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Use of sertraline, paroxetine and fluvoxamine by nursing women

Published online by Cambridge University Press:  02 January 2018

Victoria Hendrick*
Affiliation:
Neuropsychiatric Institute and Hospital, Los Angeles, California
Alan Fukuchi
Affiliation:
Clinical Laboratory, UCLA Center for Health Sciences, Los Angeles, California
Lori Altshuler
Affiliation:
Neuropsychiatric Institute and Hospital and West L, A, Veterans Administration Medical Center, Los Angeles, California
Mel Widawski
Affiliation:
Neuropsychiatric Institute and Hospital and West L, A, Veterans Administration Medical Center, Los Angeles, California
Amy Wertheimer
Affiliation:
Neuropsychiatric Institute and Hospital, Los Angeles, California, USA
Martina V. Brunhuber
Affiliation:
Neuropsychiatric Institute and Hospital, Los Angeles, California, USA
*
Dr Victoria Hendrick, Department of Psychiatry, UCLA, 300 Medical Plaza, Suite 2345, Los Angeles, CA 90095, USA
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Abstract

Background

The pharmacological treatment of depression in nursing women requires information on the magnitude of medication exposure to 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-performance liquid chromatography (limit of detections=1 ng/ml).

Results

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

Conclusions

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

Type
Papers
Copyright
Copyright © Royal College of Psychiatrists, 2001 

When new mothers experience depression, they and their clinicians need to know if antidepressant medications are safe to use while breast-feeding. Several recent reports have examined the extent of exposure that occurs to nursing infants whose mothers take antidepressants (e.g. Reference Altshuler, Burt and McMullenAltshuler et al, 1995; Reference Taddio, Ito and KorenTaddio et al, 1996; Reference Mammen, Perel and RudolphMammen et al, 1997; Reference Stowe, Owens and LandryStowe et al, 1997; Reference Yoshida, Smith and KumarYoshida et al, 1997; Reference Wisner, Perel and BlumerWisner et al, 1998; Reference Begg, Duffull and SaundersBegg et al, 1999; Reference Birnbaum, Cohen and BallyBirnbaum et al, 1999; Reference Kristensen, Ilett and HackettKristensen et al, 1999; Reference Ohman, Hagg and CarleborgOhman et al, 1999; Reference Stowe, Cohen and HostetterStowe et al, 2000). However, the research literature has consisted largely of single cases or small studies, and methodological differences have limited the information that can be drawn from them (Reference Yoshida, Smith and KumarYoshida et al, 1999). To expand this literature, we present measurements of maternal and infant serum concentrations in 50 nursing mother—infant pairs in which the mothers took therapeutic doses of sertraline, paroxetine or fluvoxamine.

METHOD

Fifty nursing mother—infant pairs who presented to UCLA's Pregnancy and Postpartum Mood Disorders Program were included in the study. The women were Caucasian (n=46), Hispanic (n=3) and Asian (n=1), in good physical health, ranging in age from 24 to 41 years old and on standard doses of antidepressant medication, taken once daily for treatment of major depression. Two women additionally were on nortriptyline and another was on alprazolam. None of the infants was on medications of any category. Seventeen women were on antidepressants during pregnancy as well as nursing. Written informed consent was obtained from each mother for collection of serum samples.

Sample collection

Maternal and infant serum samples were obtained at a minimum of 2 weeks following a fixed dose of antidepressant. For women who took the antidepressant during pregnancy, maternal and infant serum samples were obtained a minimum of 2 weeks following delivery. Serum samples were obtained from a total of 50 infants and 48 mothers.

Detection of antidepressant concentrations in serum

The detection of sertraline, desmethylsertraline, paroxetine and fluvoxamine in serum was accomplished via an isocratic high-performance liquid chromatography (HPLC) separation followed by ultraviolet detection at 225 nm. The concentration of each drug (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, defined by a signal-to-noise ratio of 7 for each drug.

Statistical analysis

The LIFEREG Procedure using SAS software was used to perform a Tobit analysis on the data. The Tobit model is a regression model for left-censored data, assuming a normal distributed error term. The model parameters are estimated by maximum likelihood. A χ2 test was used to explore whether nursing infants whose mothers 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 lower doses.

