Neonatal morbidity after fetal exposure to antipsychotics: a national register-based study.

OBJECTIVE: To investigate the admission rate to neonatal care and neonatal morbidity after maternal use of antipsychotics during pregnancy. DESIGN: A population-based register study. SETTING: Information on all singleton births between July 2006 and December 2017 in Sweden including data on prescription drugs, deliveries and infants' health was obtained from the Swedish Medical Birth Register, the Prescribed Drug Register and the Swedish Neonatal Quality Register. Exposed infants were compared with unexposed infants and with infants to mothers treated with antipsychotics before or after but not during pregnancy. PARTICIPANTS: The cohort comprised a total of 1 307 487 infants, of whom 2677 (0.2%) were exposed to antipsychotics during pregnancy and 34 492 (2.6%) had mothers who were treated before/after the pregnancy. OUTCOME MEASURES: The primary outcome was admission rate to neonatal care. Secondary outcomes were the separate neonatal morbidities. RESULTS: Of the exposed infants, 516 (19.3%) were admitted to neonatal care compared with 98 976 (7.8%) of the unexposed infants (adjusted risk ratio (aRR): 1.7; 95% CI: 1.6 to 1.8), with a further increased risk after exposure in late pregnancy. The highest relative risks were seen for withdrawal symptoms (aRR: 17.7; 95% CI: 9.6 to 32.6), neurological disorders (aRR: 3.4; 95% CI: 2.4 to 5.7) and persistent pulmonary hypertension (aRR: 2.1; 95% CI: 1.4 to 3.1) when compared with unexposed infants. The absolute risks for these outcomes were however low among the exposed infants, 1.3%, 1.8% and 1.0%, respectively, and the relative risks were lower when compared with infants to mothers treated before/after the pregnancy. CONCLUSION: Fetal exposure to antipsychotics was associated with an increased risk of neonatal morbidity. The effects in the exposed infants seem transient and predominantly mild, and these findings do not warrant discontinuation of a necessary treatment but rather increased monitoring of these infants. The increased risk of persistent pulmonary hypertension requires further studies.

Antipsychotic Use During Pregnancy and Risk for Gestational Diabetes: A National Register-Based Cohort Study in Sweden.

OBJECTIVE: We aimed to study whether antipsychotic use during pregnancy is associated with gestational diabetes. METHODS: This was a Swedish national register-based cohort study on the Medical Birth Register and the Prescribed Drug Register including all 1,307,487 singleton births between July 2006 and December 2017. Antipsychotics were divided into first-generation antipsychotics (n = 728), high-risk metabolic second-generation antipsychotics including olanzapine, clozapine and quetiapine (n = 1710), and other second-generation antipsychotics (n = 541). The risks for gestational diabetes, foetal growth disturbances, pre-eclampsia, caesarean section and preterm labour were assessed. Women treated during pregnancy were compared to women not treated during pregnancy and to women who used antipsychotics before/after but not during pregnancy. RESULTS: The crude risk ratio for gestational diabetes for women treated with high-risk metabolic second-generation antipsychotics during pregnancy was 2.2 (95% confidence interval [CI] 1.6-2.9) compared to untreated pregnant women (n = 1,296,539) and 1.8 (95% CI 1.4-2.5) compared to women treated before/after pregnancy (n = 34,492). After adjustment for maternal factors including body mass index, the risk ratios were 1.8 (95% CI 1.3-2.4) and 1.6 (95% CI 1.2-2.1). Exposed infants had an increased risk of being large for gestational age: adjusted risk ratios 1.6 (95% CI 1.3-1.9) and 1.3 (95% CI 1.1-1.6) compared to no maternal antipsychotic use during pregnancy and maternal use before/after the pregnancy. Other antipsychotics were not associated with metabolic risks. CONCLUSIONS: Olanzapine, clozapine and quetiapine used during pregnancy were associated with increased risks for gestational diabetes and the infant being large for gestational age. Enhanced metabolic monitoring should be considered for pregnant women using these drugs.

