Use of psychotropic medications in treating mood disorders during lactation : practical recommendations

Many new mothers who need antidepressant or mood-stabilising drug treatment may wish to breastfeed their infants, but are hesitant to do so because of possible harmful effects of the medication on the infant. This article reviews current data on drug excretion into breast milk and the effects on the breast-fed child, and provides recommendations for the use of the different psychotropic drugs in lactating women.Relevant literature was identified through systematic searches of MEDLINE, EMBASE and the Science Citation Index Expanded (ISI) from 1966 to February 2005. The present knowledge is based on the accumulation of case studies. No randomised controlled trials in breast-fed infants have been performed and there is a lack of long-term follow-up studies.Use of SSRIs and TCAs (except doxepin) is compatible with breastfeeding. However, if treatment with an SSRI is started in the postpartum period, fluoxetine and citalopram may not be drugs of first choice. With regard to other antidepressants, such as venlafaxine, trazodone, mirtazapine, reboxetine, moclobemide and other MAOIs, very little knowledge exists. Breastfeeding should be avoided while using lithium. Carbamazepine and sodium valproate (valproic acid) are generally better tolerated by the breast-fed infant than lithium. Data on lamotrigine are still sparse. Knowledge is also scarce on the novel antipsychotics and thus recommendations in lactating women cannot be made for these agents. It is unwise to expose infants unnecessarily to drugs that may have severe adverse effects. As such, clozapine should probably be avoided because of the risk of agranulocytosis.Our knowledge of the impact of drug exposure through breast milk is still limited. Infant drug exposure is, however, generally higher during pregnancy through placental passage than through breast milk. Despite the low dosage transferred to the infant through breast milk, premature infants and infants with neonatal diseases or inherited disturbances in metabolism may be vulnerable to such exposure.     

Drug use during breast-feeding

The physicochemical and pharmacokinetic factors involved in transfer of drugs into breast milk are reviewed. Passage of drugs into milk can best be viewed as a two-compartment system. Various ratios of the drug concentration values in the two compartments and ratios of maternal-to-infant intake have been described. Knowledge of the limitations of these methods is necessary to properly interpret and apply the literature on drug excretion into breast milk. Factors involved in choosing a drug for a nursing mother are listed, a stepwise approach to minimizing transfer of drug to the infant is presented, and the literature on the excretion of specific drugs into milk is reviewed. Generally, drugs given to nursing mothers reach infants in much smaller amounts than drugs given to pregnant women. Decisions about nursing during drug therapy and the choice of drug therapy in a nursing mother should be based on the dosage and duration of therapy, age of the infant, quantity of milk consumed, experience with the drug in infants, degree of oral absorption of the drug by the infant, potential long-term effects, possible interference with lactation, and non-dose-related toxicities (e.g., potential allergic reactions). Too often, the mother's need for a medication is perceived as a reason to discontinue nursing. By understanding the principles of drug passage into breast milk and systematically evaluating the mother's needs, infant factors, and the data on specific drugs, clinicians can usually devise treatment plans that allow nursing while minimizing the risks to the infant.     

Anticonvulsant use during lactation.

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested. Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects. In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.     

Quetiapine augmentation in lactation: a series of case reports

Treating psychiatric disorders with pharmacotherapy in the breast-feeding period presents a dilemma as such treatment carries the risk of infant exposure to medication through breast milk. However, failure to institute pharmacotherapy in postnatal women in need of such treatment exposes both mother and baby to detrimental effects of the illness. Because women presenting with psychiatric disorders during the postpartum period often have complex sets of symptoms, monotherapy may not be sufficient for symptom resolution. In this case series of 6, we examined levels of psychotropic medications secreted in breast milk and performed developmental assessments of the exposed babies with the Bayley Scales of Infant Development, Second Edition. In 3 of the 6 cases, no medication was detected in the breast milk; in all but 1 case, estimated levels of infant medication exposure were calculated to be less than 0.01 mg/kg per day for each medication. Four of the 6 babies scored as being within normal limits on the Bayley Scales of Infant Development, Second Edition, whereas 2 showed mild developmental delays. In comparison to the 4 cases of typical development, the 2 showing mild delays did not have higher estimated levels of psychotropic medication exposure through breast milk. Based on these results, in our limited sample, there appears to be low levels of infant exposure to the medications through breast milk; no association was seen between developmental outcomes and exposure through breast milk of multiple pharmacological agents. These results should be interpreted with caution, and vigilance should be exercised when advising women on combinations of medications for severe mental illness who choose to nurse.     

