Use of sertraline, paroxetine and fluvoxamine by nursing women

Background The pharmacological treatment of depression in nursing women requires information on the magnitude of medication exposureto the infant that may occur through breast milk.

Aims To examine serum concentrations of antidepressants in infants exposed to these medications through breast-feeding.

Method Maternal and infant serum concentrations of sertraline, paroxetine and fluvoxamine were determined with high-performanceliquid chromatography (limit of detection=1 ng/ml).

Results No detectable medication was present in any infant exposed to paroxetine (n=16) or fluvoxamine (n=4). Among infants exposedto sertraline (n=30), detectable medication was present in 24% of serum samples. A significant negative correlation wasfound between infant age and infant serum concentration. Sertralinewas significantly more likely to be detected in an infant ifthe mother's daily dose was 100 mg or higher. No adverse sequelaeoccurred in any infant.

Conclusions This study shows that paroxetine, fluvoxamine and sertraline produce minimal exposure to infants when taken bynursing mothers.

INTRODUCTION

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INTRODUCTION

When new mothers experience depression, they and their cliniciansneed to know if antidepressant medications are safe to usewhile breast-feeding. Several recent reports have examinedthe extent of exposure that occurs to nursing infants whosemothers take antidepressants (e.g. Altshuler et al, 1995; Taddio et al, 1996; Mammen et al, 1997; Stowe et al, 1997; Yoshida et al, 1997; Wisner et al, 1998; Begg et al, 1999; Birnbaum et al, 1999; Kristensen et al, 1999; Ohman et al, 1999; Stowe et al, 2000). However, the research literaturehas consisted largely of single cases or small studies, andmethodological differences have limited the information thatcan be drawn from them (Yoshida et al, 1999). To expand thisliterature, we present measurements of maternal and infantserum concentrations in 50 nursing mother—infant pairsin which the mothers took therapeutic doses of sertraline, paroxetineor fluvoxamine.

METHOD

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METHOD

Fifty nursing mother—infant pairs who presented to UCLA'sPregnancy and Postpartum Mood Disorders Program were includedin the study. The women were Caucasian (n=46), Hispanic (n=3)and Asian (n=1), in good physical health, ranging in age from24 to 41 years old and on standard doses of antidepressantmedication, taken once daily for treatment of major depression.Two women additionally were on nortriptyline and another wason alprazolam. None of the infants was on medications of any category. Seventeen women were on antidepressants during pregnancyas well as nursing. Written informed consent was obtained fromeach mother for collection of serum samples.

Sample collection
Maternal and infant serum samples were obtained at a minimumof 2 weeks following a fixed dose of antidepressant. For womenwho took the antidepressant during pregnancy, maternal andinfant serum samples were obtained a minimum of 2 weeks followingdelivery. Serum samples were obtained from a total of 50 infantsand 48 mothers.

Detection of antidepressant concentrations in serum
The detection of sertraline, desmethylsertraline, paroxetineand fluvoxamine in serum was accomplished via an isocratichigh-performance liquid chromatography (HPLC) separation followedby ultraviolet detection at 225 nm. The concentration of eachdrug (sertraline, desmethylsertraline, paroxetine or fluvoxamine)in the samples was calculated from its peak area ratios by using the slope and intercept of the appropriate calibration curve.The assays had a lower limit of sensitivity of 1 ng/ml, definedby a signal-to-noise ratio of 7 for each drug.

Statistical analysis
The LIFEREG Procedure using SAS software was used to performa Tobit analysis on the data. The Tobit model is a regressionmodel for left-censored data, assuming a normal distributederror term. The model parameters are estimated by maximum likelihood.A ${chi}$ ² test was used to explore whether nursing infants whosemothers took higher daily doses of sertraline (100 mg or more)were more likely to have detectable serum concentrations of medication, as compared with infants of women who took lowerdoses.

RESULTS

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RESULTS

Results of the serum assays for the mother-infant pairs areshown in Table 1. Infant ages ranged from 2 to 60 weeks andweights ranged from 3 to 10 kg at the time of the serum assays.