The use of second-generation antipsychotics amongst pregnant women is increasing. The side effects of these drugs, for example weight gain and increased blood sugar, are well described for the general population. In particular, olanzapine, quetiapine and clozapine are known to cause these effects. Studies on their effects on blood sugar control in pregnant women have however been conflicting. Pregnancy itself also imposes a risk for increased blood sugar levels and gestational diabetes. The purpose of this study was to evaluate the risk of gestational diabetes connected to the use of antipsychotics during pregnancy. The study was nationwide and register based including 1.3 million births in Sweden between July 2006 and December 2017. The rates of gestational diabetes and the infants being small for gestational age or large for gestational age amongst women treated with antipsychotics were compared to the rates in pregnant women who did not receive antipsychotics and to rates in a control group of women treated with antipsychotics before/after but not during pregnancy. Antipsychotics were divided into three groups: (i) first-generation antipsychotics, (ii) high-risk second-generation antipsychotics including olanzapine, quetiapine and clozapine, and (iii) other second-generation antipsychotics. Women treated with high-risk second-generation antipsychotics were found to have an increased risk of gestational diabetes and giving birth to an infant being large for gestational age, both when compared with untreated pregnant women and with the control group. Other antipsychotics were not connected to increased risks of these outcomes. Hence, pregnant women treated with olanzapine, quetiapine or clozapine should be monitored regarding blood sugar levels.

Parents' perspectives on dried blood spot self-sampling from children with epilepsy: A mixed-method study.

AIM: Children with epilepsy often have concomitant diagnoses. Dried blood spot samples for drug monitoring can be collected by parents at home as an alternative to traditional sampling. This mixed-method study aimed to understand the parents' perspectives on blood self-sampling from their children and to identify factors contributing to successful sampling. METHOD: Parents who had collected a sample from their child during a visit to the neuropediatric clinic were asked to fill in a questionnaire. To get in-depth information and individual perspectives, parents and nurses participated in semi-structured interviews and analysed with thematic analysis. RESULTS: The results from questionnaires (n = 64) and interviews (n = 9) were interpreted together. Watching an instruction video and practical training contributed to successful sampling. 97% of the parents managed to collect a sample, 72% thought it was easy to perform, and 80% found self-sampling at home desirable. Factors for success were as follows: high motivation, prepared parents with pre-understanding, a pragmatic attitude, flexible education, effective communication and willingness to take on the role as a performer. Risk factors were as follows: conflict, fear, unprepared parents, confused or worried children. CONCLUSION: Voluntary self-sampling at home for parents of children with epilepsy is feasible and can reduce stress factors in everyday life.

Dried Blood Spot Self-Sampling by Guardians of Children With Epilepsy Is Feasible: Comparison With Plasma for Multiple Antiepileptic Drugs.

BACKGROUND: Dried blood spot (DBS) is an attractive matrix alternative to plasma for the measurement of antiepileptic drug concentrations with the possibility of self-sampling at home. The aim of this study was to evaluate whether DBS concentrations from a children population could be used as an alternative to plasma concentrations in a clinical routine laboratory. METHODS: Children with epilepsy using carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA) had capillary blood collected for routine plasma analysis. DBS samples were collected by guardians or nurses, and the quality of sampling was compared between the groups. DBS samples were analyzed with liquid chromatography-tandem mass spectrometry methods and plasma samples with immunochemical methods. In the comparison between DBS and plasma concentrations, previously analyzed sample data were pooled with data in this study and resulted in 190 comparison pairs. A bioanalytical cross-validation according to European Medicines Agency was performed. Clinicians evaluated the results to understand if a DBS concentration was linked to a different clinical dose recommendation for the patient in comparison with plasma concentrations. RESULTS: Comparison of DBS sample quality showed that 2.3% of the capillary DBS collected by guardians were rejected and 8.0% of the capillary DBS collected by nurses. For DBS, a conversion factor of 0.85 for CBZ and 1.65 for VPA was applied for the comparison with plasma. LTG and LEV results were directly comparable. In the cross-validation, 88% of CBZ, 75% of LTG, 74% of LEV, and 94% of VPA comparisons were within 20% of the difference of the mean, although LEV had a few major differences (+31% to -40%). In 4 of the 190 comparisons, the clinical evaluation indicated a risk of conflicting decisions regarding the need for dose adjustment when using DBS concentrations. However, the risk of negative patient outcomes was considered negligible. CONCLUSIONS: Our study demonstrates that a combination of bioanalytical cross-validation and clinical evaluation is an effective way to describe the applicability of DBS as an alternative to plasma, taking into account how therapeutic drug monitoring is used in specific patient groups. For LTG, converted CBZ and VPA, DBS is a feasible alternative for self-sampling at home. DBS for LEV can only be recommended for nonadherence queries due to the high variability of the plasma/DBS concentration ratios.

MAGDALENA: study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero.