RESULTS

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

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

Pair Maternal medication Dose (mg/day) Exposed to antidepressant during pregnancy and delivery % Breast-feeding (v.formula) Infant age at serum sample (weeks) Infant weight at serum sample (kg) Maternal medication concentration (ng/ml) Infant medication concentrations (ng/ml) Maternal metabolite concentration (ng/ml) Infant metabolite concentration (ng/ml)
1 Sertraline 25 No 100 12 6.7 4 <1 4 <1
2 Sertraline 25 No 90 13 5.4 0 <1 13 <1
3 Sertraline 25 No 100 5 3.7 5 <1 20 <1
4 Sertraline 25 No 100 3 3.5 7 <1 9 <1
5a Sertraline 50 No 100 4 4.6 15 <1 39 2
6 Sertraline 50 No 100 28 7.8 18 <1 15 <1
7 Sertraline 50 No 100 16 4.4 28 <1 51 <1
8 Sertraline 50 No 100 39 9.1 15 <1 48 <1
9 Sertraline 50 No 100 10 3.7 3 <1 9 <1
10 Sertraline 50 Yes 50 4 3.4 42 <1 64 <1
11 Sertraline 50 Yes 80 6 3.9 30 <1 35 <1
12 Sertraline 50 Yes 50 6 4.7 19 <1 77 <1
13 Sertraline 50 Yes 100 60 9.6 8 <1 23 <1
14 Sertraline 50 No 100 17 7.7 6 <1 16 <1
15 Sertraline 50 Yes 100 11 5.4 30 8 50 4
16a Sertraline 75 No 50 26 8.1 19 <1 77 <1
17 Sertraline 75 No 100 17 6.3 82 <1 182 <1
18 Sertraline 75 Yes 50 5 4.1 92 <1 210 <1
19 Sertraline 100 No 100 9 4.9 45 <1 75 <1
20 Sertraline 100 No 100 2 5.5 50 <1 124 12
21 Sertraline 100 No 80 12 6.4 14 <1 27 <1
22 Sertraline 100 No 70 52 10.0 14 <1 36 <1
23 Sertraline 100 Yes 100 10 4.1 46 <1 128 <1
24a Sertraline 100 No 100 8 5.0 89 <1 265 11
25 Sertraline 100 No 50 44 7.8 64 <1 102 <1
26 Sertraline 125 No 100 14 6.8 48 <1 164 2
5b Sertraline 150 No 80 36 9.3 31 <1 61 <1
16b Sertraline 150 No 50 37 8.6 64 <1 84 <1
27 Sertraline 150 No 100 7 4.5 35 <1 120 4
28 Sertraline 150 Yes 100 8 4.7 53 2 133 2
24b Sertraline 150 No 100 19 7.3 7 <1 16 <1
29 Sertraline 150 Yes 100 3 3.7 102 <1 182 26
30 Sertraline 200 No 100 16 5.5 n/a <1 n/a <1
31 Paroxetine 5 No 100 16 5.1 <1 <1 n/a n/a
32 Paroxetine 10 No 100 3 4.6 10 <1 n/a n/a
33 Paroxetine 10 Yes 100 3 3.7 28 <1 n/a n/a
34 Paroxetine 20 Yes 100 2 4.0 42 <1 n/a n/a
35 Paroxetine 20 No 100 11 6.4 18 <1 n/a n/a
36 Paroxetine 20 No 100 12 6.4 24 <1 n/a n/a
37 Paroxetine 20 Yes 100 13 5.3 36 <1 n/a n/a
38 Paroxetine 20 No 100 14 7.8 <1 <1 n/a n/a
39 Paroxetine 20 No 100 16 4.3 38 <1 n/a n/a
40 Paroxetine 20 No 50 19 5.2 27 <1 n/a n/a
41 Paroxetine 20 No 40 19 7.3 27 <1 n/a n/a
42 Paroxetine 20 Yes 95 26 8.6 64 <1 n/a n/a
43 Paroxetine 20 No 100 4 3.0 21 <1 n/a n/a
44 Paroxetine 20 Yes 100 6 5.3 76 <1 n/a n/a
45 Paroxetine 25 Yes 100 7 4.6 84 <1 n/a n/a
46 Paroxetine 30 No 99 11 5.9 136 <1 n/a n/a
47 Fluvoxamine 100 Yes 100 8 4.7 140 <1 n/a n/a
48 Fluvoxamine 100 No 100 13 6.8 <1 <1 n/a n/a
49a Fluvoxamine 100 No 100 9 5.2 n/o <1 n/a n/a
49b Fluvoxamine 150 No 100 12 5.9 n/o <1 n/a n/a
50 Fluvoxamine 150 Yes 100 6 6.0 n/o <1 n/a n/a