Monitoring lithium in breast milk: an individualized approach for breast-feeding mothers

Lithium is a drug of choice for the management of bipolar disorder, a disease frequently affecting women in their childbearing years. Unfortunately, this drug has typically been contraindicated in nursing women. Data in humans are limited with respect to the use of this drug in lactating women, and early reports suggest high excretion into milk. The purpose of this report was to verify the excretion of lithium into human milk and to assess infant safety after breast-feeding. The authors found wide interpatient variability in lithium dose offered to the infant through breast milk (from 0% to 30% of maternal weight-adjusted dose), indicating that therapeutic drug monitoring of lithium in milk and/or in infant's blood, coupled with close monitoring of adverse effects, is a rational approach. Since therapeutic drug monitoring of lithium is routine, physicians caring for these women and infants should be encouraged to individualize their recommendations.     

Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Isoniazid is the most widely used first line antituberculosis drug.
• It is considered safe during lactation, but limited data are available on the transfer of isoniazid from circulation to milk in lactating women, which can provide an assessment of extent of exposure to the nursling.
WHAT THIS STUDY ADDS
• The study documents the transfer pattern and milk to plasma (M : P) ratio of isoniazid at a steady state.
• Peak plasma and milk concentrations of isoniazid were reached within 1 h and the projected exposure of the drug to the infant is much lower than the prophylactic dose, supporting its safety during breast feeding.  

AIM

To determine milk to plasma (M : P) ratios and infant dose (absolute and relative) for isoniazid in lactating women on antituberculosis therapy.  

METHODS

Concentrations of isoniazid in plasma and milk were measured in exclusively breast feeding women taking 300 mg day⁻¹ as treatment for tuberculosis.  

RESULTS

Peak plasma and milk concentrations of isoniazid were observed at 1 h. A mean M : P_AUC value of 0.89 (95% CI 0.7, 1.1) was calculated for isoniazid from seven women over 24 h. The mean absolute infant dose was estimated to be 89.9 μg kg day⁻¹ (95% CI 65.6, 114) and the relative infant dose was 1.2% of the weight adjusted maternal dose.  

CONCLUSIONS

The mean relative dose of isoniazid (1.2%) transmitted to the infant via breast milk is below the 10% notional level of concern. These data suggest that isoniazid therapy is safe during breastfeeding.     

Benefits and risks to mother and infant of drug treatment for postnatal depression.

The postnatal period presents a special problem to healthcare providers treating psychiatric disorders in women. Many new mothers who need antidepressant treatment may wish to breastfeed their infants, but are hesitant to do so for fear of passing on possible harmful effects of the medication through their milk. The focus of this article will be on highlighting and interpreting the existing literature on the benefits and risks to mother and infant of drug treatment for postnatal depression, as well as outlining treatment guidelines for the use of antidepressants in breastfeeding mothers. The article will specifically focus on the use of fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram, which are more commonly used and belong to the selective serotonin reuptake inhibitor group of antidepressants. The tricyclic and other newer antidepressant medications will also be discussed. As there are no published controlled studies on the use of antidepressants by breastfeeding women, publications of individual case reports, case series, and pharmacokinetic investigations serve as the basis for the development of treatment guidelines. Results from this growing body of literature are promising in that, with the exception of a few cases, no serious adverse events have been reported in infants exposed to antidepressant medications through breast milk. In addition nonpharmacological treatments consisting of different types of psychotherapies will be discussed. It is critical that healthcare providers evaluate each mother-infant dyad on an individual basis when faced with the decision to prescribe antidepressant medications during the postnatal period.     

Antibiotics and breast-feeding: a critical review of the literature

Continuous breast-feeding, an integral component of the postpartum period, is often threatened upon maternal initiation of antibiotics. The real risk of antibiotic use while breast-feeding must be carefully analysed with regard to all the variables that influence the extent of antibiotic distribution into breast milk, including breast milk composition, physicochemical properties of the antibiotic (molecular weight, lipid solubility, pH, protein binding), length of feeding, and maternal disposition. In addition, infant disposition, including ability to absorb, metabolize, eliminate, and tolerate any amounts of antibiotic, must also be considered prior to maternal administration of antibiotic. The milk to plasma (M/P) ratio is a frequently quoted parameter used to predict drug distribution into breast milk. However, its utility is questionable and often fraught with misinterpretation. An alternative approach when the amount of antibiotic concentration in breast milk is known (through clinical trials) is to calculate an estimated or expected infant drug exposure factoring in known/expected milk consumption, drug concentration and bioavailability. In this review, the following antibiotic classes and current literature regarding their distribution into breast milk are critically reviewed: beta-lactam antibiotics, fluoroquinolones, sulfonamides, macrolides, aminoglycosides, tetracyclines, nitrofurantoin, metronidazole, vancomycin, clindamycin and chloramphenicol. In the majority of instances, these antibiotics do not distribute into breast milk in sufficient concentrations to be of any clinical consequence in the breast-feeding infant.     