INTRODUCTION: Ten per cent of all pregnant women are depressed. Standard therapy of pregnant women with moderate depression is selective serotonin reuptakeinhibitors (SSRI). Observational studies on neurodevelopment after fetal SSRI exposure show conflicting results. Our primary objective is to compare the cognitive development in children exposed to sertraline and maternal depression with those exposed to maternal depression and placebo in utero. We hypothesise that there is a significant neurodevelopmental difference between the groups. As a secondary objective, we study the add-on effect of sertraline to internet-based cognitive behavioural therapy (ICBT) to treat moderate depression during pregnancy. METHODS AND ANALYSIS: MAGDALENA is a randomised, placebo-controlled, double-blinded trial in Stockholm Healthcare Region with 2.3 million inhabitants. The women are recruited in weeks 9-21 of pregnancy either through Antenatal Health Clinics or through social media. They are to be diagnosed with moderate depression without ongoing antidepressive therapy or any serious comorbidity. The women in the intervention arm receive sertraline combined with a 12-week period of ICBT; the control arm is treated with placebo and ICBT. We assess the cognitive development in the offspring at the age of 2 years using Bayley Scales of Infant and Toddler Development, third edition (BSID-III). We aim at recruiting 200 women, 100 women in each treatment arm, to ensure statistical power to detect a clinically relevant difference between the groups. ETHICS AND DISSEMINATION: This randomised trial will provide long-sought evidence about the effects of SSRI and maternal depression during pregnancy on the neurodevelopment in the offspring. The study is approved by the Regional Ethical Review Board at Karolinska Institutet in Stockholm and the Swedish Medical Products Agency. It is registered with the European Clinical Trials Database (EudraCT), Number: 2013-004444-31. Results will be disseminated at scientific conferences, published in peer-reviewed journals and made available to the public. TRIAL REGISTRATION NUMBER: EudraCT2013-004444-31; Pre-results.

Utilization of Antiepileptic Medicines in Swedish Children and Adolescents with Different Diagnoses.

This study aimed to investigate the utilization of antiepileptic drugs (AEDs) in children and adolescents with epilepsy and other diagnoses in a nationwide population between 2007 and 2014. Data on dispensed prescriptions of AEDs were collected from the Swedish Prescribed Drug Register and linked to diagnosis data from the National Patient Register covering all in- and outpatient consultations from Swedish hospitals. Children aged 0-17 years who had received at least one prescription for AEDs were selected. We calculated proportions of patients stratified by indication, sex and type of AED. A total of 18,131 patients (mean age 9.5 years, 50% boys) were initiated on AED treatment between January 2007 and December 2014. Epilepsy was the most frequent diagnosis (46%) recorded within the year prior to the first AED dispensing. Psychiatric and pain diagnoses were more common in girls (sex distribution 70/30 and 59/41, respectively). In epilepsy, the most frequently initiated AED was valproic acid in boys and lamotrigine in girls. Lamotrigine was the most frequently initiated drug in psychiatry, in both boys and girls. This nationwide study provides new knowledge on AED use in children and adolescents. The use of AEDs during the study period was mainly restricted to epilepsy, and the individual AEDs used seems to be in accordance with approved indications. However, the use of AED on non-epilepsy diagnoses, especially pain disorders, raises concerns.

Internet delivered cognitive behavior therapy for antenatal depression: A randomised controlled trial.

Major depression occurs in 5-10% of pregnancies and is associated with many negative effects for mother and child, yet treatment options are scarce. To our knowledge, this is the first published randomised controlled trial on Internet delivered Cognitive Behavior Therapy (ICBT) for this group. OBJECTIVE: To test the efficacy of a pregnancy adapted version of an existing 10-week ICBT-program for depression as well as assessing acceptability and adherence DESIGN: Randomised controlled trial. SETTING: Online and telephone. POPULATION OR SAMPLE: Self-referred pregnant women (gestational week 10-28 at intake) currently suffering from major depressive disorder. METHODS: 42 pregnant women (gestational week 12-28) with major depression were randomised to either treatment as usual (TAU) provided at their antenatal clinic or to ICBT as an add-on to usual care. MAIN OUTCOME MEASURES: The primary outcome was depressive symptoms measured with the Montgomery-Åsberg depression rating scale-self report (MADRS-S). The Edinburgh Postnatal Depression Scale and measures of anxiety and sleep were used. Credibility, satisfaction, adherence and utilization were also assessed. RESULTS: The ICBT group had significantly lower levels of depressive symptoms post treatment (p < 0.001, Hedges g =1.21) and were more likely to be responders (i.e. achieve a statistically reliable improvement) (RR = 0.36; p = 0.004). Measures of treatment credibility, satisfaction, utilization, and adherence were comparable to implemented ICBT for depression. LIMITATIONS: Small sample size and no long-term evaluation. CONCLUSION: Pregnancy adapted ICBT for antenatal depression is feasible, acceptable and efficacious. These results need to be replicated in larger trials to validate these promising findings.

