Influence of health insurance status on childhood cancer treatment outcomes in Kenya.

BACKGROUND: Survival of childhood cancer in high-income countries is approximately 80%, whereas in low-income countries, it is less than 10%. Limited access to health insurance in low-income settings may contribute to poor survival rates. This study evaluates the influence of health insurance status on childhood cancer treatment in a Kenyan academic hospital. METHODS: This was a retrospective study. All children diagnosed with a malignancy from 2010 until 2012 were included. Data on treatment outcomes and health insurance status at diagnosis were abstracted from patient charts. RESULTS: Of 280 patients, 34% abandoned treatment, 19% died, and 18% had progressive or relapsed disease resulting in 29% event-free survival. The majority of patients (65%) did not have health insurance at diagnosis. Treatment results differed significantly between patients with different health insurance status at diagnosis; 37% of uninsured versus 28% of insured patients abandoned treatment, and 24% of uninsured versus 37% of insured patients had event-free survival. The event-free survival estimate was significantly higher for patients with health insurance at diagnosis compared with those without (P = 0.004). Of patients without health insurance at diagnosis, 77% enrolled during treatment. Among those patients who later enrolled in health insurance, frequency of progressive or relapsed disease and deaths was significantly lower (P = 0.013, P < 0.001, respectively), while the event-free survival estimate was significantly higher (P < 0.001) compared with those who never enrolled. CONCLUSION: Childhood cancer event-free survival was 29% at a Kenyan hospital. Children without health insurance had significant lower chance of event-free survival. Childhood cancer treatment outcomes could be ameliorated by strategies that prevent treatment abandonment and improve access to health insurance.

A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation.

Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.

Association of placental weight with cerebral palsy: population-based cohort study in Norway.

OBJECTIVE: To study the risk of cerebral palsy (CP) associated with placental weight, and also with placental weight/birthweight ratio and placental weight/birth length ratio. DESIGN: Population-based cohort study. SETTING: Perinatal data in the Medical Birth Registry of Norway were linked with clinical data in the CP Register of Norway. POPULATION: A total of 533 743 singleton liveborn children in Norway during 1999-2008. Of these, 779 children were diagnosed with CP. METHODS: Placental weight, placental weight/birthweight ratio, and placental weight/birth length ratio were grouped into gestational age-specific quartiles. Odds ratios (OR) with 95% confidence intervals (95% CI) for CP were calculated for children with exposure variables in the lowest or in the highest quartile, using the second to third quartile as the reference. MAIN OUTCOME MEASURES: CP and CP subtypes. RESULTS: Overall, children with low placental weight had increased risk for CP (OR 1.5, 95% CI 1.2-1.7). Low placental weight/birthweight ratio (OR 1.2, 95% CI 1.0-1.4) and low placental weight/birth length ratio (OR 1.5, 95% CI 1.2-1.8) were also associated with increased risk for CP. In children born at term, low placental weight was associated with a twofold increase in risk for spastic bilateral CP (including both quadriplegia and diplegia) (OR 2.1, 95% CI 1.5-2.9). In children born preterm, high placental ratios were associated with increased risk for spastic quadriplegia. CONCLUSIONS: Our results suggest that placental dysfunction may be involved in causal pathways leading to the more severe subtypes of CP. TWEETABLE ABSTRACT: Low placental weight increases the risk for cerebral palsy, especially for the spastic bilateral subtype.

Factors influencing time to diagnosis and treatment among pediatric oncology patients in Kenya.

Early diagnosis and start of treatment are fundamental goals in cancer care. This study determines the time lag and the factors that influence the time to diagnosis and start of treatment. Study participants were parents of childhood cancer patients diagnosed between August 2013 and July 2014 in a hospital in Kenya. Patient, physician, diagnosis, treatment, health care system, and total delay were explored using a questionnaire. Demographic and medical data were collected from the patients' medical records. Parents of 99 childhood cancer patients were interviewed (response rate: 80%). Median total delay was 102 (9-1021) days. Median patient delay (4 days) was significantly shorter than health care system delay (median 87 days; P < .001). Diagnosis delay (median 94 days) was significantly longer than treatment delay (median 6 days; P < .001). days. Lack of health insurance at diagnosis and use of alternative medicine before attending conventional health services were associated with a significantly longer patient delay (P = .041 and P = .017, respectively). The type of cancer had a significant effect on treatment delay (P = .020). The type of health facility attended affected only patient delay (P = .03). Gender, age at diagnosis, stage of disease, parents' education level or income, and distance from hospital did not have a significant effect on the length of any type of delay. Training on childhood cancer should be included in the curricula for medical training institutes. In-service workshops should be held for the health workers already working. Families must be obligated to get health insurance. Families should be encourage to attend conventional health facilities and informed on symptoms of cancer through mass media.