口服拉贝洛尔母乳药动学的风险评估与哺乳期合理用药

目的：基于口服拉贝洛尔在妊娠期高血压产妇的乳汁药动学,评估哺乳期用药风险和干预哺乳时间,促进哺乳期合理用药。方法：选取2016年10月-2017年7月住院分娩的60例妊娠期高血压产妇泌乳后口服拉贝洛尔片的乳汁,采用超高效液相色谱串联质谱法（UPLC-MS/MS）测定乳汁药物浓度,并计算药动学相关参数和用药风险评估指标。结果：妊娠高血压产妇产后继续服用拉贝洛尔（100 mg,q8h,n=60）,乳汁中药动学参数：达峰时间（t_max）为（2.7±0.9）h、达峰浓度（C_max）为（268.0±71.9）ng·mL^-1、半衰期（t_1/2）为（4.1±1.7）h。母乳用药风险评估指标,TID （theoretical infant dose,理论婴儿剂量）为（0.026±0.012）（95% CI：0.025~0.027）mg·kg^-1·d^-1,RID （relative infant dose,相对婴儿剂量）为（0.53%±0.13%）（95% CI：0.49%~0.58%）。结论：妊娠期高血压产妇产后继续服用拉贝洛尔,受哺婴儿理论剂量和相对剂量均低于风险限,安全性较高,可在服药3~4 h后到下次服药周期前按需哺乳。     

Extremely Low Excretion of Daptomycin into Breast Milk of a Nursing Mother with Methicillin-Resistant Staphylococcus aureus Pelvic Inflammatory Disease

Antibiotic treatment for pelvic inflammatory disease (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.0012. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics.     

FDA对药物临床哺乳期研究的建议

目前由于哺乳期用药的人体数据极其缺乏,对哺乳期药物治疗以及是否继续母乳喂养往往难以做出准确决策。美国食品药品管理局（FDA）于2019年5月发布了“临床哺乳期研究：研究设计考虑的因素”指导原则（草案）,对药物临床哺乳期研究的诸多方面提出了细致、具体的建议（如需要进行哺乳期研究的药物、研究类型、母乳取样方法、婴儿摄入母乳量的测量、药动学分析、婴儿剂量估算、婴儿安全数据的收集和药物对产乳量的影响等）,以期促进该方面研究,获得所需信息。中国尚无类似的指导原则,详细介绍FDA该指导原则主要内容,希望对我国开展这方面的研究工作及其监管有益,也对结合国情制定类似的指导原则有所启示。     

Drug transfer to the fetus and to the breastfeeding infant: what do we know?

The pregnant patient with inflammatory bowel disease presents a number of challenges to the clinician. In addition to the management of the patient's disease activity and the potential effects of disease on pregnancy, the clinician must also take into consideration any iatrogenic complications that may arise from the medical management of these conditions. Furthermore, should the patient elect to breastfeed her infant, the effect of drugs that may be passed through the breast milk must also be considered. This article focuses specifically on the issues of drug transfer to the fetus and to the breastfeeding infant. Meperidine is the sedative of choice for endoscopic procedures on pregnant patients, while benzodiazepines and propofol may be used with certain caveats. Amoxicillin/clavulanic acid and metronidazole are preferred if antibiotics are indicated for perianal Crohn's disease or pouchitis. The majority of medications used in the treatment of luminal IBD in pregnancy are not associated with significant adverse effects, and thus can generally be used safely. Certain medications, such as aminosalicylates, corticosteroids, and cyclosporine, appear low risk, while others such as methotrexate and thalidomide are clearly contraindicated. The role of other immunomodulators and biologics remains to be clearly defined, although early experience with infliximab and similar agents appear to be low risk. Safety in breastfeeding varies considerably among medications. There are many issues to address when considering pharmaceutical intervention in the pregnant patient, and patients should be carefully counseled regarding potential teratogenicity or adverse outcomes of medication used during pregnancy and breastfeeding.     

Disopyramide and its N-monodesalkyl metabolite in breast milk.

