During pregnancy, changes in renal elimination, body composition and metabolic activity occur. Since these important alterations in physiology also affect drug disposition, pregnancy warrants a focused approach. Despite these differences, even commonly administered drugs have not undergone pharmacokinetic evaluation in pregnant women or at delivery. This is also true for analgesics routinely administered by anesthesiologists during pregnancy or at delivery, like intravenous (i.v.) paracetamol or ketorolac. We report on our observations on i.v. paracetamol and ketorolac disposition following cesarean delivery to illustrate the feasibility of such focused studies and the impact of pregnancy on drug disposition. The clinical relevance of these observations are subsequently discussed, and some future research directions are suggested.

Objective To examine the association between ischemic-hypoxic conditions (IHC) and Attention Deficit Hyperactivity Disorder (ADHD) by gestational age at delivery and race/ethnicity. Methods A nested case-control study using the Kaiser Permanente Southern California (KPSC) medical records. Study cohort were children aged 5–11 years who were delivered and cared for in KPSC Healthcare system between 1995–2010 (n =308,634). Cases were children with a clinical diagnosis of ADHD and obtained at least 2 prescriptions specific to ADHD during the follow-up period. For each case, five controls matched to cases on child age at time of diagnosis were selected. Exposures were defined based on ICD-9 codes. A conditional logistic regression model was used to estimate adjusted odds ratios (OR). Results Among eligible children, 13,613 (4.3%) had a diagnosis of ADHD. Compared to control children, case children were more likely to be male and of White or African-American race/ethnicity. Case children than controls were more likely to be exposed to IHC (OR=1.16, 95% confidence intervals [CI] 1.11–1.21). Analysis of cases and controls stratified by gestational age revealed that case children born at 28–33, 34–36, and 37–42 weeks of gestation, were significantly more likely to be exposed to IHC; 1.6-fold (95% CI, 1.2–2.2), 1.2-fold (95% CI, 1.0–1.4), and 1.1-fold (95% CI, 1.0–1.2), respectively, compared to control children. IHC was associated with increased odds of ADHD across all race/ethnicity groups. Conclusion These findings suggest that IHC is independently associated with an increased risk of childhood ADHD especially in early preterm birth.

The general pharmacokinetic principles of disposition and elimination of exogenous compounds apply, irrespective of population specific characteristics. However, pregnancy and delivery warrant a focussed approach because important alterations in physiology (e.g. renal, hepatic, metabolism, body composition) affect drug disposition in a clinical relevant way. During pregnancy, there are changes in distribution volume due to changes in body composition, in metabolic activity affecting drug metabolism and in renal elimination (GFR, tubular) capacity. The link between pregnancy related changes in medical physiology and changes in drug disposition will be illustrated based on aspects of cefazolin and paracetamol disposition during pregnancy and after delivery. Beyond these anecdotal observations, patterns related to medical physiology are unveiled. Key-Words: pregnancy – drug disposition – medical physiology – paracetamol – cefazolin