A pharmacogenomic investigation of the cardiac safety profile of ondansetron in children and pregnant women.

BACKGROUND: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication. METHODS: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data. RESULTS: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10-4). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10-7). CONCLUSIONS: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication.

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.

Listeriosis during pregnancy.

PURPOSE: Listeriosis is a rare foodborne illness caused by Listeria monocytogenes. It can be transmitted by consuming contaminated ready-to-eat food, long shelf-life products, deli meats, and soft cheeses. Listeria has a predilection to affect immunocompromised patients, elderly people, pregnant women and neonates. In particular, pregnant women are at ~18 times greater risk of infection than general population due to specific pregnancy-related suppressed cell-mediated immunity and placental tropism of L. monocytogenes. The purpose of this review is to summarize the current knowledge regarding listeriosis during pregnancy. METHODS: A literature search on Medline and Embase was done for articles about listeriosis during pregnancy. A detailed review of published data on epidemiology, pathogenesis, diagnosis, treatment and prevention of listeriosis during pregnancy was performed. RESULTS: Listeriosis during pregnancy encompasses maternal, fetal and neonatal disease. Maternal listeriosis during pregnancy usually presents as a mild febrile illness. Fetal listeriosis has a high mortality rate of 25-35%, depending on the gestational age at the time of infection. Neonatal listeriosis may present as sepsis or meningitis with severe sequels and high case fatality rate of 20%. Adequate treatment of maternal listeriosis prevents and treats fetal disease and it is of imminence importance in the treatment of the neonates. Amoxicillin or ampicillin are the first line of treatment alone or in combination with gentamicin, followed by trimethoprim/sulfamethoxazole. CONCLUSIONS: Pregnancy-associated listeriosis should be considered as a cause of fever during pregnancy and appropriate treatment should be initiated preemptively. Prevention remains the best way to control listeriosis and should be reinforced among patients, health care professionals, and regulatory agencies.

Hepatitis E infection during pregnancy.

QUESTION: Many of my patients are from Southeast Asia where hepatitis E virus (HEV) infection is quite common. What precautions can I suggest they take before traveling to these areas and what is the risk of contracting HEV during pregnancy? ANSWER: Hepatitis E is a water-borne pathogen transmitted by the fecal-oral route. To reduce the risk of contracting HEV while traveling to endemic areas, it is important to maintain hygienic practices such as hand washing with safe water, particularly before handling food, avoiding drinking water or using ice cubes of unknown purity, and avoiding eating unpeeled fruits and vegetables. Currently there is no vaccine available in Canada for HEV. Hepatitis E infection during pregnancy, especially in the third trimester, is characterized by a more severe infection that sometimes results in fulminant hepatitis, increasing maternal and fetal mortality and morbidity.

First trimester exposure to topiramate and the risk of oral clefts in the offspring: A systematic review and meta-analysis.

Topiramate (TPM) is an increasingly used drug during childbearing ages for treatment of epilepsy, migraine, and appetite suppression as well as for off-label indications such as sleep and psychiatric disorders. Presently, while some reports suggested an increased risk of oral cleft (OC), these reports are balanced by studies that could not confirm such association. We conducted a meta-analysis of all studies reporting on women exposed to TPM during pregnancy. Of the 2327 publications reviewed, 6 articles met the inclusion criteria including 3420 patients and 1,204,981 controls. The odd ratio (OR) of OC after the first trimester exposure to TPM exposure was 6.26 (95% confidence interval: 3.13-12.51; P = 0.00001). This study provides strong evidence that TPM is associated with an increased risk of OC in infants exposed to TPM during embryogenesis and should lead to a careful review of TPM use in women of reproductive ages.

Donated breast milk stored in banks versus breast milk purchased online.

QUESTION: One of my patients asked if she could buy human milk on the Internet to feed her infant if the need arose. Is using donated breast milk from the milk bank safer than buying it online? ANSWER: The World Health Organization and the American Academy of Pediatrics recommend the use of donated breast milk as the first alternative when maternal milk is not available, but the Canadian Paediatric Society does not endorse the sharing of unprocessed human milk. Human breast milk stored in milk banks differs from donor breast milk available via the Internet owing to its rigorous donor-selection process, frequent quality assurance inspections, regulated transport process, and pasteurization in accordance with food preparation guidelines set out by the Canadian Food Inspection Agency. Most samples purchased online contain Gram-negative bacteria or have a total aerobic bacteria count of more than 10(4) colony-forming units per millilitre; they also exhibit higher mean total aerobic bacteria counts, total Gram-negative bacteria counts, coliform bacteria counts, and Staphylococcus spp counts than milk bank samples do. Growth of most bacteria species is associated with the number of days in transit, which suggests poor collection, storage, or shipping practices for milk purchased online.

Hepatitis A infection during pregnancy.

QUESTION: Many of my patients are from Southeast Asia, where hepatitis A virus (HAV) infection is quite common. What precautions can I suggest my pregnant patients take before traveling to these areas and what is the risk of contracting HAV during pregnancy? ANSWER: Hepatitis A virus is a water-borne pathogen transmitted by the fecal-oral route. To reduce the risk of contracting HAV while traveling to endemic areas, it is important to maintain hygienic practices such as hand washing with safe water, particularly before handling food, avoiding drinking water or using ice cubes of unknown purity, and avoiding eating unpeeled fruits and vegetables. An HAV vaccine is available and can be administered before traveling to endemic countries. Hepatitis A virus infection has a largely favourable expected outcome even during pregnancy. Infection occurring in the second or third trimester has been reported to be associated with preterm labour.

Toxoplasmosis and pregnancy.

Question Congenital toxoplasmosis is a dangerous fetal infection. Why is routine screening for Toxoplasma gondii infection during pregnancy not available for most Canadians? Answer Low prevalence of the infection, high cost associated with testing, low sensitivity of screening tests, false-positive test results, and limitations of treatment effectiveness are all cited as reasons for not routinely screening for T gondii infection in Canada. Currently, screening for the detection of T gondii is only performed in Nunavik and other parts of northern Quebec owing to the high prevalence of infection in this region. Congenital toxoplasmosis causes neurologic or ocular disease (leading to blindness), as well as cardiac and cerebral anomalies.

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.

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.

Myasthenia gravis during pregnancy.

QUESTION: One of my patients who has been diagnosed with myasthenia gravis (MG) is planning pregnancy. Her MG is controlled with medications. Can her condition or her medications adversely affect her pregnancy? ANSWER: The course of MG during pregnancy is unpredictable, but there is no evidence that MG can adversely affect pregnancy outcomes. Examination of most of the medications used for symptom control has so far shown reassuring results. Prepregnancy thymectomy might decrease the need for medications during pregnancy. The newborn should be carefully monitored for signs of transitory MG.