The plasma and breast milk were sampled from a woman who was breastfeeding whilst taking disopyramide (200 mg three times daily). Paired samples taken on the fifth to eighth day of treatment showed that disopyramide was present in breast milk in a similar concentration to plasma (mean +/- s.d. milk; plasma ratio 0.9 +/- 0.17). The estimated dose likely to be ingested by an infant is less than 2 mg kg-1 day-1. The active N-monodesalkyl metabolite of disopyramide (NMD) although present in plasma in much smaller concentrations than the parent compound, was excreted in breast milk (mean +/- s.d. milk: plasma ratio 5.6 +/2.9) in concentrations similar to those of disopyramide. The pharmacological and toxicological properties of the disopyramide metabolite need to be considered when assessing likely effects on the infant. No adverse effects were noted in the infant in this case. Maternal plasma and breast milk were sampled again along with infant plasma after 28 days. Disopyramide and NMD were undetectable in the infant's serum. No evidence was found to indicate that the concentrations of disopyramide or NMD in breast milk might be sufficient to pose a definite risk to the infant. Whenever disopyramide is prescribed in a breast feeding mother, close observation of the baby and measurement of both disopyramide and its active metabolite NMD in breast milk or infant plasma is recommended, pending further investigation.     

Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation

Knowledge of pharmacokinetics and the use of a mechanistic-based approach can improve our ability to predict the effects of pregnancy for medications when data are limited. Despite the many physiological changes that occur during pregnancy that could theoretically affect absorption, bioavailability does not appear to be altered. Decreased albumin and alpha(1)-acid glycoprotein concentrations during pregnancy will result in decreased protein binding for highly bound drugs. For drugs metabolised by the liver, this can result in misinterpretation of total plasma concentrations of low extraction ratio drugs and overdosing of high extraction ratio drugs administered by non-oral routes. Renal clearance and the activity of the CYP isozymes, CYP3A4, 2D6 and 2C9, and uridine 5'-diphosphate glucuronosyltransferase are increased during pregnancy. In contrast, CYP1A2 and 2C19 activity is decreased. The dose of a drug an infant receives during breastfeeding is dependent on the amount excreted into the breast milk, the daily volume of milk ingested and the average plasma concentration of the mother. The lipophilicity, protein binding and ionisation properties of a drug will determine how much is excreted into the breast milk. The milk to plasma concentration ratio has large inter- and intrasubject variability and is often not known. In contrast, protein binding is usually known. An extensive literature review was done to identify case reports including infant concentrations from breast-fed infants exposed to maternal drugs. For drugs that were at least 85% protein bound, measurable concentrations of drug in the infant did not occur if there was no placental exposure immediately prior to or during delivery. Knowledge of the protein binding properties of a drug can provide a quick and easy tool to estimate exposure of an infant to medication from breastfeeding.     

Characterization of the penetration of garenoxacin into the breast milk of lactating women

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin. Plasma samples were collected predose and repeatedly up to 72 hours postdose. Breast milk was collected predose and for 6- to 12-hour intervals repeatedly up to 120 hours postdose. Breast milk/plasma concentration ratios for garenoxacin ranged from 0.35 to 0.44 up to 24 hours postdose, and the mean peak breast milk concentration was 3.0 microg/mL (0- to 6-h collection interval). Overall, garenoxacin exposure in breast milk was minimal, with a mean of 0.07% of the administered dose recovered within 120 hours. Indeed, garenoxacin was undetectable in the breast milk of a majority of subjects within 84 hours of dosing. As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg. These findings indicate that, like other quinolone antimicrobials, garenoxacin is secreted in breast milk.     

Use of antibiotic and analgesic drugs during lactation.

During lactation, multiple situations can arise that require maternal pharmacological treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse effects when used during lactation, and even temporary interruption of breast feeding can be difficult for the nursing dyad, decisions regarding maternal medication use during breast feeding should be based on accurate and up-to-date information. This article reviews available data on the most commonly used antibiotics and analgesics. The use of most antibiotics is considered compatible with breast feeding. Penicillins, aminopenicillins, clavulanic acid, cephalosporins, macrolides and metronidazole at dosages at the low end of the recommended dosage range are considered appropriate for use for lactating women. Fluoroquinolones should not be administered as first-line treatment, but if they are indicated, breast feeding should not be interrupted because the risk of adverse effects is low and the risks are justified. Paracetamol (acetaminophen), low-dose aspirin (acetylsalicylic acid) [up to 100 mg/day] and short-term treatment with NSAIDs, codeine, morphine and propoxyphene are considered compatible with breast feeding. Safer alternatives should be considered instead of dipyrone, aspirin at a dosage >100 mg/day and pethidine (meperidine). In the light of the many safe alternatives for pain control, breast-feeding mothers should not be allowed to experience pain or be made to feel that they must choose between analgesia and breast feeding.     

