An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Preliminary evidence of a sensitive period for olfactory learning by human newborns.

AIM: To test the hypothesis that a brief window of time immediately after delivery may be a particularly sensitive period for olfactory learning by human neonates. METHODS: Fifty-five vaginally delivered newborns were exposed to an odorant for 30 min beginning 4-37 min after birth (Early exposure) or 12-h post-partum (Late exposure). Several days later, newborns' head orientation responses to the exposure odour versus an unfamiliar odour or an odourless control stimulus were tested. RESULTS: Infants in the Early exposure group spent significantly more time oriented towards the familiar scent rather than a novel odour (Z = 2.869; n = 28; p < 0.01), or an odourless stimulus (Z = 2.550; n = 28; p < 0.01). Infants in the Late exposure condition did not respond differentially to the exposure odour versus a novel odour (Z = 1.105; n = 27, p = 0.27), and spent more time oriented towards an odourless stimulus than to the exposure odour (Z = 2.042; n = 27, p < 0.05). CONCLUSION: Infants in the Early exposure group, but not in the Late exposure group, became familiar with the exposure odour and retained a memory trace of it during the test trials.

Breast odour as the only maternal stimulus elicits crawling towards the odour source.

UNLABELLED: In previous studies, newborn infants placed on their mother's chest grasped a nipple and sucked without assistance. Furthermore, neonates sucked preferentially from an untreated breast rather than the alternative breast that had been washed to eliminate its natural odour. This study investigated the influence of breast odours per se on orientated physical movement of neonates. In total, 22 babies were observed during two trials on a warming bed. In one trial, a pad carrying the mother's breast odour was placed 17 cm in front of the baby's nose; in the other trial a clean pad was used. More babies moved towards and reached the breast pad than the clean pad. CONCLUSION: Natural breast odous unsupported by other maternal stimuli therefore appear to be sufficient to attract and guide neonates to the odour source.

Soothing effect of amniotic fluid smell in newborn infants.

Newborn young of several mammalian species are attracted to the odor of amniotic fluid (AF); these chemical cues also appear to calm neonates and help them adapt to their novel postnatal environment. AF odor likewise elicits positive (head orientation) responses by human infants. The present study systematically examined whether the odors of AF and mother's breasts influence the crying of the newborn infant, when separated from its mother. The total crying time from 31-90 min postnatal was registered on tapes in 47 healthy fullterm newborns, allocated to one of three conditions; exposure to either AF or breast odor or no exposure (controls). Babies exposed to AF smell cried significantly less (median 29 s) than babies in the two other groups (breast odor--301 s, controls--135 s). The data are consistent with the hypothesis that the fetus may become familiar with chemical cues present in the intrauterine environment. Our data provide new evidence of the human baby's fine olfactory discrimination capacity, and add to the growing body of evidence indicating that naturally occurring odors play an important role in the mediation of infants' early behavior.

Natural odour preferences of newborn infants change over time.

At their first sucking contact, neonates prefer an unwashed breast to a washed one, but an amniotic fluid (AF)- treated breast over a "natural odour" breast. We examined the development of these neonatal olfactory preferences. On days 3-4 significantly more babies still selected their mother's unwashed breast (n = 21) than the washed alternative (n = 8). Preferences for natural breast odours were more pronounced for girls than boys. In a subsequent experiment comprising another 28 babies, the number of babies who selected a naturally scented (n = 9) vs an AF-treated breast (n = 19) on days 2-5 were not reliably different. However, babies who selected the natural breast had longer pre-test maternal contact and had spent more time breastfeeding. Ten babies who chose the AF breast in the latter experiment were tested in the same manner several days later; all preferred the naturally smelling breast. While preferences for AF fade after birth, responsiveness to natural breast odours may be enhanced by postnatal experience.

Attractiveness of amniotic fluid odor: evidence of prenatal olfactory learning?

Human infants are responsive to maternal odors beginning shortly after birth. In several non-human mammals, the fetus is capable of olfactory learning and in some species neonates are attracted to the odor of amniotic fluid (AF). The present study examined the responses of newborn babies to AF in a biologically relevant context, i.e. during their initial attempt to locate the mother's nipple/areola. We observed newborns' spontaneous choice between a breast with the nipple/areola moistened with AF and an untreated breast; 23 of 30 infants chose the AF-treated breast. All babies had been washed before the observations, and only 12/30 sucked their hands/fingers prior to approaching the nipple/ areola. In a previous study with unwashed newborns, the corresponding proportion was 27/30 (p < 0.001). We tentatively suggest that the observed attraction to AF odor may reflect fetal exposure to that substance (i.e. prenatal olfactory learning). Because of the salience of biological odors for neonates, products that eliminate or mask such cues should be avoided during the perinatal period.

Does the newborn baby find the nipple by smell?

We studied the involvement of naturally occurring odours in guiding the baby to the nipple. One breast of each participating mother was washed immediately after delivery. The newborn infant was placed prone between the breasts. Of 30 infants, 22 spontaneously selected the unwashed breast. The washing procedure had no effect on breast temperature. We concluded that the infants responded to olfactory differences between the washed and unwashed breasts.