant exposure, which in turn could be more useful to assess safety.^34,105

Oral bioavailability of antidepressant drugs is usually good or complete (>80%), with the exception of fluvoxamine (53%), nortryptiline (51%), dothiepin (30%), amoxapine (18–54%), nefazodone (20%), and mirtazapine (50%). Oral absorption in the infant is important for determining how much drug reaches the systemic circulation. Yet, even low exposure to some medications might cause adverse effects in breastfed infants.

Actually, this body of knowledge challenges us to elegant reasoning in order to anticipate side effects, but we must admit that it is rarely a determinant in the assessment of the lactational risk for drugs used by the nursing mother. This is evident when we try to compare pharmacokinetic data (Table 1) with the advice from authoritative sources mainly based on the existence of documented side effects (Table 2). Sertraline could represent a good example, as the positive clinical assessment of safety during lactation is not consistent with its pharmacokinetic characteristics (long half-life, possible high M/P, complete oral bioavailability).

An obvious limitation to our study consists in not reviewing among the pharmacokinetics characteristics the relative infant dose (RID), i.e., the daily dosage of drug received by an infant through breastmilk (in mg/kg/day), expressed as a percentage of the weight-adjusted maternal daily dosage (in mg/kg/day). Although the RID provides a standardized mean of referencing infant exposure on a dose/weight basis,³⁴ its calculation requires knowledge of the previous concentration of a certain drug in milk, the volume of milk ingested by the nursing infant, and the infant's as well as mother's weight. Fortinguerra et al.¹⁰⁵ have recently reported that only three out of 23 reviewed antidepressants (citalopram, escitalopram, and fluoxetine) expressed an RID higher than 10%, a cutoff commonly accepted for compatibility during breastfeeding,¹⁰⁶ yet not automatically leading to an absolute contraindication to breastfeeding.

From the present review we can summarize advice to the nursing mother as follows:

An overall analysis done by Weissman et al.¹⁰⁷ on 57 studies showed that antidepressant drugs, although commonly detectable in a mother's milk, are not always found in the child's serum. Birnbaum et al.¹⁰⁸ in a case series study documented that antidepressants are not detected in infants' serum when mothers used these drugs only during the postpartum period. Consistently, the great majority of antidepressants are not contraindicated during breastfeeding.¹⁰⁵

Among antidepressants, SSRIs, currently used as first-choice treatment for PPD, are compatible with breastfeeding⁴⁷ but could interfere with the human lactation physiology, delaying secretory activation.¹⁰⁹ Sertraline,^67–70 paroxetine,^65,66 and the tricyclic nortriptyline^36,37 have a better safety profile during lactation. When attempting to choose the safest SSRI for the nursing woman, an M/P ratio <1.0 should be reasonable, but not supported by evidence-based information.⁴⁵

Fluoxetine^53–60 must be carefully used, while the tricyclic doxepine^33,36,37,78 and the atypical nefazodone^36,37,93 should be better avoided.

Until recently, use of lithium during lactation has been discouraged and typically considered contraindicated in breastfeeding, considering that lithium is secreted at high levels in breastmilk and has toxicity for infants. In contrast, serum lithium levels in nursing infants of mothers treated with lithium for bipolar disorders have been reported to be low; moreover, no significant adverse clinical or behavioral effects in the infants were noted.¹⁰² These findings encourage current reassessment of recommendations against lithium during breastfeeding, at least when the mother follows a lithium monotherapy, adheres to infant monitoring recommendations, and has a healthy infant.

Herbal preparations for depression, such as St. John's wort, are often preferred over pharmaceutical preparations because “natural” treatments are assumed to be safe, but concerns about hepato- and nephrotoxicity in pregnancy and lactation have been raised, at least in animal studies.⁸⁹ The available evidence suggests that the Hypericum extracts are similarly effective as standard antidepressants and have fewer side effects.⁹⁰ Hyperforin, the active component of St. John's wort, is excreted into breastmilk at low levels,⁹¹ and no increased adverse effects in the nursing infant have been documented.⁹²

