Irena Nulman

Use of lidocaine-prilocaine cream for vaccination pain in infants

PURPOSE To determine whether use of lidocaine-prilocaine 5% cream (EMLA) decreases pain associated with diphtheria-pertussis-tetanus (DPT) vaccination in infants. METHODS Randomize, double-blind, controlled trial in outpatient pediatric practice, Toronto, Ontario, Canada. Before vaccination, parents applied 2.5 gm of EMLA or placebo to the infants leg and covered it with an occlusive dressing for at least 60 minutes. The infant received a 0.5 ml intramuscular injection of DPT at 2 degree to 8 degree C with a 1.6 cm 25-gauge needle; the infant was videotaped. The Modified Behavioral Pain Scale (MBPS) was used to assess baseline and postvaccination pain scores. Latency and duration of infant cry were also measured. RESULTS A total of 49 evaluable infants received EMLA, and 47 infants received placebo. There were no significant differences in demographic data; mean age was 5 months; and 50% of the subjects were male. The median difference in pre-vaccination and postvaccination MBPS scores was lower for EMLA than for placebo (p = 0.001). The latency to the first cry was longer for subjects who were treated with EMLA (p = 0.0004)), but the total crying time was shorter (10.3 seconds vs 25.2 seconds; p = 0.027). Of the study group, 90% (45/50) of subjects treated with EMLA and 12% (6/49) of subjects treated with placebo had local skin reactions (p < 0.0001), mainly skin blanching. CONCLUSIONS Pretreatment with EMLA decreases infant pain from DPT vaccinations. Application of these data is limited to healthy infants receiving DPT vaccinations.

Malformation rates in children of women with untreated epilepsy: A meta-analysis

AbstractBackground: It is widely quoted that women with epilepsy have a higher than baseline risk for giving birth to a child with malformations, independent of the effects of antiepileptic drugs. Objective: To determine, based on available evidence, if epilepsy per se represents a teratogenic risk. To systematically review all studies investigating the occurrence of major malformation rates among children of treated or untreated women with epilepsy and non-exposed controls who do not have epilepsy. Methods: A meta-analysis, using a random effects model, was conducted of all cohort and case-control studies reporting malformation rates in children of women with epilepsy exposed or unexposed to antiepileptic drugs compared with that of children of nonepileptic women. Medline (1966–2001), EMBASE, the Cochrane database as well as REPROTOX (an information system on environmental hazards to human reproduction and development) databases were accessed. Results: We found ten studies reporting results of untreated epilepsy (n = 400) and their non-epileptic healthy controls (n = 2492). Nine out of ten studies also reported results on 1443 patients exposed to antiepileptic drugs and their 2526 unexposed healthy controls. The risk for congenital malformations in the offspring of women with untreated epilepsy was not higher than among nonepileptic controls (odds ratio [OR] = 1.92; 95% CI 0.92–4.00). There was evidence of publication bias, thus with bias removed the OR was 0.99 (95% CI 0.49–2.01). In contrast, the offspring of epileptic women who received antiepileptic drugs had higher incidences of malformation than controls (OR 3.26; 95% CI 2.15–4.93). Conclusion: Our study does not support the commonly held view that epilepsy per se represents a teratogenic risk. Our study suggests that this view is the result of a publication bias, with several small (<100 participants) positive studies leading to a premature conclusion.

Neurodevelopment of Children Following Prenatal Exposure to Venlafaxine, Selective Serotonin Reuptake Inhibitors, or Untreated Maternal Depression

