Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low.

PURPOSE: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. METHOD: Pregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. RESULTS: Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. CONCLUSION: Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood.

AIM: This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. METHODS: Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. RESULTS: Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. CONCLUSION: This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ.

No detection of BK virus, JC virus, KI, WU and Merkel cell polyomaviruses in cerebrospinal fluid of patients with neurological complications after hematopoetic stem cell transplantation.

Neurological complications, often due to viral reactivation, after allogeneic hematopoetic stem cell transplantation (HSCT) are associated with increased mortality. Here, cerebrospinal fluid from 20 HSCT patients with neurological symptoms were analyzed and found to be negative by PCR for BK virus, JC virus, KI, WU and Merkel cell polyomavirus DNA.

Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study.

AIM: Antiepileptic drugs (AEDs) are known teratogens. Some specificity between different AEDs has been noted in the literature. The aim was to compare the teratogenic effect of valproic acid (VPA) and carbamazepine (CBZ) in monotherapy. METHODS: Infants exposed to AEDs (n = 1398) in early pregnancy were identified from the Swedish Medical Birth Registry. The number of infants with congenital malformations and exposed to AED was compared with the expected number estimated from all infants born (n = 582656). RESULTS: 90% (1256) of the AED exposed children were exposed to AEDs in monotherapy, 56% were exposed to CBZ and 21% to VPA. The odds ratio (OR) for having a malformation in the AED exposed group was 1.86 [95% confidence interval (95% CI) 1.42-2.44]. Exposure to VPA in monotherapy compared with CBZ in monotherapy gave OR = 2.51 (95% CI 1.43-4.68) for a neonatal diagnosis of malformations. However, there is no information available on the number of therapeutic abortions, or the different types of epilepsy or drug dosage in the two treatment groups. CONCLUSION: There was a small increase in the risk of having a major malformation after exposure to AEDs in monotherapy. Exposure to VPA seems to carry a higher risk than exposure to CBZ.

Recurrent and prolonged frontal sinusitis.

The purpose of the study was to find the factors that predict the prolongation or recurrence of frontal sinusitis, to analyse the results of endoscopic surgery and trephination and also to analyse the value of the clinical estimation made by the treating specialist. The study was partly prospective, partly retrospective, and it was carried out in 1995-97. The follow-up continued until the end of 1998. The sample consisted of 456 patients (264 men and 192 women) treated for acute frontal sinusitis in Turku University Central Hospital. The collected information consisted of patient history, treatment, outcome and possible re-operations. To be able to evaluate conservative treatment in relation to operative treatment in patients with prolonged disease, a matched conservatively treated patient was selected for each endoscopically operated patient. Of the 456 patients, 359 healed normally, 85 developed prolonged disease, while recurrences were found in 50 patients. Endoscopic surgery was performed in 35 patients. The mean time interval between the endoscopic sinus operation (FESS) and healing was 8.2 weeks. Trephination was performed in 52 patients and FESS in 35 patients. In the statistical analysis, the factors having significance in predicting the outcome of the disease were, in the bivariate analysis, atopy and type of primary operation, chronic rhinitis, polyps, type of previous operations and of re-operations. Neither trephination nor FESS proved markedly better than the other one. Our conclusion was that the prognosis of frontal sinusitis is difficult to predict with any single factor, but is affected by many of them.

Posterior ocular malformations in children: somatic, neuroradiological and cognitive aspects.

AIM: To investigate associated neurological, endocrinological and cognitive dysfunctions in children with visual impairment caused by optic nerve hypoplasia or optic nerve/fundus coloboma and/or microphthalmus. METHODS: Forty children born between 1990 and 1998 were assessed by neurological examination, re-evaluation of neuroradiological investigations, review of medical records and examination of cognitive levels. RESULTS: Neurological dysfunctions (epilepsy and/or motor impairment) were found in 13/28 children with optic nerve hypoplasia and in 3/12 children with coloboma/microphthalmus. The optic pathways were thin in 22/24, an abnormal posterior pituitary gland and/or thin infundibulum was found in 16/22 and absence of septum pellucidum in 14/27 children with optic nerve hypoplasia. Other types of cerebral abnormalities occurred in 9/26 children. Among children with coloboma/microphthalmus, the optic pathways were thin in 4/8 children but none had pituitary or cerebral midline abnormalities. Sixteen children with optic nerve hypoplasia were receiving hormone substitution but none of the children with coloboma/microphthalmus. Thirteen of the 16 children with optic nerve hypoplasia and with an abnormal pituitary region had endocrinological deficiencies. Mental retardation was found in 9/24 of the children with optic nerve hypoplasia and in 5/10 of the children with coloboma/microphthalmus. CONCLUSION: Endocrinological. neurological and neuroradiological defects seem more common in children with optic nerve hypoplasia than in children with coloboma. A pituitary region that appears abnormal in magnetic resonance imaging seems to predict endocrinological deficits in children with optic nerve hypoplasia.

Psychomotor development in preschool children exposed to antiepileptic drugs in utero.