Discussion

Theoretically, the ideal antidepressant for the nursing woman would be highly bound to plasma proteins, with a short half-life, a low M/P ratio, and a poor absorption in order to minimize the drug exposure of the nursing infant. Actually, from the present review we have shown that for any specific drug, danger for the nursing infant can be poorly anticipated on the basis of pharmacokinetic data. A full clinical evaluation of the lactational risk for any drug assumed by the mother should also necessarily consider the proven side effects, if any, in the nursing infant. We must admit that current information on side effects during breastfeeding is mainly based on case reports and/or case series. In contrast, controlled studies on the use of drugs during lactation are still lacking, consequently impeding a reliable ascription of any reported side effect to medication taken by the breastfeeding mother. Therefore, side effects in the nursing infants have been probably overestimated,¹¹⁰ and the list of drugs commonly considered as contraindicated during breastfeeding has been improperly too long, possibly limiting the well-known favorable impact that breastfeeding carries on the health of the nursing infant and on his or her family and society.²⁰

When studies on the lactational risk of a drug are lacking, the manufacturer-provided drug label should not be considered per se a reliable source of information, as it usually indicates that the drug is not recommended during lactation. According to the Italian Medicines Agency, e.g., about 80% of drugs marketed in Italy in 2004 were contraindicated, while only 1% were clearly permitted during breastfeeding,¹¹¹ thus possibly exerting a strong negative influence on both health professionals and families regarding the start and/or continuation of breastfeeding.

The need for complete and correct information about the use of drugs during breastfeeding is currently recognized by the international scientific community.

This matter has also been addressed by the U.S. Food and Drug Administration, with the publication on May 2008 of the Proposed Rule for Pregnancy and Lactation Labeling for Human Prescription Drug and Biological Products. Thus the Food and Drug Administration started a new approach in labeling drugs and biological products for use during pregnancy and lactation, allowing women who are breastfeeding to give truly informed consent. The manufacturer-provided drug labels will have to present in a clearer and better organized way what it is important to know.¹¹² This initiative means another small step forward in the promotion of breastfeeding.

Advice by different authoritative sources on the lactational risk for medications taken by the nursing woman has a certain degree of inconsistency; such a metavariability, yet predictable according to common sense, has also been remarked on in the scientific literature, at least for the drug category of beta-blockers.¹¹³

Also, regarding the specific issue of antidepressants, there are no commonly accepted decisional algorithms on risk assessment during lactation, as is evident from the numerous retrievable reviews,^114–121 as well as from the present article. Therefore, it is always necessary to perform an individualized analysis of risk/benefit ratio,¹²² which should take into account that the breastfed child has a higher risk of developing side effects, when he or she has already been exposed to the drug during pregnancy^123–126 and during the first 2 months of life,³⁸ when the ability to metabolize the drug is still limited, as suggested by LactMed.

The long-term effects on a child's neurological development cannot be excluded, when considering a breastfeeding mother receiving psychotropic treatment. This is especially true for the modern SSRIs, as there are no studies with adequate follow-up, rather than for the old but well-known tricyclic antidepressants.⁹ However, such hypothetical, still unproven risk for the child, resulting from prolonged exposure to small doses of psychotropic drugs through breastmilk, does not justify avoiding or stopping medications for PPD. In fact, the documented positive effects of breastfeeding on the mother and her baby outweigh the possible adverse effects of antidepressant drugs on both.¹¹⁷

Finally, for antidepressants with a lower safety profile, it is anyway useful to apply strict child monitoring to identify early the commonest side effects: weight gain and/or excessive sedation.^{115,117,127,128}

Conclusions

Given the negative consequences of PPD on the growth and the development of the child, appropriate treatment, including pharmacotherapy, is necessary and advisable. Most antidepressants taken by the nursing woman are excreted in breastmilk, but the risk for the exposed infants is usually overemphasized.

When assessing the lactational risk, the commonly alleged importance of pharmacological data must be reconsidered, as they are simply subsidiary to the clinical report of documented side effects in the nursing infant.

At the present state of the art, the great majority of antidepressants are safe during breastfeeding, despite some controversies in the literature when judging the lactational risk.

Healthcare professionals should set aside any prejudices they may have toward depressed mothers who want to breastfeed.

