SMOFlipid was safe, well tolerated, and showed beneficial effect in terms of reduction of oxidative stress by reducing lipid peroxidation levels in high-risk preterm neonates.

Aims Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20-80 mg (0.3-1.14 mg kg −1 ). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms.Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24-0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg −1 day −1 and a bioavailability of 100% was 17.4 (10.8-24) mg kg. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07-3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 mg l −1 . Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.

Antidepressants are often used antenatally, and placental transfer may lead to adverse effects (toxicity) in the neonate. Pregnant women taking fluoxetine (n=4), sertraline (n=4), paroxetine (n=2) or venlafaxine (n=1) in the last trimester were studied. Maternal and cord sera were collected at delivery and infant serum on day 5 after birth for measurement of antidepressant concentrations. Neonatal Abstinence Scores (NAS) were measured in the infants on days 13 after birth. In maternal serum, median drug concentrations were: fluoxetine (96 microg/l), norfluoxetine (110 microg/l), sertraline (11 microg/l), desmethylsertraline (38 microg/l), paroxetine (mean 12 microg/l), venlafaxine (220 microg/l), and O-desmethylvenlafaxine (392 microg/l). Corresponding median values in cord serum were: fluoxetine (65 microg/l), norfluoxetine (81 microg/l), sertraline (10 microg/l), desmethylsertraline (27 microg/l), paroxetine (mean 6 microg/l), venlafaxine (232 microg/l), and O-desmethylvenlafaxine (406 microg/l). Corresponding median cord:maternal concentration ratios were 0.67 for fluoxetine and 0.72 for norfluoxetine, 0.67 for sertraline and 0.63 for demethylsertraline, 0.52 (mean) for paroxetine, and 1.1 and 1.0 for venlafaxine and O-desmethylvenlafaxine respectively. The neonates of two patients taking fluoxetine had high NAS. Only fluoxetine and norfluoxetine were detected in infant serum. Our data show substantial placental transfer of antidepressants, but only fluoxetine persisted in the infants serum. Neonatal toxicity may be associated with serotonin uptake blockade, and also be influenced by neonatal clearance.

The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.