Comparison between dried blood spot and plasma sampling for therapeutic drug monitoring of antiepileptic drugs in children with epilepsy: A step towards home sampling.

OBJECTIVES: To investigate if dried blood spots could be used for therapeutic drug monitoring of the antiepileptic drugs, carbamazepine, lamotrigine and valproic acid in children with epilepsy. METHODS: Fingerprick blood samples from 46 children at a neuropediatric outpatient clinic was collected on filterpaper at the same time as capillary plasma sampling. A validated dried blood spot liquid chromatography tandem mass spectrometry method for carbamazepine, lamotrigine and valproic acid was compared with the routine plasma laboratory methods. Method agreement was evaluated and plasma concentrations were estimated by different conversion approaches. RESULTS: Strong correlation was shown between dried blood spot and plasma concentrations for all three drugs, with R2 values>0.89. Regression analysis showed a proportional bias with 35% lower dried blood spot concentrations for valproic acid (n=33) and concentrations were 18% higher for carbamazepine (n=17). A ratio approach was used to make a conversion from dried blood spots to estimated plasma for these two drugs. Dried blood spot concentrations were directly comparable with plasma for lamotrigine (n=20). CONCLUSIONS: This study supports that dried blood spot concentrations can be used as an alternative to plasma in a children population for three commonly used antiepileptic drugs with the possibility to expand by adding other antiepileptic drugs. Clinical decisions can be made based on converted (carbamazepine, valproic acid) or unconverted (lamotrigine) dried blood spot concentrations. Dried blood spot sampling, in the future taken at home, will simplify an effective therapeutic drug monitoring for this group of patients who often have concomitant disorders and also reduce costs for society.

Neonatal Morbidity After Maternal Use of Antidepressant Drugs During Pregnancy.

OBJECTIVES: To estimate the rate of admissions to NICUs, as well as infants' morbidity and neonatal interventions, after exposure to antidepressant drugs in utero. METHODS: Data on pregnancies, deliveries, prescription drug use, and health status of the newborn infants were obtained from the Swedish Medical Birth Register, the Prescribed Drug Register, and the Swedish Neonatal Quality Register. We included 741 040 singletons, born between July 1, 2006, and December 31, 2012. Of the infants, 17 736 (2.4%) had mothers who used selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Infants exposed to an SSRI were compared with nonexposed infants, and infants exposed during late pregnancy were compared with those exposed during early pregnancy only. The results were analyzed with logistic regression analysis. RESULTS: After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval: 1.4-1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5% compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6 [95% confidence interval: 1.5-1.8]). Respiratory and central nervous system disorders and hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary hypertension (number needed to harm: 285). CONCLUSIONS: Maternal use of antidepressants during pregnancy was associated with increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk for severe disease was low, however.

Peritoneal dialysis impairs nitric oxide homeostasis and may predispose infants with low systolic blood pressure to cerebral ischemia.

BACKGROUND & PURPOSE: Infants on chronic peritoneal dialysis (PD) have an increased risk of developing neurological morbidities; however, the underlying biological mechanisms are poorly understood. In this clinical study, we investigated whether PD-mediated impairment of nitric oxide (NO) bioavailability and signaling, in patients with persistently low systolic blood pressure (SBP), can explain the occurrence of cerebral ischemia. METHODS & RESULTS: Repeated blood pressure measurements, serial neuroimaging studies, and investigations of systemic nitrate and nitrite levels, as well as NO signaling, were performed in ten pediatric patients on PD. We consistently observed the loss of both inorganic nitrate (-17 ± 3%, P < 0.05) and nitrite (-34 ± 4%, P < 0.05) during PD, which may result in impairment of the nitrate-nitrite-NO pathway. Indeed, PD was associated with significant reduction of cyclic guanosine monophosphate levels (-59.4 ± 15%, P < 0.05). This reduction in NO signaling was partly prevented by using a commercially available PD solution supplemented with l-arginine. Although PD compromised nitrate-nitrite-NO signaling in all cases, only infants with persistently low SBP developed ischemic cerebral complications. CONCLUSIONS: Our data suggests that PD impairs NO homeostasis and predisposes infants with persistently low SBP to cerebral ischemia. These findings improve current understanding of the pathogenesis of infantile cerebral ischemia induced by PD and may lead to the new treatment strategies to reduce neurological morbidities.

