Citalopram has a half-life of approximately 35 hours. The activity of the metabolites norcitalopram and desmethylcitalopram amounts to 13%. On the basis of over 65 mother-child pairs (Lee 2004A, Weissman 2004, Heikkinen 2002), it can be summarized that the relative dose a fully breastfed child receives, including active metabolites, is on average 3-5% (maximum about 10%). Citalopram could be detected only in traces in the child's serum, if at all (Berle 2004). The maximum values amounted to approximately one-fifteenth of the therapeutic maternal concentration. Restless sleep was noted in one baby aged about 6 weeks whose mother received 40 mg a day. With steady-state conditions, a level of 205 jig/1 was found in the milk and 12.7 |ig/l in the baby's serum. A relative dosage of 5.4% was calculated. Following a reduction of the maternal dosage by half, and two feeds of infant formula, the baby's sleep pattern was normal (Schmidt 2000). Of 31 examined children (Lee 2004A), 3 showed insignificant and non-specific symptoms - for example, restlessness in a 2-month-old child, whose symptoms resolved after weaning. Few case reports present breastfed children with somnolence. For the remaining children described in the literature, toxic symptoms are not mentioned. Also, the further development up to the age of 1 year was predominantly unremarkable (Weissman 2004, Heikkinen 2002, Rampono 2000).
Escitalopram is an active isomer of citalopram with a molecular mass of 414. At 56%, the protein binding is lower than that of citalopram (80%) and could facilitate a transfer to the milk. Data are insufficient with respect to lactation. A case report describes a child aged 3 weeks, whose weight gain was insufficient from the beginning of the maternal therapy and up to the age of 4 months. In addition, slightly elevated liver enzymes, moderate muscle hypertonia of the upper extremities, irritability, and frequent crying were observed. The symptoms resolved after adding formula feeding in the fifth month (Mcrlob 2005). A similar observation was documented by the current author and colleagues. A hyperirritable newborn started high-pitched crying 2 hours after breastfeeding (5-6 hours after escitalopram intake by the mother), every afternoon. When the mother took her tablet in the morning instead, her child's symptoms appeared at the same time interval after breastfeeding. After adding formula, symptoms improved, and resolved completely after weaning on day 11.
Up to 94% of fluoxetine and its active metabolite norfluoxetine is bound to plasma protein. The half-life of fluoxetine is 4 days; that of norfluoxetine is 7 days. The M/P ratio is 0.25. Experience with 16 mother-baby pairs in two studies showed that the relative dosage of fluoxetine plus norfluoxetine taken in by the breastfed baby was, on average, 6.5%, with a maximum of 17%. The children were unremarkable (Yoshida 1998A, Taddio 1996, Burch 1992). Another case report described an infant with screaming attacks, watery stools, and increasing vomiting, whose symptoms disappeared when he changed to artificial feeding. When he was put to breast again, the symptoms reappeared (Lester 1993). The mother took 20 mg fluoxetine daily. A relative dosage of around 8%, including norfluoxetine, was calculated. Therapeutic concentrations (340 ng/1 fluoxetine and 208|ig/l norfluoxetine), such as would be expected in an adult taking 20 mg, were found in the serum of the 10-week-old baby. In an additional case, there were indications of increased irritability in the baby during the first 2 weeks of his mother's therapy with 20 mg fluoxetine daily; 28.8fig/l fluoxetine and 41.6 ng/1 norfluoxetine were measured in the milk (Isenberg 1990). From this, a dosage for the child of about 11 [ig/kg/daily - corresponding to 3,2% of the maternal weight-related dosage - was calculated. A case report describes an infant with questionable convulsive-like symptoms and a cyanotic attack, whose mother took carbamazepine and buspirone in addition to fluoxetine. Further development of the baby through to the end of the first year of life was normal. The authors were, with justification, hesitant to conclude that there was a connection between the medication and the symptoms (Brent 1998). Four additional children, who were followed up neurologically until age of 1, were unremarkable (Yoshida 1998A).
Chambers (1998) found a statistically significant lower weight gain of about 9% in a group of 28 breastfed children whose mothers were taking fluoxetine, compared to a control group of 34 breastfed children who were not exposed to psychoactive medication. However, no other symptoms were observed.
Epperson (2003) studied the potential effects of maternal fluoxetine on the serotonin metabolism in five newborns. All but one infant experienced little or no decline in whole blood (platelet) 5-hydroxytryptamine (5-HT) concentrations after exposure to fluoxetine through breast milk. The substantial reduction in platelet 5-HT seen in one infant, and the coupling of this drop with a measurable plasma fluoxetine level, raises some concern. Possible reasons for the infant's measurable plasma fluoxetine level include his mother's high plasma drug level and his being breastfed exclusively. However, the observations may be coincidental, and the infant experienced no discernible adverse effects.