In turn, depressed mothers should be adequately supported to start and maintain lactation, as they encounter greater obstacles and constraints to cope with breastfeeding than the general population of new mothers.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Munk-Olsen

, Laursen

, Pedersen

et al. New parents and mental disorders: A population-based register study. JAMA, 2006; 296:2582–2589.

Halbreich

, Karkun

. Cross-cultural and social diversity of prevalence of postpartum depression and depressive symptoms. J Affect Disord, 2006; 91:97–111.

Wisner

, Moses-Kolko

, Sit

DKY

. Postpartum depression: A disorder in search of a definition. Arch Womens Mental Health, 2010; 13:37–40.

Gavin

, Gaynes

, Lohr

et al. Perinatal depression: A systematic review of prevalence and incidence. Obstet Gynecol, 2005; 106:1071–1083.

O'Hara

, Zekoski

, Philipps

et al. Rates and risk of postpartum depression: A meta-analysis. Int Rev Psychiatry, 1996; 8:37–54.

Hormann

. Breastfeeding and maternal depression: Relationship, constraints and opportunity for improving women's health. Davanzo

. Nutrition with Human Milk. Research and Practice. Graphart: Trieste, 2010; 103–108.

Romito

, Saurel-Cubizolles

, Lelong

. What makes new mothers unhappy: Psychological distress one year after birth in Italy and France. Soc Sci Med, 1999; 49:1651–1661.

Beck

. Predictors of postpartum depression: An update. Nurs Res, 2001; 50:275–285.

Wisner KL Parry

, Piontek

. Postpartum depression. N Engl J Med, 2002; 347:194–199.

10.

Robertson

, Grace

, Wallington

et al. Antenatal risk factors for postpartum depression: A synthesis of recent literature. Gen Hosp Psychiatry, 2004; 26:289–295.

11.

Grussu

, Quatraro

. Prevalence and risk factors for a high level of postnatal depression symptomatology in Italian women: A sample drawn from ante-natal classes. Eur Psychiatry, 2009; 24:327–333.

12.

Rambelli

, Montagnani

, Oppo

et al. Panic disorder as a risk factor for post-partum depression: Results from the Perinatal Depression-Research & Screening Unit (PND-ReScU) study. J Affect Disord, 2010; 122:139–143.

13.

Howell

, Mora

, Leventhal

. Correlates of early postpartum depressive symptoms. Matern Child Health J, 2006; 10:149–157.

14.

Dietz

, Williams

, Callaghan

et al. Clinically identified maternal depression before, during, and after pregnancies ending in live births. Am J Psychiatry, 2007; 164:1515–1520.

15.

Musters

, McDonald

, Jones

. Management of postnatal depression. BMJ, 2008; 337:399–403.

16.

O'Hara

. Postpartum depression: What we know. J Clin Psychol, 2009; 65:1258–1269.

17.

Dossett

. Perinatal depression. Obstet Gynecol Clin North Am, 2008; 35:419–434.

18.

Freeman

. Postpartum depression treatment and breastfeeding. J Clin Psychiatry, 2009; 70:e35.

19.

Kendall-Tackett

, Hale

. The use of antidepressants in pregnant and breastfeeding women: A review of recent studies. J Hum Lact, 2010; 26:187–195.

20.

, Chung

, Raman

et al. A summary of the Agency for Healthcare Research and Quality's evidence report on breastfeeding in developed countries. Breastfeed Med, 2009; 4,Suppl 1:S-17–S-30.

21.

World Health Organization. Global Strategy for Infant and Young Child Feeding. World Health Organization: Geneva, 2003.

22.

World Health Organization/UNICEF. Acceptable Medical Reasons for Use of Breast-Milk Substitutes. Department of Child and Adolescent Health and Development, World Health Organization: Geneva, 2009.

23.

Wright

, Schanler

. The resurgence of breastfeeding at the end of the second millennium. J Nutr, 2001; 131:421S–425S.

24.

Cattaneo

, Burmaz

, Arendt

et al. Protection, promotion and support of breast-feeding in Europe: Progress from 2002 to 2007. Public Health Nutr, 2010; 13:751–759.