A LC-MS/MS method for therapeutic drug monitoring of carbamazepine, lamotrigine and valproic acid in DBS.

BACKGROUND: Therapeutic drug monitoring of antiepileptic drugs in children with epilepsy assists for personalized drug therapy but require numerous patient visits for venous blood sampling. DBS is an alternative matrix applicable to home sampling which can save time and reduce stress for this patient group. RESULTS: A fast LC-MS/MS method for quantification of carbamazepine, lamotrigine and valproic acid based on DBS sampling was developed. The method showed linearity in therapeutically relevant concentration ranges and compatible with unknown volume sampling and expected hematocrit range of the patient group. CONCLUSION: A LC-MS/MS method for the three most commonly used antiepileptic drugs has been fully validated and clinically applied on DBSs from patients at the neuropediatric clinic at Karolinska University Hospital.

Plasma nitrate/nitrite removal by peritoneal dialysis might predispose infants with low blood pressure to cerebral ischaemia.

The underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis (PD) are poorly understood. We report on four male infants treated with PD who developed symptomatic cerebral ischaemia. Blood pressure (BP) levels were low both before the event and at presentation. In two patients, we observed that the removal of nitrate and nitrite by PD could have impaired the nitrate/nitrite--nitrite oxide (NO) pathway, a system that generates NO independently of NO synthase. Our observation suggests that low BP and reduced NO bioavailability puts infants treated with PD at risk for impaired cerebral blood flow and consequently for brain ischaemia.

Neonatal adaptation in infants prenatally exposed to antidepressants--clinical monitoring using Neonatal Abstinence Score.

BACKGROUND: Intrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) has routinely been used to assess infants exposed to antidepressants in utero. AIM: The purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero. METHOD: Retrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized. RESULTS: 220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%). CONCLUSION: Severe abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described.

High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

A comparison of 4ß-hydroxycholesterol : cholesterol and 6ß-hydroxycortisol : cortisol as markers of CYP3A4 induction.

AIM: To compare plasma 4ß-hydroxycholesterol : cholesterol with urinary 6ß-hydroxycortisol : cortisol as markers of cytochrome P4503A4 activity before and after treatment with rifampicin for 2 weeks. METHOD: 6ß-hydroxycortisol and cortisol were determined by liquid chromatography tandem mass spectrometry and 4ß-hydroxycholesterol was determined by gas chromatography-mass spectrometry in three groups of healthy volunteers. RESULTS: Induction ratios for 6ß-hydroxycortisol : cortisol were 1.8, 3.9 and 4.5 for 20 mg day(-1) , 100 mg day(-1) or 500 mg day(-1) of rifampicin, respectively. The corresponding ratios for 4ß-hydroxycholesterol : cholesterol were 1.5, 2.4 and 3.8. CONCLUSIONS: Plasma 4ß-hydroxycholesterol : cholesterol gave similar induction ratios to urinary 6ß-hydroxycortisol : cortisol.

Pediatric tick-borne infections of the central nervous system in an endemic region of Sweden: a prospective evaluation of clinical manifestations.

UNLABELLED: Tick-borne encephalitis (TBE) and neuroborreliosis (NB) are well-known central nervous system (CNS) infections in children. Childhood tick-borne CNS infections are generally described as mild conditions. However, this view has recently been challenged, and the natural course, including potential sequelae, has been debated. If the diseases present with nonspecific symptoms and signs, some children may elude diagnosis. This study estimates the incidence of symptomatic tick-borne CNS infections in children under medical care and describes the spectrum of manifestations. One hundred twenty-four children with neurologic symptoms attending the Pediatric Emergency Department were included prospectively. Anti-TBE virus and anti-Borrelia serology results were analyzed together with inflammatory parameters in the blood and cerebrospinal fluid. Nearly one fourth of the children with neurologic symptoms were diagnosed with a tick-borne CNS infection (TBE, n = 10 [8%] and NB, n = 21 [16.8%]). In general, these children displayed an indistinct medical history and presented with nonspecific signs such as malaise/fatigue and headache. Diagnosis was based on analysis of acute and convalescent sera. Blood inflammatory parameters were nonspecific and did not contribute to the diagnostics. CONCLUSION: Pediatric tick-borne CNS infections are unexpectedly common and should be considered in children with unspecific and unexplained acute CNS-related symptoms.

