Research report
Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-milk

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Abstract

We have studied ten breast-feeding mothers who were prescribed tricyclic antidepressant drugs and have also compared their infants' development with a similar group (n=15) who were bottle-fed. Concentrations of tricyclic drugs in maternal plasma and urine, in fore-milk and hind-milk and in infant plasma (n=6) and urine (n=9) were measured by gas chromatography (GC) and by an enzyme immunoassay (EIA). The fat concentration in milk was also measured. Infants' health and development were monitored by physical examination and by the Bayley Scales of Infant Development up to 30 months. The amounts of tricyclic drugs and their principal metabolites in maternal plasma were significantly correlated with the oral dose and with the amounts in breast-milk. Drug concentrations in fore-milk, but not in hind-milk, increased in line with its fat content, which was maximal in hind-milk. Correlations between gas chromatographic and enzyme immunoassays of maternal samples were high provided that the values for amitriptyline and nortriptyline were excluded; immunoreactivities to these compounds were abnormally high, suggesting that metabolites were also being measured by EIA. The daily doses of drugs ingested by breast-fed infants were about 1% of the maternal dose/kg and the immunoassay detected very small amounts of tricyclics in infants' plasma and urine. No acute toxic effects were found in the ten medicated breast-fed infants and there was no evidence of developmental delays in comparison with bottle-fed infants. Although the number of subjects in this study is small, when taken in conjunction with other published findings, we have not found any reason to prevent mothers who are taking established tricyclic antidepressants from breast-feeding their babies if they want to do so.

Introduction

About one in ten new mothers is found to be clinically depressed post-natally (O'Hara and Zekoski, 1988O'Hara and Swain, 1996) and some of these women are likely to be prescribed antidepressant drugs. The transfer of psychotropic drugs to the infant in breast-milk has been investigated in very few subjects and, apart from one study by Buist and Janson (1995), the assessment of possible adverse effects in infants has been unsystematic. The published literature on tricyclic antidepressant drugs (TCA) and breast-feeding consists of research into a total of 44 mother–infant dyads (see review by Yoshida and Kumar, 1996) and it is clear that all TCA drugs pass into breast-milk. There are however substantial variations in reported milk concentrations of TCA drugs and their principal metabolites in relation to the oral doses being ingested by the mothers as well as to plasma concentrations. Such variations may be due in part to differences in fat content of the breast-milk which has usually not been measured and in part to methodological differences between case studies. Parent TCA drugs or their metabolites have been detected in the blood of only 3 infants out of a total of 26 who were tested. Two of these infants, whose mothers were taking nortriptyline, were reported by Wisner and Perel (1991)to be thriving. Although nortriptyline was not detected in the infants' sera, its metabolite, hydroxynortriptyline, was. There is one report of toxic effects in an infant whose mother was taking doxepin (Matheson et al., 1985). Doxepin was not found in the infant's plasma, but on two separate occasions relatively high concentrations of 58 and 66 ng/ml of desmethyldoxepin were detected. Possible toxic effects (colic, vomiting and watery stools) have also been described (Lester et al., 1993) in a breast-fed infant whose mother was taking a non-TCA antidepressant, fluoxetine, but abnormally high concentrations of fluoxetine and nor-fluoxetine (340 and 208 ng/ml) were found in the infant's plasma.

Some authors recommend that tricyclic antidepressant drugs can be safely prescribed (Buist and Janson, 1995, Wisner and Perel, 1991, Erickson et al., 1979, Bader and Newman, 1980, Brixen–Rasmussen et al., 1982, Kemp et al., 1985, Wright et al., 1991) while others have suggested that breast-feeding is better discontinued (Matheson et al., 1985, Gelenberg, 1979, Sovner and Orsulak, 1979). Some authors leave the decision open (Stancer and Reed, 1986, Pittard and O'Neal, 1986, Buist et al., 1990) and others seem to be shuffling the responsibility for the decision on to the mother (American Academy of Pediatrics, 1982). Indecision is a prominent feature of depressive illness and it therefore seems doubly unfair to load depressed mothers with a doctors' dilemma.

Breast-feeding is generally believed to improve babies' general health, immunological status and cognitive development (Hanson et al., 1982, Hanson and Bergström, 1990, Lucas et al., 1992) and, in mothers who want to breast-feed, to enhance their relationships with their infants (Pascoe and French, 1988, Pollock, 1994). Discontinuation of breast-feeding may greatly distress some mothers and add to their problems in relating with the child. Upon recovery, many such mothers see the period of their illness as an irreparable gap in their relationship with their babies and their sense of loss is greater if they also have had to give up breast-feeding. Sometimes, doctors try to compromise by delaying prescribing or by using sub-therapeutic dose regimes which can prolong a mother's depression and lead to a greater sense of failure.

Section snippets

Subjects

Subject mothers were those who wished to continue breast-feeding while they were taking antidepressant drugs prescribed during admission to the Mother and Baby Unit in the Bethlem Royal Hospital and who were also able to provide informed consent.

Subject babies were healthy infants who had no history of clinical jaundice and no other perinatal complications. One infant had been prematurely born at 36 weeks gestation (birth weight, 2.4 kg) but at the time his mother started taking an

Sampling of maternal plasma, urine and breast-milk

We sampled maternal plasma and urine in the morning 12–15 hours after the last dose of drug. We tried to sample both fore-milk and hind-milk whenever other samples were collected, either with a manual or with an electric breast-pump, according to the mother's preference. Fore-milk is milk that is obtained in the first few minutes of the feed and hind-milk comes from the latter part of the feed. Hind-milk is lower in volume and has a higher fat and calorie content. These samples were stored at

Gas chromatography (GC)

Table 2 lists the TCA drugs and the doses taken by the ten breast-feeding mothers. Measures obtained by GC of the total concentrations of the parent antidepressant drugs and their active metabolites in maternal plasma, fore-milk and hind-milk are shown, as well as the fat content of the milk samples.

Across all breast-feeding subjects there was a significant correlation between the oral dose of TCA and the plasma concentration of the parent compound (r=0.78, df=20, p<0.0001), the principal

Discussion

This research has attempted to address some of the problems highlighted by previous studies (see review by Yoshida and Kumar, 1996), notably the need to incorporate measures of the fat content of breast milk into evaluations of transfer of lipophyllic drugs from plasma into milk, the use of newer and more sensitive assay methods for testing for small amounts of drugs and metabolites in samples from infants and an attempt systematically to record any acute toxic effects in infants of drugs in

Acknowledgements

This work was supported by the Wellcome Trust. We are very grateful to the mothers who, with their babies, took part in this study.

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