No detectable medication was present in any infant exposed to paroxetine or fluvoxamine. Detectable medication (parent and/or metabolite) was present in 24% (8/33) of the serum samples obtained from infants exposed to sertraline. Concentrations of 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 repeat serum samples on themselves and their infants after being on the higher medication dosage for at least 1 week.

Maternal dosage of sertraline correlated highly with infant serum concentration of desmethylsertraline after controlling for infant age, gestational exposure and breast-feeding exposure (parameter estimate=0.09, d.f.=1, P=0.03). Maternal serum concentrations of sertraline and desmethylsertraline correlated highly with infant serum concentration of desmethylsertraline (parameter estimate=0.20, d.f.=1, P<0.001 and parameter estimate=0.07, d.f.=1, P=0.008, respectively) after controlling for infant age, gestational exposure and breast-feeding exposure. This analysis used all the available maternal and infant serum samples shown in Table 1.

A significant negative correlation was found between infant age and infant serum concentration of desmethylsertraline after controlling for maternal dosage, gestational exposure and breast-feeding exposure (parameter estimate=-1.46, d.f.=1, P=0.002). Among women who breast-fed fully, the likelihood of their infants having a detectable level of medication (sertraline or desmethylsertraline) was significantly higher if their dose was 100 mg or more (χ2=6.81, d.f.=1, P=0.009).

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

DISCUSSION

This study found that serum concentrations of medication were undetectable in all infants exposed to paroxetine or fluvoxamine and in the majority of infants exposed to sertraline while nursing. When medication was present in the sertraline-exposed infants, it was usually in the form of the metabolite desmethylsertraline. Maternal serum concentrations of sertraline and desmethylsertraline correlated highly with infant serum concentrations of desmethylsertraline. Maternal dosage of sertraline also correlated highly with infant serum concentrations of desmethylsertraline; doses of 100 mg or above were significantly more likely to produce detectable concentrations in the infant. A significant negative correlation emerged between infant age and serum concentration of desmethylsertraline.

This study's findings suggests that paroxetine, fluvoxamine and sertraline are reasonable choices for nursing women requiring treatment for depression. In comparison with fluoxetine, these medications appear to produce less exposure to nursing infants and have not been linked with the adverse events of neonatal irritability, sleep disturbance and poor feeding that have been reported in association with fluoxetine exposure through breast-feeding (Reference Lester, Cucca and AndreozziLester et al, 1993; Reference Brent and WisnerBrent & Wisner, 1998; Reference Chambers, Anderson and ThomasChambers et al, 1999; Reference Kristensen, Ilett and HackettKristensen et al, 1999). For infants that are healthy and full-term, these findings provide no reason to discourage nursing among women taking paroxetine, fluvoxamine or sertraline at standard therapeutic dosages. The use of additional medications that 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 safe for the nursing infant (Reference MitchellMitchell, 1999).

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

  1. This study found that the use of fluvoxamine, paroxetine and sertraline by nursing women produces minimal medication exposure to the infants.

  2. The presence of low detectable serum concentrations of medication was not associated with adverse effects in the infants.

  3. Maternal serum concentrations and dosage of medication can be employed to estimate infant serum concentrations.

LIMITATIONS

  1. Use of maternal reports rather than paediatric examinations in assessing for potential medication-related adverse events in the infants.

  2. Single serum measurement of medication in the mother—infant pairs.

  3. Lack of evaluation of infants' long-term outcomes associated with their early exposure to antidepressant medications.

Acknowledgements

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

Footnotes

Declaration of interest

This study was supported by the National Institute of Mental Health, Smith Kline Beecham and Pfizer.

References

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Figure 0

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

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