OBJECTIVE Effects on child neurodevelopment of neurotransmitter reuptake inhibitors used as antidepressants during pregnancy have not been adequately studied. The authors compared the effects of prenatal exposure to venlafaxine (serotonin-norepinephrine reuptake inhibitor), selective serotonin reuptake inhibitors (SSRIs), and maternal depression. METHOD A cohort derived from a prospectively collected database included four groups of children born to 1) depressed women who took venlafaxine during pregnancy (N=62), 2) depressed women who took SSRIs during pregnancy (N=62), 3) depressed women who were untreated during pregnancy (N=54), and 4) nondepressed, healthy women (N=62). The childrens intelligence and behavior outcomes were evaluated with standardized instruments at one time point between the ages of 3 years and 6 years, 11 months. RESULTS The children exposed to venlafaxine, SSRIs, and maternal depression during pregnancy had similar full-scale IQs (105, 105, and 108, respectively). The IQs of the venlafaxine and SSRI groups were significantly lower than that of the children of nondepressed mothers (112). The three groups exposed to maternal depression had consistently, but nonsignificantly, higher rates of most problematic behaviors than the children of nondepressed mothers. Severity of maternal depression in pregnancy and at testing predicted child behavior. Maternal IQ and child sex predicted child IQ. Antidepressant dose and duration during pregnancy did not predict any cognitive or behavioral outcome. CONCLUSIONS Factors other than antidepressant exposure during pregnancy strongly predict childrens intellect and behavior. Depression during pregnancy is a significant risk factor for postpartum depression. Children of depressed mothers may be at risk of future psychopathology.

Identifying the behavioural phenotype in fetal alcohol spectrum disorder: sensitivity, specificity and screening potential

SummaryBackground: In most cases of Fetal Alcohol Spectrum Disorder (FASD), the pathognomonic facial features are absent making diagnosis challenging, if not impossible, particularly when no history of maternal drinking is available. Also because FASD is often comorbid with Attention Deficit Hyperactivity Disorder (ADHD), children with FASD are frequently improperly diagnosed and receive the wrong treatment. Since access to psychological testing is typically limited or non-existent in remote areas, other diagnostic methods are needed to provide necessary interventions. Objectives: To determine if a characteristic behavioural phenotype distinguishes children with FASD from typically developing children and children with ADHD and use this information to create a screening tool for FASD diagnosis. Methods: Parents and caregivers completed the Child Behavior Checklist (CBCL), a well-established standardized tool for evaluating children’s behavioural problems. Results from 30 children with Fetal Alcohol Syndrome or Alcohol-Related Neurodevelopmental Disability, 30 children with ADHD, and 30 typically developing healthy children matched for age and socioeconomic status with FASD were analyzed. Based on our previous work, 12 CBCL items that significantly differentiated FASD and control groups were selected for further analyses. Stepwise discriminant function analysis identified behavioural characteristics most strongly differentiating groups and Receiver Operating Characteristics (ROC) curve analyses determined sensitivity and specificity of different item combinations. Results: Seven items reflecting hyperactivity, inattention, lying and cheating, lack of guilt, and disobedience significantly differentiated children with FASD from controls. ROC analyses showed scores of 6 or higher on these items differentiated groups with a sensitivity of 86%, specificity of 82%. For FASD and ADHD, two combinations of items significantly differentiated groups with high sensitivity and specificity (i) no guilt, cruelty, and acts young (sensitivity = 70%; specificity = 80% (ii) acts young, cruelty, no guilt, lying or cheating, steals from home, and steals outside (sensitivity = 81%; specificity = 72%). These items were used to construct a potential FASD screening tool. Conclusions: Our findings identifying the behavioural characteristics differentiating children with FASD from typically developing children or children with ADHD have the potential for development of an empirically derived tool for FASD tool to be used in remote areas where psychological services are not readily available. This technique may speed up diagnosis and intervention for children without ready access to formal assessments.