UNLABELLED: The aim of this study was to assess psychomotor development with the Griffiths' test in preschool children exposed to antiepileptic drugs (AED) in utero. The study sample consisted of 76 children exposed to AED in utero and 71 unexposed children. The children (exposed and unexposed) have since birth been included in a population-based longitudinal follow-up study of children born to women with meticulously treated epilepsy during pregnancy, initiated in 1985. In total, 67 exposed and 66 unexposed children were tested with the Griffiths' test, which consists of 6 subsets: locomotor function, personal and social behaviour, hearing and speech, eye and hand coordination, performance, and practical reasoning. There was no significant difference in the global scores of the Griffiths' test between the two groups of children. Children exposed to phenytoin in utero (n = 16) showed a significant but subtle reduction in the scores for locomotor development compared with the unexposed children (mean scores: 98 vs 106: 95% confidence interval for the difference in mean scores: -14.0 to -0.4). There was no such difference for the children exposed to carbamazepine in utero (n = 35). The exposed children had significantly fewer siblings (p < 0.01). A significant number of the mothers with AED treatment had no higher level of education than compulsory school (p < 0.01). No other differences in socioeconomic status were observed between the groups. CONCLUSION: The subtle delay in locomotor development evaluated with the Griffiths' test at 4.5-5 y of age in children exposed to phenytoin may indicate a subtle influence on psychomotor development, which may be more obvious at school age: thus, larger studies and further follow-up are warranted.

Body dimensions of infants exposed to antiepileptic drugs in utero: observations spanning 25 years.

PURPOSE: To investigate the influence of maternal antiepileptic drug (AED) treatment on pregnancy duration, birth weight, body length, head circumference, and intrauterine growth in infants exposed in utero to antiepileptic drugs in Sweden between 1973-1997, with 963 singleton infants. METHODS: Data collected from (a) 1973-1981 (record linkage between a hospital discharge register and a medical birth register); (b) 1984-1995 (prospectively collected information in one defined catchment area with two delivery hospitals); and (c) 1995-1997 (medical birth register data). Observed numbers of infants below a defined size for body measurements compared with expected numbers calculated from all births in Sweden after stratification for year of birth, maternal age, parity, and education or smoking habits in early pregnancy. Standard deviation scores estimated with same stratification procedures. RESULTS: Fraction of monotherapy exposures increased from approximately 40% to approximately 90% from 1973 to 1997. Significantly increased numbers of infants with small body measurements found in exposed group. Negative influence on body dimensions decreased over time. More marked effects found in infants exposed to polytherapy. In monotherapy, only infants exposed to carbamazepine consistently showed reduction in body dimensions. Significant effect on gestational age in girls and on number of small for gestational age (<2 SD) in boys. CONCLUSIONS: Polytherapy with antiepileptic drugs and negative influence on body dimensions decreased. In monotherapy, only carbamazepine has a negative influence on body dimensions in this study.

Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study.

The aim of this study was to assess psychomotor development, using Griffiths' test, and the incidence of minor anomalies at birth in children who had been exposed to antiepileptic drugs (AEDs) in utero. The study sample comprised 100 children of mothers who were treated with AEDs during pregnancy and 100 matched control children. Women with epilepsy were recruited from a pregnant urban population (450 000 inhabitants). The lowest possible dose of the fewest AEDs to maintain seizure control was used. Drug levels were controlled on a monthly basis. The children were assessed at 9 months of age. The study children had a significant increase in the number of minor anomalies (31 compared with 18 control children; odds ratio 2.4, CI 1.15 to 5.02, P=0.02 McNemars test), and an increased number of facial anomalies after carbamazepine exposure (11 compared with six control children). Drug exposure did not influence the Griffiths' score at 9 months of age. Even a meticulous AED treatment strategy during pregnancy increases the number of minor anomalies. However, treatment with AEDs does not necessarily influence short-term psychomotor development.

Visual and ocular outcome in children after prenatal exposure to antiepileptic drugs.

PURPOSE: To prospectively study the incidence of structural and/or functional ophthalmological abnormalities in the offspring to an unselected population of women with epilepsy, subjected to a well controlled antiepileptic drug (AED) treatment during pregnancy. METHODS: Forty-three children prenatally exposed to antiepileptic drugs and 47 controls were included. Blinded ophthalmological examinations including fundus photography were performed at a median age of 7 years and 4 months. RESULTS: No major eye anomalies were found except in one child in the exposed group who had nystagmus and low vision. The visual acuity was lower in the eye with lowest acuity among the exposed children (p < 0.05). No other significant difference was found between the two groups. CONCLUSION: The results suggest that a well-controlled treatment with AEDs, preferably monotherapy, during pregnancy does not have any major adverse effects on the development of the eye and ophthalmological functions.

Operative treatment of frontal sinusitis.

