Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

Caffeine is a commonly consumed drug during pregnancy with the potential to affect the developing fetus. Findings from previous studies have shown inconsistent results. We recruited a cohort of 2643 pregnant women, aged 18-45 years, attending two UK maternity units between 8-12 weeks gestation from September 2003 to June 2006. We used a validated tool to assess caffeine intake at different stages of pregnancy and related this to late miscarriage and stillbirth, adjusting for confounders, including salivary cotinine as a biomarker of smoking status. There was a strong association between caffeine intake in the first trimester and subsequent late miscarriage and stillbirth, adjusting for confounders. Women whose pregnancies resulted in late miscarriage or stillbirth had higher caffeine intakes (geometric mean = 145 mg/day; 95% CI: 85 to 249) than those with live births (103 mg/day; 95% CI: 98 to 108). Compared to those consuming <100 mg/day, odds ratios increased to 2.2 (95% CI: 0.7 to 7.1) for 100-199 mg/day, 1.7 (0.4 to 7.1) for 200-299 mg/day, and 5.1 (1.6 to 16.4) for 300+ mg/day (P trend =0.004). Greater caffeine intake is associated with increases in late miscarriage and stillbirth. Despite remaining uncertainty in the strength of association, our study strengthens the observational evidence base on which current guidance is founded.

Studies on the effects of caffeine on health, while numerous, have produced inconsistent results. One of the most uncertain and controversial effects is on pregnancy outcome. Studies have produced conflicting results due to a number of methodological variations. The major challenge is the accurate assessment of caffeine intake. The aim of the present study was to explore different methods of assessing caffeine exposure in pregnant women. Twenty-four healthy pregnant women from the UK city of Leeds completed both a detailed questionnaire, the caffeine assessment tool (CAT) designed specifically to assess caffeine intake and a prospective 3 d food and drink diary. The women also provided nine saliva samples over two consecutive days for estimation of caffeine and a metabolite (paraxanthine). Caffeine intakes from the CAT and diary showed adequate agreement (intra-class correlation coefficient of 0·5). For saliva caffeine and paraxanthine measures, the between-sample variation (within the same woman) was greater than between-woman and between-day variation. However, there was still adequate agreement between these measures and the CAT. The CAT is a valuable tool that is now being used in a large prospective study investigating caffeine's role in pregnancy outcome.

To assess the scale of the possible exposure by the breast-fed infant to potentially harmful substances in breast milk, methodologically robust studies are essential. Many studies in this field, however, do not report details of crucial issues such as recruitment and milk sampling. The aims of the study reported here were to develop robust methods for the study of contaminants in breast milk, and to develop a framework for future research and population monitoring. Three cohorts of women and babies were recruited by midwives from five sites in northern England. Cohort 1 (cross-sectional, n = 322) were asked to provide two milk samples, one at one week following birth and one at a subsequent time point. Cohort 2 (longitudinal, n = 54) were asked to provide five samples at specified time points over the first 12-16 weeks after birth. Cohort 3 (convenience, n = 18), mothers of babies in the Special Care Unit, were asked to donate surplus breast milk. A novel method of analysing fat concentration in small volumes was developed and tested. A randomly selected set of samples from different donors and stages of lactation was screened for organochlorine pesticide residues, polychlorinated biphenyls, dioxins/furans, phthalates and heavy metals. A total of 453 samples were donated. Cohort 3 was the least successful route of recruitment. Cohorts 1 and 2 combined were most representative of the population. Sample collection, transport and storage procedures, and the collection of data on life style and diet, were robust and acceptable to women. Midwifery involvement in recruitment was an essential component. This study offers a framework both for the conduct of future research studies, and for the establishment of regional and national monitoring mechanisms for contaminants in breast milk. Similar work on contaminants in formula as fed to babies is needed to inform risk assessment methods.

This is a repository copy of Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study..