25.

Henderson

, Evans

, Straton

et al. Impact of postnatal depression on breastfeeding duration. Birth, 2003; 30:175–180.

26.

Akman

, Kuscu

, Yurdakul

et al. Breastfeeding duration and postpartum psychological adjustment: Role of maternal attachment styles. J Paediatr Child Health, 2008; 44:369–373.

27.

Dennis

, McQueen

. The relationship between infant-feeding outcome and postpartum depression: A qualitative systematic review. Pediatrics, 2009; 123:e736–e751.

28.

Dørheim

, Bondevik

, Eberhard-Gran

et al. Sleep and depression in postpartum women: A population-based study. Sleep, 2009; 32:847–855.

29.

Field

. Postpartum depression effects on early interactions, parenting, and safety practices: A review. Infant Behav Dev, 2010; 33:1–6.

30.

Grote

, Vik

, von Kries

et al. Maternal postnatal depression and child growth: A European cohort study. BMC Pediatr, 2010; 10:14.

31.

WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment, 2010. WHO Collaborating Centre for Drug Statistics Methodology: Oslo, 2009.

32.

American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics, 2001; 108:776–789.

33.

World Health Organization, UNICEF. Breastfeeding and Maternal Medication. Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs. World Health Organization-UNICEF: Geneva, 2002.

34.

Hale

, Hartmann

. Hale & Hartmann's Textbook of Human Lactation. Hale Publishing: Amarillo, TX, 2007.

35.

British National Formulary (BNF) 59. British Medical Association and Royal Pharmaceutical Society of Great Britain: London, 2010.

36.

Briggs

, Freeman

, Yaffe

. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8^th. Lippincott Williams & Wilkins: Philadelphia, 2008.

37.

Hale

. Medication and Mothers' Milk, 14^th. Hale Publishing: Amarillo, TX, 2010.

38.

LactMed. TOXNET. toxnet.nlm.nih.gov/index.html. 2010 June .

39.

Akus

, Bartick

. Lactation safety recommendations and reliability compared in 10 medication resources. Ann Pharmacother, 2007; 41:1352–1360.

40.

Misri

, Burgmann

, Kostaras

. Are SSRIs safe for pregnant and breastfeeding women? Can Fam Physician, 2000; 46:626–633.

41.

Nordeng

, Lindemann

, Perminov

et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr, 2001; 90:288–291.

42.

Berle

JØ

, Steen

, Aamo

et al. Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: Infant exposure, clinical symptoms, and cytochrome p450 genotypes. J Clin Psychiatry, 2004; 65:1228–1234.

43.

Moses-Kolko

, Bogen

, Perel

et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. JAMA, 2005; 293:2373–2383.

44.

Chambers

, Hernandez-Diaz

, Van Marter

et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med, 2006; 354:579–587.

45.

Gentile

, Rossi

, Bellantuono

. SSRIs during breastfeeding: Spotlight on milk-to-plasma ratio. Arch Womens Ment Health, 2007; 10:39–51.

46.

Toh

, Mitchell

, Louik

et al. Selective serotonin inhibitor use and risk of gestational hypertension. Am J Psychiatry, 2009; 166:320–328.

47.

Ellfolk

, Malm

. Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors (SSRIs) Reprod Toxicol, 2010; 30:249–260.

48.

Heikkinen

, Ekblad

, Kero

et al. Citalopram in pregnancy and lactation. Clin Pharmacol Ther, 2002; 72:184–191.

49.

Rampono

, Kristensen

, Hackett

et al. Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants. Br J Clin Pharmacol, 2000; 50:263–268.

50.

Franssen

, Meijs

, Ettaher

et al. Citalopram serum and milk levels in mother and infant during lactation. Ther Drug Monit, 2006; 28:2–4.

51.

Schmidt

, Olesen

, Jensen

. Citalopram and breast-feeding: serum concentration and side effects in the infant. Biol Psychiatry, 2000; 47:164–165.

52.

Potts

, Young

, Carter

et al. Necrotizing enterocolitis associated with in utero and breast milk exposure to the selective serotonin reuptake inhibitor, escitalopram. J Perinatol, 2007; 27:120–122.