Treatment of Epilepsy in Pregnancy

Pregnant women with epilepsy constitute 0.5% of all pregnancies. Proper seizure control is the primary goal in treating women with epilepsy. The commonly used anticonvulsants are established human teratogens. Factors such as epilepsy, anticonvulsant-induced teratogenicity, patient’s genetic predisposition and the severity of convulsive disorder may attribute to adverse pregnancy outcome for the children of women with epilepsy. Anticonvulsant interaction with folic acid and phytomenadione (vitamin K) metabolism may lead to an increased risk for neural tube defect and early neonatal bleeding. Psychological, hormonal and pharmacokinetic changes in pregnancy may escalate seizure activity.Preconceptional counselling should include patient education to ensure a clear understanding of risks of uncontrolled seizures and possible teratogenicity of anticonvulsants. Genetic counselling should be performed if both parents have epilepsy or the disease is inherited. Seizure control should be achieved at least 6 months prior to conception and, if clinically possible, by the lowest effective dose of a single anticonvulsant according to the type of epilepsy. The new anticonvulsants are not recommended in pregnancy and require further research to prove their safety in humans.Folic acid 5 mg/day should be administered 3 months before conception and during the first trimester to prevent folic acid deficiency-induced malformations. Antenatal management should include assessment of patients for anticonvulsant-associated birth defects through detailed ultrasound examination and levels of maternal serum α-fetoproteins. Therapeutic drug monitoring should be performed monthly, or as clinically indicated. If phénobarbital, carbamazepine or phenytoin is administered, maternal phytomenadione supplementation should begin 4 weeks before the expected date of delivery.In order to prevent convulsions during labour, proper seizure control should be achieved during the third trimester. Benzodiazepines or phenytoin are found to be effective for seizure cessation during labour and delivery. Phytomenadione should be administered immediately after birth to the newborn. The neonate should be assessed carefully for epilepsy and anticonvulsant-associated dysmorphology. Advising the patient on postpartum management regarding contraception and breast-feeding will help maximise the best possible outcome for the newborn and mother. With proper preconceptional, antenatal and postpartum management up to 95% of these pregnancies have been reported to have favourable outcomes.

Alcohol Use and Pregnancy Consensus Clinical Guidelines

OBJECTIVE to establish national standards of care for the screening and recording of alcohol use and counselling on alcohol use of women of child-bearing age and pregnant women based on the most up-to-date evidence. EVIDENCE published literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library in May 2009 using appropriate controlled vocabulary (e.g., pregnancy complications, alcohol drinking, prenatal care) and key words (e.g., pregnancy, alcohol consumption, risk reduction). Results were restricted to literature published in the last five years with the following research designs: systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment (HTA) and HTA-related agencies, national and international medical specialty societies, clinical practice guideline collections, and clinical trial registries. Each article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES the quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR the Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada. ENDORSEMENT these consensus guidelines have been endorsed by the Association of Obstetricians and Gynecologists of Quebec; the Canadian Association of Midwives; the Canadian Association of Perinatal, Womens Health and Neonatal Nurses (CAPWHN); the College of Family Physicians of Canada; the Federation of Medical Women of Canada; the Society of Rural Physicians of Canada; and Motherisk. SUMMARY STATEMENTS: 1. There is evidence that alcohol consumption in pregnancy can cause fetal harm. (II-2) There is insufficient evidence regarding fetal safety or harm at low levels of alcohol consumption in pregnancy. (III) 2. There is insufficient evidence to define any threshold for low-level drinking in pregnancy. (III) 3. Abstinence is the prudent choice for a woman who is or might become pregnant. (III) 4. Intensive culture-, gender-, and family-appropriate interventions need to be available and accessible for women with problematic drinking and/or alcohol dependence. (II-2). RECOMMENDATIONS 1. Universal screening for alcohol consumption should be done periodically for all pregnant women and women of child-bearing age. Ideally, at-risk drinking could be identified before pregnancy, allowing for change. (II-2B) 2. Health care providers should create a safe environment for women to report alcohol consumption. (III-A) 3. The public should be informed that alcohol screening and support for women at risk is part of routine womens health care. (III-A) 4. Health care providers should be aware of the risk factors associated with alcohol use in women of reproductive age. (III-B) 5. Brief interventions are effective and should be provided by health care providers for women with at-risk drinking. (II-2B) 6. If a woman continues to use alcohol during pregnancy, harm reduction/treatment strategies should be encouraged. (II-2B) 7. Pregnant women should be given priority access to withdrawal management and treatment. (III-A) 8. Health care providers should advise women that low-level consumption of alcohol in early pregnancy is not an indication for termination of pregnancy. (II-2A).

A survey of physicians knowledge regarding awareness of maternal alcohol use and the diagnosis of FAS.

