Perinatal exposure to antiretroviral therapy is associated with increased blood mitochondrial DNA levels and decreased mitochondrial gene expression in infants.

BACKGROUND: The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV)-uninfected, ART-exposed infants born to HIV-positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. METHODS: In this prospective cohort study, longitudinal mtDNA:nuclear DNA and mtRNA:beta-actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. RESULTS: Log(10) mtDNA levels at birth were higher in ART-exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0-3 days after birth). ART-exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period-from age 4 days to age 6 weeks-(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log(10) mtRNA levels at birth were lower in ART-exposed infants than in control infants (P = .03), but were not statistically different later. CONCLUSIONS: When control infants and ART-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART-exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied.

Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) are increasingly being used during pregnancy to treat a variety of conditions. An evaluation of the risk of premature closure of the ductus arteriosus is useful in determining the safety of NSAIDs at different stages of pregnancy. OBJECTIVE: To determine whether NSAID use during the third trimester of pregnancy is associated with an increased risk of premature constriction of the ductus arteriosus. METHODS: A systematic review was conducted of MEDLINE (1966-2004), Embase (1980-2004), and the Cochrane Database of Systematic Reviews (1991-2004). Summary estimates of the odds ratios, comparing ductal outcomes in exposed and unexposed fetuses, and their 95% confidence intervals were calculated assuming a random effects model. RESULTS: Based on 217 patients exposed to indomethacin and 221 to placebo, the risk of ductal closure was 15-fold higher in the group of women exposed to NSAIDs compared with those receiving either placebo or other NSAIDs (8 studies; OR = 15.04, 95% CI 3.29 to 68.68). There was no significant increased risk of ductal closure in the infants of women treated with indomethacin compared with those receiving other drugs (4 studies; OR = 2.12, 95% CI 0.48 to 9.25). Similar results were found when calculating rate differences. CONCLUSIONS: Short-term use of NSAIDs in late pregnancy is associated with a significant increase in the risk of premature ductal closure.

Recruitment in pediatric clinical trials: an ethical perspective.

PURPOSE: There is a paucity of clinical trials in pediatric surgical disciplines. This is partly due to difficulties in recruiting participants. Frequently the origin of these problems lies in the ethical issues surrounding clinical trials in children. We reviewed the ethical barriers to recruitment in pediatric clinical trials and present recommendations to increase recruitment without violating accepted ethical boundaries. METHODS AND MATERIALS: A literature search using the MEDLINE, EMBASE and Google engines was performed. All available North American guidelines were reviewed. Guidelines at a major North American center were also reviewed as an example of institutional directives. RESULTS: Seven categories of ethical issues hampering recruitment were identified. The perspectives of different investigators are discussed as well as their recommended practical approaches to resolve the issues. CONCLUSIONS: Several recommendations are presented to help investigators enhance approval and recruitment rates in clinical trials involving children.

Effects of aspirin consumption during pregnancy on pregnancy outcomes: meta-analysis.

BACKGROUND: We assessed the effects and safety of aspirin treatment during pregnancy on fetal and neonatal outcomes. METHODS: We searched MEDLINE (1966-2001), EMBASE (1980-2000), TOXLINE (1994-2000), EB M Cochrane Database of Systematic Reviews (1991-2000), Reproductive Toxicology (2001), teratology texts, and bibliographies of all the included studies. We looked for published randomized controlled studies reporting aspirin treatment to improve outcomes of moderate- and high-risk pregnancies. The key words used to search for articles about exposure to aspirin were salicylic acid, pregnancy, and pregnancy complications; key words used to search for outcome were neonatal diseases and abnormalities. Based on our search strategy, 1904 citations were identified; their titles and abstracts were reviewed by one reviewer. Of these citations, 182 papers were selected for detailed review. Two reviewers independently determined whether a study should be included in the final analysis. In cases of disagreement, the decision was based on the assessment of a third reviewer. RESULTS: Data were extracted independently by each reviewer. We calculated the pooled relative risk (RR) or weighted mean difference and 95% confidence intervals (CI), assuming a random-effect model. Thirty-eight studies met the inclusion criteria. The risk for miscarriage did not differ between women treated with aspirin andplacebo (seven studies; RR, 0.92; 95% CI, 0.71-119). Women who took aspirin had a significantly lower risk of preterm delivery than did those treated with placebo (22 studies; RR, 0.92; 95% CI, 0.86-0.98). There was no significant difference in perinatal mortality (20 studies; RR, 0.92; 95% CI, 0.81-1.05) and in the rate of small-for-gestational-age infants (12 studies; RR, 0.96; 95% CI, 0.87-1.07) among offspring of mothers treated with aspirin and those of mothers treated with a placebo. CONCLUSION: For women with moderate- and high-risk pregnancies, aspirin treatment seemed to have a small but significant effect on reducing the rate of preterm deliveries, but did not reduce the rate of perinatal death.