53.

Kristensen

, Ilett

, Hackett

et al. Distribution and excretion of fluoxetine and norfluoxetine human milk. Br J Clin Pharmacol, 1999; 48:521–527.

54.

Chambers

, Anderson

, Thomas

et al. Weight gain in infants breastfed by mothers who take fluoxetine. Pediatrics, 1999; 104:e61.

55.

Lester

, Cucca

, Andreozzi

et al. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry, 1993; 32:1253–1255.

56.

Brent

, Wisner

. Fluoxetine and carbamazepine concentrations in a nursing mother/infant pair. Clin Pediatr, 1998; 37:41–44.

57.

Taddio

, Ito

, Koren

. Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk. J Clin Pharmacol, 1996; 36:42–47.

58.

Yoshida

, Smith

, Craggs

. Fluoxetine in breast-milk and developmental outcome of breast-fed infants. Br J Psychiatry, 1998; 172:175–178.

59.

Epperson

, Jatlow

, Czarkowski

et al. Maternal fluoxetine treatment in the postpartum period: Effects on platelet serotonin and plasma levels in breastfeeding mother-infant pairs. Pediatrics, 2003; 112:e425.

60.

Nulman

, Rovet

, Stewart

et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry, 2002; 159:1889–1895.

61.

Wright

, Dawling

, Ashford

. Excretion of fluvoxamine in breastmilk [letter] Br J Clin Pharmacol, 1991; 31:209.

62.

Hendrick V Fukuchi

, Altshuler

et al. Use of sertraline, paroxetine and fluovoxamine by nursing women. Br J Psychiatry, 2001; 179:163–166.

63.

Piontek

, Wisner

, Perel

et al. Serum fluvoxamine levels in breastfed infants. J Clin Psychiatry, 2001; 62:111–113.

64.

Kristensen

, Hackett

, Kohan

et al. The amount of fluvoxamine in milk is unlikely to be a cause of adverse affects in breastfed infants. J Hum Lact, 2002; 18:139–143.

65.

Ohman

, Hagg

, Carleborg

et al. Excretion of paroxetine into breast milk. J Clin Psychiatry, 1999; 60:519–523.

66.

Stowe

, Cohen

, Hostetter

et al. Paroxetine in human breast milk and nursing infants. Am J Psychiatry, 2000; 157:185–189.

67.

Epperson

, Czarkowski

, Ward-O'Brien

et al. Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs. Am J Psychiatry, 2001; 158:1613–1617.

68.

Kristensen

, Ilett

, Dusci

et al. Distribution and excretion of sertraline and N-desmethylsertraline in human milk. Br J Clin Pharmacol, 1998; 45:453–457.

69.

Wisner

, Perel

, Blumer

. Serum sertraline and N-desmethylsertraline levels in breast-feeding mother-infant pairs. Am J Psychiatry, 1998; 155:690–692.

70.

Mammen

, Perel

, Rudolph

. Sertraline and norsertraline levels in three breastfed infants. J Clin Psychiatry, 1997; 58:100–103.

71.

Ferreira

, Carceller

, Agogué

et al. Effects of selective serotonin inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics, 2007; 119:52–59.

72.

Pae

, Kim

, Lee

et al. Very low dose quetiapine-induced galactorrhea in combination with venlafaxine. Hum Psychopharmacol, 2004; 19:433–434.

73.

Lobo

, Loghin

, Knadler

et al. Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet, 2008; 47:103–109.

74.

Schimmell

, Katz

, Shaag

et al. Toxic neonatal effects following maternal clomipramine therapy. Clin Toxicol, 1991; 29:479–484.

75.

Wisner

, Perel

, Foglia

. Serum clomipramine and metabolite levels in four nursing mother-infant pairs. J Clin Psychiatry, 1995; 56:17–20.

76.

Ilett

, Lebedevs

, Wojnar-Horton

et al. The excretion of dothiepin and its primary metabolites in breast milk. Br J Clin Pharmacol, 1992; 33:635–639.

77.

Buist

, Janson

. Effect of exposure to dothiepin and northiaden in breast milk on child development. Br J Psychiatry, 1995; 167:370–373.

