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