Facundo Garcia-Bournissen

Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women

A new strain of influenza A virus (novel influenza A H1N1) that originated in swine has rapidly spread from the initial outbreak in Mexico and the southern United States to Canada and many countries in Europe and Asia. Consequently, the World Health Organization raised the level of alert for an

Recurrence and Outcomes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children

OBJECTIVES: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Childrens Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes. RESULTS: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes. CONCLUSIONS: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.

The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs.

Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. To date, there has not been any attempt at a systematic evaluation of this model. The aim of this study was to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a pharmacokinetic model to account for nonplacental pharmacokinetic parameters in the perfusion results. In general, the fetal‐to‐maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery of the infant. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R2 = 0.85, P < 0.0001). Placental perfusion experiments can be used to predict placental drug transfer when adjusting for extra parameters and can be useful for assessing drug therapy risks and benefits in pregnancy.

Motherisk Rounds: Risks of Statin Use During Pregnancy: A Systematic Review

Although statins have been identified as potential teratogens on the basis of theoretical considerations and small case series, the available evidence is far from conclusive. In fact, epidemiological data collected to date suggest that statins are not major teratogens. The actual risk for an exposed pregnancy seems to be small, if present at all, and does not by itself warrant termination of pregnancy. Nevertheless, given the scarcity of available data, it is still advisable to avoid use of these drugs in patients who are planning pregnancy in order to reduce the risks as much as possible.

Adverse events after the use of benznidazole in infants and children with Chagas disease.

BACKGROUND: Chagas disease is caused by infection with Trypanosoma cruzi. In adults, treatment with benznidazole is associated with a high incidence of adverse drug reactions (ADRs). However, in infants and children, treatment with benznidazole seems associated with a lower incidence and decreased severity of ADRs, but these effects have not been clearly characterized. OBJECTIVE: We aimed to describe ADRs observed in infants and children treated with benznidazole. PATIENTS AND METHODS: We conducted a prospective cohort study of infants and children in Argentina with Chagas disease treated with benznidazole. RESULTS: A total of 107 infants and children diagnosed with asymptomatic Chagas disease (mean age: 6.9 years) were enrolled in the study. Sixty-two events (in 44 children) were considered benznidazole related. Mean ADR duration was 8.2 days. ADRs were mild (80.6%), moderate (16%), or severe (3.2%). Most (77.3%) ADRs were in children older than 7 years. Skin was the organ with the highest incidence of ADRs (21%), followed by the central nervous system (9%) and the gastrointestinal tract (8.5%). Also, the ADR rate was lower in infants and toddlers compared with older children (18% vs 53%) (P < .001). CONCLUSIONS: Treatment with benznidazole was well tolerated in children. Most ADRs were mild and did not require treatment suspension. A strong association was observed between ADR incidence and patient age, and most ADRs occurred in children older than 7 years. We believe that anxiety over potential severe ADRs in children with Chagas disease is not justified and should not be an obstacle to using benznidazole.

Maternal-fetal transport of hypoglycaemic drugs.

Due to legal, ethical and monetary problems, drug studies in pregnancy are rare. Numerous pharmacokinetic and pharmacodynamic changes occur in pregnancy that can affect the efficacy and safety of drugs, and these are difficult to predict without appropriate studies.Drugs potentially useful and safe in pregnancy have to either not cross the placenta and/or be harmless to the fetus at clinically relevant concentrations. The first characteristic can be predicted using in vitro models such as the placenta perfusion model. In the case of glibenclamide (glyburide), in vitro experiments showed minimal maternal-fetal transfer, leading to completion of a successful clinical trial of this drug in gestational diabetes. Insulin, the main drug used in diabetes during pregnancy, has also been shown not to cross the placenta in vitro, as has insulin lispro. Animal insulin may cross the placenta when complexed with anti-insulin antibodies. Other sulphonylurea drugs (tolbutamide and chlorpropamide) have been shown to cross the placenta both in vitro and in vivo and to produce toxicity in the fetus.This review summarises the pharmacokinetic data available for hypoglycaemic drugs during pregnancy, as well as the potential role for the in vitro placenta perfusion model in the preclinical evaluation of drugs with potential usefulness in pregnancy.