78.

Frey

, Scheidt

, von Brenndorff

. Adverse effects in a newborn infant breast-fed by a mother treated with doxepin. Ann Pharmacother, 1999; 33:690–693.

79.

Gelenberg

. Single case study. Amoxapine, a new antidepressant, appears in human milk. J Nerv Ment Dis, 1979; 167:635–636.

80.

Perez

, Henriquez

. Galactorrhea associated with maprotiline HCl [letter] Am J Psychiatry, 1983; 140:641.

81.

Buist

, Norman

, Dennerstein

. Mianserine in breast milk [letter] Br J Clin Pharmacol, 1993; 36:133–134.

82.

Mayersohn

, Guentert

. Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet, 1995; 29:292–332.

83.

Haas

, Kaplan

, Barenboim

et al. Bupropion in breast milk: An exposure assessment for potential treatment to prevent post-partum tobacco use. Tob Control, 2004; 13:52–56.

84.

Briggs

, Samson

, Ambrose

et al. Excretion of bupropion in breast milk. Ann Pharmacother, 1993; 27:431–433.

85.

Baab

, Peindl

, Piontek

et al. Serum bupropion levels in 2 breastfeeding mother-infant pairs. J Clin Psychiatry, 2002; 63:910–911.

86.

Davis

, Miller

, Nolan

. Bupropion levels in breast milk for 4 mother-infant pairs: More answers to lingering questions. J Clin Psychiatry, 2009; 70:297–298.

87.

Chaudron

, Schoenecker

. Bupropion and breastfeeding: A case of a possible infant seizure. J Clin Psychiatry, 2004; 65:881–882.

88.

Shelton

, Keller

, Gelenberg

et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA, 2001; 285:1978–1986.

89.

Gregoretti

, Stebel

, Candussio

et al. Toxicity of Hypericum perforatum (St John's wort) administered during pregnancy and lactation in rats. Toxicol Appl Pharmacol, 2004; 200:201–205.

90.

Linde

, Berner

, Kriston

. St John's wort for major depression. Cochrane Database Syst Rev, 2008; 4:CD000448.

91.

Klier

, Schmid-Siegel

, Schäfer

et al. St. John's wort (Hypericum perforatum) and breastfeeding: Plasma and breast milk concentrations of hyperforin for 5 mothers and 2 infants. J Clin Psychiatry, 2006; 76:305–309.

92.

Lee

, Minhas

, Matsuda

, Lam

et al. The safety of St. John's wort (Hypericum perforatum) during breastfeeding. J Clin Psychiatry, 2003; 64:966–968.

93.

Yapp

, Ilett

, Kristensen

et al. Drowsiness and poor feeding in a breast-fed infant: Association with nefazodone and its metabolites. Ann Pharmacother, 2000; 34:1269–1272.

94.

Klier

, Mossaheb

, Lee

et al. Mirtazapine and breastfeeding: Maternal and infant plasma levels. Am J Psychiatry, 2007; 164:348–349.

95.

Kristensen

, Ilett

, Rampono

et al. Transfer of the antidepressant mirtazapine into breast milk. Br J Clin Pharmacol, 2007; 63:322–327.

96.

Aichhorn

, Whitworth

, Weiss

. Mirtazapine and breast-feeding. Am J Psychiatry, 2004; 161:2325.

97.

Tonn

, Reuter

, Hiemke

et al. High mirtazapine plasma levels in infant after breast feeding: Case report and review of the literature. J Clin Psychopharmacol, 2009; 29:191–192.

98.

Lee

, Giesbrecht

, Dunn

et al. Excretion of quetiapine in breast milk. Am J Psychiatry, 2004; 161:1715–1716.

99.

Rampono

, Kristensen

, Ilett

et al. Quetiapine and breast feeding. Ann Pharmacother, 2007; 41:711–714.

100.

Misri

, Corral

, Wardrop

et al. Quetiapine augmentation in lactation: A series of case reports. J Clin Psychopharmacol, 2006; 26:508–511.

101.