When the medical therapy fails trephination is the primary operation indicated in acute eroding sinusitis when drainage is necessary to avoid severe complications. In recent years also endoscopic transnasal surgery has been recommended for exenteration of the underlying disease in the ostiomeatal unit as well as for opening of the obstructed nasofrontal duct in acute phase of the disease. In Turku University Central Hospital endoscopic frontal sinus surgery is still reserved for cases with prolonged or delayed disease performed as a secondary operation after trephination and CT examination. Failures are common after these operations and both types of surgical treatment may be needed. Three percent of our patients developed a persistent chronic infection inside the frontal sinus. In these cases external osteoplastic approach is recommended. In these operations we have used bioactive glass as obliteration material with promising clinical results.

Report on results of frontal sinus obliterations in Turku University Central Hospital 1977-1994.

When a sinusitis develops into a chronic stage, for which endoscopic sinus surgery is not radical or successful enough, we currently perform in our hospital obliteration of the infected frontal sinuses. The present study is a partly retrospective and partly prospective evaluation of the outcome of patients operated on by osteoplastic approach. Obliteration materials used during years 1977-1994 have been ossar, collagen matrix and since 1990 bioactive glass. Although major differences between the obliteration materials could not be demonstrated the obliteration with bioactive glass has proven to be a safe and effective method for patients who did not show any improvement after endoscopic sinus surgery.

The value of computerised rhinomanometry and a simple manometry with saline in predicting the outcome of patients with acute trephined frontal sinusitis.

Infection of the anterior ethmoids and recessus frontalis causes swelling of the mucosa and obstruction of the nasofrontal duct, impairing the drainage of the frontal sinus. During the healing process the obstruction diminishes gradually. Prolongation of this process can lead to chronic infection of the nasofrontal region causing recurrent or chronic frontal sinusitis. In our everyday work we need a simple and reliable method to evaluate the patency of the nasofrontal duct, in order to be able to assess the recovery and to find those patients whose disease tends to become chronic. For this purpose we have measured the patency of the nasofrontal duct in 58 patients with frontal sinusitis after trephination with computerized rhinomanometry (RM) and with a simple salinemanometry (SM). The validity of the two methods to predict the further outcome of the patients has been compared in order to find out if SM would prove to be at least almost as reliable as rhinomanometry. Our statistics prove that SM is a useful aid in assessing the short-term recovery process of the patients. The long-term predictive value still remains to be seen.

Antiepileptic drug treatment during pregnancy and neonatal screening results.

Many antiepileptic drugs induce hepatic metabolic enzymes and thus enhance metabolism of steroid and thyroid hormones. Antiepileptic drugs readily cross the placenta and the foetal liver is metabolically active. We therefore evaluated the neonatal screening results of TSH and 17-hydroxyprogesterone in 34 study children and their matched controls. There were no statistically significant differences in the results between the groups.

Prediction of the clinical outcome of acute frontal sinusitis with ventilation measurement of the nasofrontal duct after trephination: a long-term follow-up study.

Acute frontal sinusitis has become an increasing clinical problem in the region that is served by the hospital represented by the authors of this study. The standard surgical treatment protocol after the failure of conservative therapy has been to perform trephination of the involved frontal sinus. More sophisticated procedures have been used in patients with prolonged or recurrent disease. The authors have developed a simple ventilation test of the nasofrontal duct that can be used to determine which patients require further surgery. In a long-term follow-up study of 85 patients, this ventilation test was shown to predict the cases that would heal uneventfully after trephination and the cases that would require further surgery because of an obstructed nasofrontal duct. The findings of this study are of special interest for modern functional endoscopic sinus surgery, the purpose of which is to open up the nasofrontal region.

Borrelia infection in children.

All children (less than or equal to 15 years) admitted during 1986 to Sachs Children's Hospital and presenting signs of facial palsy and/or meningitis, or with a history of known tick bite followed by headache, fatigue and muscle pain, were investigated for antibodies to Borrelia in serum and cerebrospinal fluid. (The hospital's catchment area has a high incidence of tick-borne Borrelia infections.) Significantly elevated antibody titre was found in 15 of the 33 patients, in three cases only in cerebrospinal fluid. Eight of the 15 children had facial palsy, which was concomitant with meningitis in six cases. Intravenous penicillin was given to all 15 patients with positive antibody titre, and additionally to three severely ill small children with facial palsy and meningitis. Furthermore, two cases of erythema chronicum migrans, which is considered pathognomonic for Borrelia infection, were treated with penicillin perorally. Cases of Borrelia infection occurred throughout the year, but with a peak in August. To emphasize the variety of symptoms, three cases are presented in some detail.

Marketing of obsolete antibiotics in Central America.

In 1977 the World Health Organisation published a list of essential drugs that would provide the basis for rational drug utilisation in developing countries. Only 16 antibiotics were included. A review of antibiotics marketed in Central America revealed that in only two of eight countries were less than 200 antibiotic drug products sold. At least a third of these were drug combinations of questionable value. Adequate information about adverse drug effects was frequently not provided to doctors in the manufacturers' drug descriptions. Furthermore compounds could be obtained without prescription. Thus there is a high potential risk for misuse of antibiotics in the countries studied which might be reduced by adhering to the principles outlined in the W.H.O. report on essential drugs.