Prenatal Exposure to Mycophenolate Mofetil: An Updated Estimate

Mycophenolate mofetil (MMF) has become a major therapeutic option in the management of patients undergoing transplantation, as well as in the treatment of autoimmune conditions. Case reports have suggested that MMF use during pregnancy is associated with a specific pattern of congenital malformations. Because many pregnancies are unplanned, it is imperative to assess the teratogenic risk of MMF. Using the Organization of Teratology Information Specialists network, we prospectively identified and followed pregnant women exposed to MMF during pregnancy to update this teratogenic potential. Ten cases were identified and all received the drug during embryogenesis at the recommended doses (500 to 1500 mg daily). There were four miscarriages and one elective abortion due to fear of teratogenesis. None of the five live births had malformations. It is possible that, similar to other human teratogens discovered first by case reports, the absolute risk from MMF may be smaller than originally calculated based on case reports. Because the major malformations phenotypic of MMF may be visualized in utero (e.g., microtia, cleft palate, congenital diaphragmatic hernia, and cardiac malformation), diagnostic imaging should be performed.

Methamphetamine detection in maternal and neonatal hair: implications for fetal safety

Background: Methamphetamine misuse is a serious health problem of epidemic proportions. Use of this drug, particularly during pregnancy, is difficult to ascertain. Sparse information is available on gestational exposure. Objectives: To quantify methamphetamine accumulation in hair, identify the use of methamphetamine with other drugs of abuse and characterise correlations between concentrations of methamphetamine in maternal and neonatal hair. Subjects and methods: Motherisk laboratory at the Hospital for Sick Children routinely carries out analysis of methamphetamine in hair. Mothers and infants with positive results for methamphetamine in hair were identified. Drugs present in hair were analysed by ELISA and positive results were confirmed by gas chromatgraphy/mass spectrometry. Results: 396 people positive for methamphetamine in their hair were identified from our database. Almost 85% of them were positive for at least one other drug of abuse, mostly cocaine. Eleven mother–baby pairs with hair positive for methamphetamine were identified. Methamphetamine levels in hair ranged between 0.13 and 51.97 ng/mg in the mothers and between 0 and 22.73 ng/mg in the neonates. Methamphetamine levels in mothers and neonates correlated significantly. One (9%) neonate was negative for methamphetamine even though the mother was positive. Conclusion: To our knowledge, this is the first report on fetal exposure to methamphetamine during pregnancy, showing transplacental transfer of the drug, with accumulation in fetal hair. Hair measurement for methamphetamine in neonates is a useful screening method to detect intra-uterine exposure to the drug. The data also indicate that positive exposure to methamphetamine strongly suggests that the person is a polydrug user, which may have important implications for fetal safety.

Is use of nifurtimox for the treatment of Chagas disease compatible with breast feeding? A population pharmacokinetics analysis

Introduction Women with Chagas disease receiving treatment with nifurtimox are discouraged from breast feeding. Many patients who would receive treatment with nifurtimox live in extreme poverty, have limited access to resources such as clean water and baby formula and may not have safe alternatives to breast milk. Aim We aimed to estimate, using limited available pharmacokinetics data, potential infant exposure to nifurtimox through breast milk. Methods Original nifurtimox plasma concentrations were obtained from published studies. Pharmacokinetic parameters were estimated using non-linear mixed-effect modelling with NONMEM V.VI. A total of 1000 nifurtimox plasma–concentration profiles were simulated and used to calculate the amount of drug that an infant would be exposed to, if breast fed 150 ml/kg/day. Results Breast milk concentrations on the basis of peak plasma levels (1361 ng/ml) and milk–plasma ratio were estimated. We calculated infant nifurtimox exposure of a breastfed infant of a mother treated with this drug to be below 10% of the maternal weight-adjusted dose, even if milk–plasma ratio were overestimated. Simulation led to similar estimates. Discussion Risk for significant infant exposure to nifurtimox through breast milk seems small and below the level of exposure of infants with Chagas disease receiving nifurtimox treatment. This potential degree of exposure may not justify discontinuation of breast feeding.

MOTHERISK ROUNDS: Medications for Restless Legs Syndrome in Pregnancy

According to epidemiological data, pregnant women have a two or three times higher risk of experiencing restless legs syndrome (RLS) than the general population. Current evidence suggests that dopaminergic dysfunction, impaired iron homeostasis, and genetic predisposition may be involved in the pathophysiology of RLS. Four classes of medications have been used for patients with RLS, but pregnancy elicits a therapeutic concern. Although two dopamine agonists, ropinirole and pramipexole, have been approved by the FDA for the treatment of RLS and are currently the first-line treatment for daily symptoms, there is very little information on the teratogenic risks of these new medications. Therefore, they are not currently recommended for use during pregnancy. Medications with a more extensive safety record in pregnancy include opioids; antiepileptics, such as carbamazepine and gabapentin; and certain benzodiazepines. Ruling out iron deficiency should be an integral part of a treatment plan for RLS in pregnancy. Before management with medication is introduced, every patient should be assessed for iron status with measurement of serum ferritin.