Verbeeck

, Ross

, McKenna

. Excretion of trazodone in breast milk. Br J Clin Pharmacol, 1986; 22:367–370.

102.

Viguera

, Newport

, Ritchie

et al. Lithium in breast milk and nursing infants: Clinical implications. Am J Psychiatry, 2007; 164:342–345.

103.

Grandjean

, Aubry

. Lithium: Updated human knowledge using an evidence-based approach: Part III: Clinical safety. CNS Drugs, 2009; 23:397–418.

104.

Ito

. Drug therapy for breastfeeding women. N Engl J Med, 2000; 343:118–126.

105.

Fortinguerra

, Clavenna

, Bonati

. Psychotropic drug use during breastfeeding: A review of the evidence. Pediatrics, 2009; 124:e547–e556.

106.

Bennett

, Astrup-Jensen

, Bates

et al. Use of the monographs on drugs. Bennett

. Drugs and Human Lactation, 2^nd. Elsevier: Amsterdam, 1996; 67–74.

107.

Weissman

, Levy

, Hartz

et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk and nursing infants. Am J Psychiatry, 2004; 161:1066–1078.

108.

Birnbaum

, Cohen

, Bailey

et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: A case series. Pediatrics, 1999; 104:1–6.

109.

Marshall

, Nommsen-Rivers

, Hernandez

et al. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrinol Metab, 2010; 95:837–846.

110.

Anderson

, Pochop

, Manoguerra

. Adverse drug reactions in breastfed infants: Less than imagined. Clin Pediatr (Phila), 2003; 42:325–340.

111.

Davanzo

. Farmaci e allattamento materno. Boll Inform Farm, 2005; XII,2:66–71.

112.

Feibus

. FDA's proposed rule for pregnancy and lactation labeling: Improving maternal child health through well-informed medicine use. J Med Toxicol, 2008; 4:284–288.

113.

Davanzo

, Rubert

, Oretti

. Meta-variability of advice on drugs in the breastfeeding mother: the example of beta-blockers. Arch Dis Child Fetal Neonatal Ed, 2008; 93:F249–F250.

114.

Misri

, Kostaras

. Benefits and risks to mother and infant of drug treatment for postnatal depression. Drug Saf, 2002; 25:903–911.

115.

Eberhard-Gran

, Eskild

, Opjordsmoen

. Use of psychotropic medications in treating mood disorders during lactation: Practical recommendations. CNS Drugs, 2006; 20:187–198.

116.

Payne

. Antidepressant use in the postpartum period: Practical considerations. Am J Psychiatry, 2007; 164:1329–1332.

117.

ACOG Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol, 2008; 111:1001–1020.

118.

Field

. Breastfeeding and antidepressants. Infant Behav Dev, 2008; 31:481–487.

119.

Moretti

. Psychotropic drugs in lactation—Motherisk Update 2008. Can J Clin Pharmacol, 2009; 16:e49–e57.

120.

Lanza di Scalea

, Wisner

. Antidepressant medication use during breastfeeding. Clin Obstet Gynecol, 2009; 52:483–497.

121.

Howland

. Prescribing psychotropic medications during pregnancy and lactation: Principles and guidelines. J Psychosoc Nurs Ment Health Serv, 2009; 47:19–23.

122.

Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #18: Use of antidepressants in nursing mothers. Breastfeed Med, 2008; 3:44–52.

123.

Kallen

. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med, 2004; 158:312–316.

124.

Louik

, Lin

, Werler

et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med, 2007; 356:2675–2683.

125.

Maschi

, Clavenna

, Campi

et al. Neonatal outcome following pregnancy exposure to antidepressants: A prospective controlled cohort study. BJOG, 2008; 115:283–289.

126.

Belik

. Fetal and neonatal effects of maternal drug treatment for depression. Semin Perinatol, 2008; 32:350–354.

127.

Hendrick

, Smith

, Hwang

et al. Weight gain in breastfed infants of mothers taking antidepressant medications. J Clin Psychiatry, 2003; 64:410–412.

128.

Rubin

, Lee

, Ito

. When breastfeeding mothers need CNS-acting drugs. Can J Clin Pharmacol, 2004; 11:e257–e266.