Tick-borne encephalitis in childhood: rare or missed?

Retrospective evaluation of medical history and 3635 anti-TBE (tick-borne encephalitis) serologies during the years 2003-2008 indicates that childhood TBE is characterized by vague symptoms. Clinical findings suggest a nonspecific inflammatory disease with restricted encephalitic profile compared with adult TBE. Childhood TBE might elude diagnosis, which is unsatisfactory because of potential long-term consequences.

Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4ß-hydroxycholesterol.

PURPOSE: The purpose of this study was to determine the 4ß-hydroxycholesterol to cholesterol ratio in mothers and neonates at the time of birth and 4 months post-partum. METHOD: 21 mothers and 22 neonates were recruited at the delivery ward at Karolinska University Hospital, Huddinge, Sweden. Blood samples taken from mothers and neonates at birth and 4 months post-partum were analysed for 4ß-hydroxycholesterol and cholesterol. RESULTS: The median plasma concentration of 4ß-hydroxycholesterol was higher in mothers at delivery (50 ng/mL) compared to healthy non-pregnant women (29 ng/mL). The pregnant women had a higher median cholesterol concentration (6.2 mmol/L) compared to healthy non-pregnant women (4.6 mmol/L) but this could only partly explain the increased 4ß-hydroxycholesterol. The major cause is an increased CYP3A activity during pregnancy. The median 4ß-hydroxycholesterol/cholesterol ratio·10(4) was elevated in mothers at time of birth compared to non-pregnant women (0.19 and 0.15, respectively) but decreased to 0.15 4 months post-partum. Neonates had a median 4ß-hydroxycholesterol/cholesterol ratio·10(4) (0.19) comparable to adults already at birth, but lower 4ß-hydroxycholesterol (12 ng/mL) and cholesterol (1.8 mmol/L) concentrations. CONCLUSION: Pregnancy leads to increased CYP3A enzyme activity as determined by the 4ß-hydroxycholesterol/cholesterol ratio. Neonates have low 4ß-hydroxycholesterol and cholesterol concentrations but similar total CYP3A activity as adults already at birth.

School performance at age 16 in children exposed to antiepileptic drugs in utero--a population-based study.

PURPOSE: In order to evaluate long-term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children's school grades at age 16. METHODS: We used the Patient Register, the Medical Birth Register, and a local study at South Hospital, Stockholm, to identify women with epilepsy in Sweden who had given birth between 1973 and 1986. The Swedish School Mark Registry was used to obtain information about school grades from the last year of compulsory school, at age 16. Exposed children were compared to all other children born in Sweden between 1973 and 1986. KEY FINDINGS: Medical records were analyzed for 1,235 children. Six hundred forty-one children had been exposed in utero to antiepileptic drugs (AEDs) in monotherapy, 429 in polytherapy, and 165 to no known AED. Children exposed to polytherapy had an increased risk of not receiving a final grade--odds ratio (OR) 2.99 [95% confidence interval (CI) 2.14-4.17]. Children exposed to monotherapy, mainly carbamazepine or phenytoin, did not have a significantly increased risk of not receiving a final grade-OR 1.19 (95% CI 0.79-1.80). Children born to women with epilepsy had a decreased chance of getting a "pass with excellence." SIGNIFICANCE: Exposure to several AEDs in utero may have negative effects on neurodevelopment, and polytherapy should, if possible, be avoided in pregnant women.

Long-term consequences after exposure to antiepileptic drugs in utero.

Most pregnant women with epilepsy need pharmacological treatment during pregnancy. Children exposed to antiepileptic drugs have an increased risk of being born with major malformations. Some antiepileptic drugs seem to have negative effects on psychomotor or cognitive development in children exposed during foetal life. Neither carbamazepine nor lamotrigine in monotherapy seem to affect the cognition of exposed children. Several studies have shown negative effects on the long-term neurodevelopment of children prenatally exposed to valproic acid or polytherapy (two or more antiepileptic drugs during pregnancy). For most of the newer antiepileptic drugs there are insufficient data regarding long-term outcome.