BackgroundAlcohol is the most widely used drug in the world that is a human teratogen whose use among women of childbearing age has been steadily increasing. It is also probable that Fetal Alcohol Syndrome is under diagnosed by physicians. The objectives of this study were twofold: 1) to evaluate the experience, knowledge and confidence of family physicians with respect to the diagnosis of FAS and 2) to evaluate physicians awareness of maternal drinking patterns.Methods and ParticipantsA multiple choice anonymous questionnaire was sent to a randomly selected group of family physicians in the Metropolitan Toronto area.ResultsThere was a 73% (75/103) total response rate; Overall, 6/75 (8%) of family physicians reported that they had actually diagnosed a child with FAS. 17.9% had suspicions but did not make a diagnosis and 12.7% reported making a referral to confirm the diagnosis. Physician rated confidence in the ability to diagnosis FAS was low, with 49% feeling they had very little confidence. 75% reported counselling pregnant women and 60.8% reported counselling childbearing women in general on the use of alcohol. When asked what screening test they used to detect the use of alcohol, 75% described frequency/quantity. Not a single respondent identified using the current accepted screening method for alcohol use (TWEAK) which is recommended by The Centre for Addiction and Mental Health.ConclusionsFamily physicians do not feel confident about diagnosing FAS. None of the physicians were aware of the current screening methods to accurately gage alcohol use in pregnant and childbearing women

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients.

BACKGROUND Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. METHOD We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. RESULTS Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. CONCLUSION Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

Pregnancy outcomes following maternal exposure to second-generation antipsychotics given with other psychotropic drugs: a cohort study

Objectives Second-generation antipsychotics (SGAs), in conjunction with other psychotropic medications, are increasingly used to treat psychiatric disorders in pregnancy. The few available studies investigating the reproductive safety of SGAs did not reach conclusive results, and none have compared monotherapy with polytherapy involving other psychotropic medications. Design Descriptive cohort study using a prospectively collected database. Setting Motherisk Program, The Hospital for Sick Children, Toronto, Canada. Participants 133 women exposed to SGAs and other psychotropic drugs and 133 matched healthy controls were assessed and analysed. Outcomes of mother–child pairs exposed to SGAs in monotherapy (N=37) were compared with those exposed to SGAs with other psychotropic medications (in polytherapy; N=96). Main outcome measures Maternal, pregnancy, delivery and neonatal outcomes. Results 72% of exposed women received SGAs in polytherapy, and 101 women took their medications throughout pregnancy. These women had significantly higher pre-pregnancy weight, experienced more associated comorbidities and instrumental deliveries, and delivered a greater proportion of large for gestational age neonates. There were no differences in maternal weight gain in pregnancy between the exposed and comparison groups and between the monotherapy-exposed and polytherapy-exposed subgroups. The exposed neonates were more likely to be born premature, were admitted more often to the neonatal intensive care unit, presented with poor neonatal adaptation signs and had higher rates of congenital malformations. All the aforementioned neonatal outcomes were found mainly in the polytherapy subgroup. Conclusions The use of SGAs in polytherapy was prevalent in the assessed cohort and was associated with adverse pregnancy outcomes for both the mother and the child. In utero exposure to SGA monotherapy appears to be associated with less risk to the fetus. Future research should focus on polytherapy in pregnancy in order to define its reproductive safety and to separate the effects of medication exposure, underlying psychopathology and associated comorbidities.

Binge alcohol consumption by non-alcohol – dependent women during pregnancy affects child behaviour, but not general intellectual functioning; a prospective controlled study

SummaryEffects of binge ethanol consumption during early gestation on child neurodevelopment have not been elucidated. To study whether binge drinking affects cognitive abilities and behavior of exposed children, a prospective observational study comparing 51 children exposed to binge drinking during the first trimester of pregnancy to 51 children not exposed to any teratogens was conducted. The children’s physical development, intelligence, language abilities and behavior were assessed.Temperament test results showed that children exposed in utero to maternal binge drinking displayed a greater degree of disinhibited behavior and that this behavior was associated with early drinking variables. Although binge alcohol drinking by non-alcohol-dependent women during the first trimester of pregnancy does not appear to affect intelligence or cognitive and language development of young children, binge drinking in pregnancy does increase the likelihood of certain behavioral characteristics that might predispose these children to later behavioral dysfunction.