Collection and use of exposure data from human milk biomonitoring in the United States

Human milk is a unique biological matrix that can be used to estimate exposures in both the mother and the breastfed infant. In addition, the presence of environmental chemicals in human milk may act as a sentinel for exposures to a broader population. Several factors play a role in determining the quantity of chemicals transferred to milk and, subsequently, to the breastfeeding infant, including maternal, infant, and chemical characteristics. Exposure to certain environmental chemicals during critical periods can disrupt normal infant development, yet few data exist to quantify the hazards posed by environmental chemicals in human milk. Chemicals measured in human milk may also provide insights to agents suspect in altering breast development and breast-related disease risk. Carefully designed exposure assessment and toxicokinetic studies are needed to elucidate mechanisms and establish relationships between human milk and other biologic matrices. Data from human milk biomonitoring studies can be used to inform and validate models that integrate information about chemical properties, human metabolism, and biomarker concentrations. Additional research is needed to determine the degree to which environmental chemicals enter, are present in, and are excreted from human milk, their impact on the host (mother), and the extent of their bioavailability to breastfeeding infants. This article describes how the collection and use of exposure data from human milk biomonitoring in the United States can be designed to inform future research and policy.     

Cyclosporine and lactation: when the mother is willing to breastfeed

We describe a woman treated with cyclosporine after renal transplantation who commenced breastfeeding of her newborn infant. The child had no apparent clinical adverse effects to cyclosporine. To confirm the safety of breastfeeding and guide the patient and her clinician, cyclosporine concentrations in maternal blood, breast milk, and infant blood were measured. Maternal cyclosporine concentration (1-hour postdose) was 49 μg/L, and the breast milk cyclosporine concentration (2-hour postdose) was 46 μg/L. Infant cyclosporine blood concentration shortly after breastfeeding was undetectable (<10 μg/L). Analysis revealed that the estimated infant exposure to cyclosporine via breast milk was minimal and provided reassurance to continue breastfeeding in this case.     

乳汁中药物浓度测定的研究进展

母乳喂养对婴儿来说是一种非常健康及有营养的获取能量的方式，对母亲和婴儿都有益处。患有某些疾病的哺乳母亲在进行药物治疗时，需要考虑药物是否会进入乳汁而对婴儿产生一些不良反应或对母亲产生影响。由于许多药物的哺乳期用药安全性并不十分明确，因此在临床治疗中不推荐哺乳期妇女使用。测定乳汁中的药物浓度可以明确合理的给药时间和给药剂量，提高用药安全性，对临床用药具有非常重要的意义。但乳汁成分复杂，含有大量脂质和蛋白质等干扰物质，使乳药浓度测定有一定困难。本文综述了国内外乳药浓度测定方法，以期为哺乳期合理用药提供参考。     

Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression

This study presents the case of a 35-year-old breastfeeding mother who delivered her fourth child 5 months previously and was prescribed 100 mg amisulpride twice daily and 250 mg desvenlafaxine in the morning for treatment-resistant depression. Arriving at this regimen took approximately 2 months postbirth. Because she was keen to continue breastfeeding her infant, and published data on the use of amisulpride and desvenlafaxine were very limited, the clinical team sought assistance from the therapeutic drug monitoring laboratory to quantify infant dose-exposure to guide consideration of continuing breastfeeding. A sampling schedule for milk and plasma from mother and plasma from her infant was agreed and drug concentrations were measured by high-performance liquid chromatography. Absolute (theoretic) infant dose (μg/kg/d) was calculated as the product of the average concentration in milk and an assumed milk intake of 0.15 L/kg/day (294 mg/kg/day for desvenlafaxine and 183 mg/kg/day for amisulpride), and relative infant dose was estimated as absolute infant dose expressed as a percentage of the maternal dose in μg/kg/day (7.8% for desvenlafaxine and 6.1% for amisulpride). Consistent with the infant being partially breastfed, the ratio of drug in the infant's plasma to that in mother's plasma was lower at 1.7% for desvenlafaxine and 3.9% for amisulpride. A pediatric assessment of the infant found achievement of expected developmental progress for age and no detectable drug-related adverse effects. Assessing the safety of breastfeeding was difficult because it involved simultaneous use of two drugs for which there was limited previous experience. However, after discussion of the infant dose-exposure data and lack of adverse effects, the mother elected to continue partial breastfeeding for the next few months. The clinical team plans a reassessment of the infant's progress in 3 months.