Digoxin-carvedilol interactions in children.

Digoxin is often coadministered with carvedilol in children with severe ventricular failure. In eight children (age 2 weeks to 8 years), the oral clearance of digoxin decreased by half with carvedilol, and two of them had digoxin toxicity. Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity.

Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis.

OBJECTIVE: The purpose of this study was to determine, on the basis of published reports, whether aspirin use during the first trimester of pregnancy is associated with an increased risk of congenital malformations. STUDY DESIGN: We reviewed the literature for published studies that reported exposure to aspirin during the first trimester of pregnancy and congenital malformations. Two reviewers independently determined whether a study should be included in the final analysis and extracted the data. We calculated the pooled odds ratio and 95% CI. RESULTS: Twenty-two studies met the inclusion criteria. In the eight studies that reported an overall risk, the risk of congenital malformations in offspring of women who were exposed to aspirin was not significantly higher than that in control subjects (odds ratio, 1.33; 95% CI, 0.94-1.89). However, a significantly increased risk of gastroschisis (odds ratio, 2.37; 95% CI, 1.44-3.88) was found. CONCLUSION: We found no evidence of an overall increase in the risk of congenital malformations that could be associated with aspirin. Aspirin exposure during the first trimester may be associated with an increased risk of gastroschisis.

Perinatal outcome following third trimester exposure to paroxetine.

BACKGROUND: Paroxetine hydrochloride is commonly used for maternal depression, panic disorder, and obsessive-compulsive disorder. The drug readily crosses the human placenta. Although it does not appear to increase teratogenic risk, there have been case reports of neonatal withdrawal. Symptoms were described soon after birth and lasted up to 1 month. OBJECTIVE: To investigate whether there is a clinically important discontinuation syndrome in neonates exposed to paroxetine in utero. METHODS: Prospective, controlled cohort study. PATIENTS: Fifty-five pregnant women counseled prospectively by the Motherisk program in Toronto, Ontario, regarding third-trimester exposure to paroxetine and their infants were included in the study group. Pregnant women who discontinued paroxetine before the third trimester or those receiving other drugs known to cause withdrawal-type symptoms, such as opioids or benzodiazepines, were excluded. A comparison group of 27 women using paroxetine during the first or second trimester and 27 women using nonteratogenic drugs were matched for maternal age, gravity, parity, social drug use, and nonteratogenic drug use. RESULTS: Of the 55 neonates exposed to paroxetine in late gestation, 12 had complications necessitating intensive treatment and prolonged hospitalization. The most prevalent clinical picture was respiratory distress (n = 9), followed by hypoglycemia (n = 2), and jaundice (n = 1). The symptoms disappeared within 1 to 2 weeks. In the comparison group, only 3 infants experienced complications (P =.03). In logistic regression, only third-trimester exposure to paroxetine was associated with neonatal distress (odds ratio, 9.53; 95% confidence interval, 1.14-79.3). CONCLUSION: When used near term, paroxetine is associated with a high rate of neonatal complications, possibly caused by its common discontinuation syndrome.