Shahnaz Akhtar Chaudhry

A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk

Background Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety. Methods and Findings Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. Conclusions The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.

The fetal safety of Levetiracetam: A systematic review

OBJECTIVE To systematically review the available published evidence on the fetal safety of Levetiracetam with focus on birth defects. RESULTS Eight studies met the inclusion criteria; five pregnancy registries and one population based cohort study. A total of 27 major congenital malformations were reported among 1213 Levetiracetam monotherapy - exposed pregnant women, yielding an overall major malformation rate of 2.2% (27/1213) [95% confidence interval of 1.53-3.22]. In contrast, Levetiracetam polytherapy was associated with significantly higher malformation rate of 6.3% (34/541) [95% CI of 4.53-8.65] (P<0.001). Additionally 2 studies investigating child neurodevelopment in Levetiracetam - exposed children revealed that the measured achievements were well above those children exposed to valproic acid, and similar to unexposed controls. CONCLUSIONS The current evidence suggests that the overall risk of major malformation after first trimester exposure to Levetiracetam is within the population baseline risk of 1-3%, with no apparent adverse effects on long term child development.

The pharmacogenetics of codeine pain relief in the postpartum period

The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manage postpartum pain.

Assessment of hair cortisol as a potential biomarker for possible adrenal suppression due to inhaled corticosteroid use in children with asthma: A retrospective observational study

BACKGROUND Inhaled corticosteroids (ICS) are the recommended long-term control therapy for asthma in children. However, concern exists regarding potential adrenal suppression with chronic ICS use. Our pilot study reported that hair cortisol in children was 50% lower during ICS therapy than prior to therapy, suggestive of adrenal suppression. OBJECTIVE To evaluate hair cortisol concentration (HCC) as a potential biomarker for possible adrenal suppression from ICS use in children with asthma. METHODS A retrospective observational study was performed at asthma clinics in Vancouver, Winnipeg, and Toronto, Canada. Children (n = 586) were recruited from July 2012 to December 2014 inclusive of those without asthma, with asthma not using ICS, and with asthma using ICS. The most recent three-month HCC was measured by enzyme immunoassay and compared among the groups. Quantile regression analysis was performed to identify factors potentially affecting HCC. RESULTS The median HCC was not significantly different among the children: No ICS (n = 47, 6.7 ng/g, interquartile range (IQR) 3.7-9.8 ng/g), ICS Treated (n = 360, 6.5 ng/g, IQR 3.8-14.3 ng/g), and Controls (n = 53, 5.8 ng/g, IQR 4.6-16.7 ng/g). 5.6% of the children using ICS had hair cortisol <2.0 ng/g compared to none in the control groups (P < .05, comparing ICS Treated (20/360) to all Controls combined (0/100)) and only half had been exposed to systemic corticosteroids. Age, sex, BMI, and intranasal corticosteroid use were significantly associated with HCC. CONCLUSIONS Results suggest HCC may be a potential biomarker for adrenal suppression as a population of children using ICS with HCC < 2.0 ng/g was identified compared to none in the control groups. Further research is needed to determine if those children have or are at risk of adrenal suppression or insufficiency.