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Table 1 Serum concentrations of antidepressants in 50 nursing mother—infant pairs

No detectable medication was present in any infant exposed toparoxetine or fluvoxamine. Detectable medication (parent and/ormetabolite) was present in 24% (8/33) of the serum samplesobtained from infants exposed to sertraline. Concentrationsof sertraline and desmethylsertraline, when present, were 2-8 and 2-12 ng/ml, respectively.

Four mothers (nos 5, 16, 24 and 49) titrated their dose of the antidepressant upwards to help their mood and obtained repeatserum samples on themselves and their infants after being onthe higher medication dosage for at least 1 week.

Maternal dosage of sertraline correlated highly with infantserum concentration of desmethylsertraline after controllingfor infant age, gestational exposure and breast-feeding exposure(parameter estimate=0.09, d.f.=1, P=0.03). Maternal serum concentrationsof sertraline and desmethylsertraline correlated highly withinfant serum concentration of desmethylsertraline (parameterestimate=0.20, d.f.=1, P<0.001 and parameter estimate=0.07,d.f.=1, P=0.008, respectively) after controlling for infantage, gestational exposure and breast-feeding exposure. Thisanalysis used all the available maternal and infant serum samplesshown in Table 1.

A significant negative correlation was found between infantage and infant serum concentration of desmethylsertraline aftercontrolling for maternal dosage, gestational exposure and breast-feedingexposure (parameter estimate=-1.46, d.f.=1, P=0.002). Amongwomen who breast-fed fully, the likelihood of their infantshaving a detectable level of medication (sertraline or desmethylsertraline)was significantly higher if their dose was 100 mg or more ( ${chi}$ ²=6.81,d.f.=1, P=0.009).

Mothers were questioned about potential adverse sequelae totheir infants and did not report any such findings. Specificenquiries were made regarding gastro-intestinal symptoms (e.g.vomiting, watery stool), lethargy, changes in sleep patternsand easy bruising. None of the women in the study was on other medications and the infants were in good health.

DISCUSSION

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DISCUSSION

This study found that serum concentrations of medication wereundetectable in all infants exposed to paroxetine or fluvoxamineand in the majority of infants exposed to sertraline whilenursing. When medication was present in the sertraline-exposedinfants, it was usually in the form of the metabolite desmethylsertraline.Maternal serum concentrations of sertraline and desmethylsertralinecorrelated highly with infant serum concentrations of desmethylsertraline.Maternal dosage of sertraline also correlated highly with infantserum concentrations of desmethylsertraline; doses of 100 mgor above were significantly more likely to produce detectableconcentrations in the infant. A significant negative correlationemerged between infant age and serum concentration of desmethylsertraline.

This study's findings suggests that paroxetine, fluvoxamineand sertraline are reasonable choices for nursing women requiringtreatment for depression. In comparison with fluoxetine, thesemedications appear to produce less exposure to nursing infantsand have not been linked with the adverse events of neonatalirritability, sleep disturbance and poor feeding that have been reported in association with fluoxetine exposure through breast-feeding (Lester et al, 1993; Brent & Wisner, 1998; Chambers etal, 1999; Kristensen et al, 1999). For infants that are healthyand full-term, these findings provide no reason to discouragenursing among women taking paroxetine, fluvoxamine or sertralineat standard therapeutic dosages. The use of additional medicationsthat are commonly taken in the post-partum period (e.g. antihistamines,decongestants, pain medications) should be kept to a minimum until more is known about whether such combinations are safefor the nursing infant (Mitchell, 1999).

Clinical Implications and Limitations

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Clinical Implications and...

CLINICAL IMPLICATIONS

This study found that the use of fluvoxamine, paroxetine andsertraline by nursing women produces minimal medication exposureto the infants.
The presence of low detectable serum concentrationsof medicationwas not associated with adverse effects in theinfants.
Maternal serum concentrations and dosage of medicationcan beemployed to estimate infant serum concentrations.

LIMITATIONS

Use of maternal reports rather than paediatric examinationsin assessing for potential medication-related adverse eventsin the infants.
Single serum measurement of medication inthe mother—infant pairs.
Lack of evaluation of infants'long-term outcomes associatedwith their early exposure toantidepressant medications.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

This project was supported by grant no. MH0145101 from the National Institute of Mental Health, Bethesda, Maryland. Preparationof this report was supported in part by Smith Kline Beechamand Pfizer.

REFERENCES

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