All in all, of 80 published mother-child pairs (Weissman 2004), only 5 infants showed symptoms. The majority of children did not show any side effects of maternal fluoxetine therapy during lactation. However, the rate of symptomatic children is greater than that of the other SSRIs, possibly because fluoxetine's relative dose is higher and its half-life is longer.
Fluvoxamine has a half-life of 16 hours. Levels of 310 pg/l fluvoxamine in the serum and 90 pg/1 in the milk of a breastfeeding mother taking 200 mg daily have been reported. Based on this, an M/P ratio of 0.3 can be calculated; thus the infant would get 13.5pg/kg daily, which represents 0.5% of the maternal weight-related dosage (Wright 1991). A second case report observed proportionally lower concentrations when the dosage was 100 mg daily. Mathematically, this too represents a relative dosage of 0.5%. Cognitive and motor development of (his baby, who was breastfed for 5 months, tested at 4 months and again at 21 months, was unremarkable (Yoshida 1997B).
In a third mother-child pair, where the mother was taking 200 mg fluvoxamine daily, a level of 48 pg/kg a day was calculated, representing a relative dosage of 1.6% for the clinically unremarkable baby (Hagg 2000A). A further group of authors reported on the determination of fluvoxamine levels in the scrum of a 10-week-old breastfed baby, which, based on the maximum active ingredient concentration in the milk, indicated a relative dosage of only 0.6% for the baby. Nevertheless, 45% of the maternal serum concentration was found in his serum. During the period of observation (up to the age of 4 months), the baby's development was unremarkable (Arnold 2000). No substance was detected in the serum of five additional children without symptoms (Weissman 2004, Hendrick 2001 A).
Based on about 110 mother-child pairs, the average relative dose of paroxetine (half-life 22 hours) for a fully breastfed child is 1%. In almost all infants, paroxetine could not be detected in blood and no side effects were observed, apart from one child with lethargy possibly associated with prenatal exposure (Berle 2004, Merlob 2004, Weissman 2004, Hendrick 2001 A). Peak values in the milk correlated with the dosage. The highest level was 101|ig/l, with a daily maternal dosage of 50 mg. This represents a relative dosage of less than 2% (Slowe 2000). Another woman took 20 mg paroxetine daily, and 7.6 (ig of the medication were detected per liter of the mother's milk. Thus, the baby received 1.14|ig/kg paroxetine daily, which represents about 0.4% of the maternal weight-related dosage (Spigset 1996). With respect to serum concentrations and symptoms in the neonatal period, there has been one recorded exception, in a 5-day-old newborn who had 31.4|ig/l in the blood. Although the milk value (153|ig/l) was also five times higher than the average level found in other studies, lethargy, poor weight gain, and hypotonia persisting through the first 4-6 weeks of life could also be attributed to the prenatal exposure (cited in Weissman 2004).
Sertraline has a half-life of 26 hours. Based on about 110 mother-child pairs, the average relative dose for a fully breastfed child is almost 2% (Merlob 2004, Weissman 2004. Hendrick 2001 A). In 1997, Stowe analyzed 148 milk samples from 12 mothers. The highest concentrations for sertraline were around 173 pg/1; for desmethylsertraline, which has a significantly lower psychopharma-cological action, it was 294(ig/l. Maternal dosages ranged from 25 to 200 mg daily. There were traces of sertraline in the scrum of some children, and in three of them a level of about 10\i%/\ desmethylsertraline was measured (Merlob 2004, Weissman 2004, Hendrick 2001 A). In other infants either no substance was found or the levels were near or below the level of quantifiability (Wisner 2006, Berle 2004). In only one breastfed baby were serum levels equal to 50% of the maternal values found (Wisner 1998). The authors of the study could not understand this, and suggested direct administration of the medication to the baby as the cause. None of the babies was remarkable. Decreasing serum values of desmethylsertraline with age were observed among 30 breastfed children (Hendrick 2001 A). A maternal dosage of above 100 mg/day was significantly correlated with the detection of sertraline in the infant's serum. Breastfed infants showed little or no change in platelet 5-hydroxytryptamine (5-HT) levels after exposure through breastfeeding. According to the authors of this study, the observations suggest that peripheral or central 5-HT transport in these infants is not affected by sertraline therapy of their mothers.
Recommendation. Sertraline, paroxetin, Citalopram, and fluvoxamin are the drugs of choice among SSRIs for breastfeeding mothers. In case of fluox-etin or escitalopram therapy, special attention should be paid to potential side effects in the breastfed child. In general, monotherapy should be the goal. If symptoms appear that are potentially associated with SSRI therapy, a pediatrician and a teratology information center should be contacted to decide individually upon measuring drug values in the infant's serum, supplementary formula feeding, weaning, and/or changing therapy. As with alt psychoactive drugs, there is insufficient experience on the long-term effects on breastfed children as a result of ongoing therapy to their mothers.
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