Bone mineral density and vitamin D status in ambulatory and non-ambulatory children with cerebral palsy.

UNLABELLED: This study assessed distal femur and lumbar spine bone mineral density (BMD) Z-scores in children with cerebral palsy. BMD z-score was lower in non-ambulatory than in ambulatory children. Somewhat surprisingly, among ambulatory children, those with better walking abilities had higher BMD z-score than those with more impaired walking ability. INTRODUCTION: Children with cerebral palsy (CP) have increased risk for low bone mineral density (BMD). The aim was to explore the difference in BMD at the distal femur and lumbar spine between ambulatory and non-ambulatory children with CP and the relationship between vitamin D status and BMD. METHODS: Fifty-one children (age range 8-18 years; 20 girls) with CP participated. Their BMD Z-scores were measured in the lumbar spine and the distal femur using dual X-ray absorptiometry, and 25-hydroxy-vitamin D (25-OHD) concentrations were measured in serum. Children with GMFCS level I-III were defined as 'walkers' while children with level IV-V were defined as 'non-walkers. RESULTS: Non-walkers had lower mean BMD Z-scores (range -1.7 to -5.4) than walkers at all sites (range -0.8 to -1.5). Among walkers, BMD Z-scores at the distal femur were lower in those with GMFCS level II than with level I (p values < 0.004). A similar difference was found between the affected and unaffected limb in children with hemiplegia. Mean 25-OHD concentration was 45 nmol/L (SD = 18); lower in walkers (mean = 41 nmol/L; SD = 18) than in non-walkers (mean = 53 nmol/L; SD = 19; p = 0.041). There were no correlations between 25-OHD and BMD z-scores. CONCLUSIONS: The main predictor of low BMD Z-scores in the distal femur was the inability to walk, but the results suggest that the degree of the neuromotor impairment may also be a significant predictor. Vitamin D status did not correlate with BMD z-scores.

Thrombophilia testing in children: a 7 year experience.

BACKGROUND: Incidence of venous thromboembolism (VTE) in children is reported to be increasing. We examined thrombophilia testing results in children with VTE that presented in inpatient and outpatient settings to explore patterns of thrombophilia testing. PATIENTS/METHODS: Children, ages 0-20 years with VTE seen at our institution from Jan 2005 to Apr 2012 were studied retrospectively. All patients with VTE confirmed by imaging were eligible and the presence of significant risk factors was evaluated. Thrombophilia was diagnosed if >1 tests confirmed: persistently low protein C (PC), protein S (PS), and antithrombin (AT) following VTE resolution, persistent antiphospholipid antibodies (APA) positivity >12 weeks from first test, factor V Leiden (FVL) and prothrombin mutation (PTm) hetero- or homozygosity, elevated plasminogen activator inhibitor (PAI-1) levels with 4G/5G or 4G/4G polymorphisms, methylene tetrahydrofolate reductase (MTHFR) polymorphisms with elevated fasting homocysteine levels. RESULTS: Three hundred ninety-two patients met inclusion criteria. At least one test was ordered in 157/239 inpatients. All 153 outpatients had >1 test ordered. Thrombophilia rate differences between inpatients and outpatients did not reach statistical significance except for PC deficiency, which was significantly higher in outpatients. Of inpatients, central venous line (CVL) was significantly associated with not having tests done (P < 0.0022). CONCLUSIONS: This study of pediatric VTE demonstrated a low thrombophilia rate in both inpatient and outpatient populations. The role of testing in other pediatric patients should be further explored.

Cytomegalovirus antibody status at 17-18 weeks of gestation and pre-eclampsia: a case-control study of pregnant women in Norway.

OBJECTIVE: To assess the association between maternal cytomegalovirus (CMV) antibodies in mid-pregnancy and pre-eclampsia. DESIGN: Nested case-control study. SETTING: Pregnancies registered in the Norwegian Mother and Child Cohort Study (MoBa): a large population-based pregnancy cohort (1999-2006). SAMPLE: A cohort of 1500 women with pre-eclampsia and 1000 healthy pregnant women. METHODS: Plasma samples and pregnancy-related information were provided by the MoBa. Antibody status (CMV IgG and CMV IgM) and levels (CMV IgG) at 17-18 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME MEASURE: A diagnosis of pre-eclampsia, as defined in the Medical Birth Registry of Norway. RESULTS: There was no evidence of an effect of CMV IgG seropositivity on the likelihood of developing pre-eclampsia, and CMV IgG antibody levels among women who were seropositive did not differ between groups. Adjusted for maternal age, parity and smoking, the odds ratio for pre-eclampsia in women seropositive for CMV IgG was 0.89 (95% CI 0.74-1.05; P = 0.17). The proportions of women who were seropositive for IgM did not differ between women with pre-eclampsia and women who were healthy (P = 0.98). Among nulliparous women, the proportion of women who were seropositive for CMV IgG was slightly lower among women with pre-eclampsia (53.5%) than among healthy women (59.8%) (P = 0.03). Subgroup analyses were performed for women with early or late onset pre-eclampsia, with preterm delivery and/or with neonates that were small for gestational age, but antibody status did not differ between pre-eclampsia subtypes and controls. CONCLUSIONS: The presence of maternal antibodies to CMV was not associated with pre-eclampsia in our study. The results suggest that CMV infection is unlikely to be a major cause of pre-eclampsia.

Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.

Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21(ras) (Ras) proteins by accelerating the hydrolysis of active Ras-guanosine triphosphate to inactive Ras-guanosine diphosphate. Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile chronic myelogenous leukemia (JCML) and other malignant myeloid disorders, and heterozygous Nf1 knockout mice spontaneously develop a myeloid disorder that resembles JCML. Both human and murine leukemias show loss of the normal allele. JCML cells and Nf1-/- hematopoietic cells isolated from fetal livers selectively form abnormally high numbers of colonies derived from granulocyte-macrophage progenitors in cultures supplemented with low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). Taken together, these data suggest that neurofibromin is required to downregulate Ras activation in myeloid cells exposed to GM-CSF. We have investigated the growth and proliferation of purified populations of hematopoietic progenitor cells isolated from Nf1 knockout mice in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF), as well as to GM-CSF. We found abnormal proliferation of both immature and lineage-restricted progenitor populations, and we observed increased synergy between SCF and either IL-3 or GM-CSF in Nf1-/- progenitors. Nf1-/- fetal livers also showed an absolute increase in the numbers of immature progenitors. We further demonstrate constitutive activation of the Ras-Raf-MAP (mitogen-activated protein) kinase signaling pathway in primary c-kit+ Nf1-/- progenitors and hyperactivation of MAP kinase after growth factor stimulation. The results of these experiments in primary hematopoietic cells implicate Nf1 as playing a central role in regulating the proliferation and survival of primitive and lineage-restricted myeloid progenitors in response to multiple cytokines by modulating Ras output.

Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method.

Infants with low birth weight are at increased risk of perinatal brain injury. Disruption of normal cortical development may have consequences for later motor, behavioural and cognitive development. The aim of this study was to measure cerebral cortical thickness, area and volume with an automated MRI technique in 15-year-old adolescents who had low birth weight. Cerebral MRI for morphometric analysis was performed on 50 very low birth weight (VLBW, birth weight

Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients.

Complementary DNA encoding three catalytic subunits of protein phosphatase 1 (PP1 alpha, PP1 beta, and PP1 gamma) and the insulin-stimulated protein kinase 1 (ISPK-1) was analyzed for variations in the coding regions related to insulin-resistant glycogen synthesis in skeletal muscle of 30 patients with non-insulin-dependent diabetes mellitus (NIDDM). The human ISPK-1 cDNA was cloned from T-cell leukemia and placental cDNA libraries and mapped to the short arm of the human X chromosome. Single-strand conformation polymorphism (SSCP) analysis identified a total of six variations in the coding regions of the PP1 genes: two in PP1 alpha at codons 90 and 255; one in PP1 beta at codon 67; and three in PP1 gamma at codons 11,269, and 273, respectively. All were, however, silent single nucleotide substitutions. SSCP analysis of the ISPK-1 gene identified one silent polymorphism at codon 266 and one amino acid variant at codon 38 (Ile-->Ser). This variant was primarily found in one male NIDDM patient. This subject, however, did not exhibit an impairment of muscle insulin-stimulated glycogen synthase activation. No significant differences were found in mRNA levels in muscle of the four genes between 15 NIDDM patients and 14 healthy subjects. Our findings suggest that 1) genetic abnormalities in the coding regions of PP1 alpha, PP1 beta, PP1 gamma, and ISPK-1 are unlikely to be frequently occurring causes of the reduced insulin-stimulated activation of the glycogen synthesis in muscle from the analyzed group of NIDDM patients; 2) the mRNA levels of PP1 alpha, PP1 beta, PP1 gamma, and ISPK-1 are normal in muscle from the NIDDM patients; and 3) putative inherited defects in insulin-stimulated activation of muscle glycogen synthesis in patients with insulin-resistant NIDDM may be located further upstream of ISPK-1 in the insulin action cascade.

Omega-3 fatty acids: essential fatty acids with important biological effects, and serum phospholipid fatty acids as markers of dietary omega 3-fatty acid intake.

Serum phospholipid eicosapentaenoic (PL-EPA) and docosahexaenoic acid (PL-DHA) concentrations are associated with the dietary intake of omega 3 fatty acids. PL-EPA and PL-DHA concentrations measured 4 y apart in 211 diabetic patients were highly correlated, with Spearman correlation coefficients of 0.49 (p = 0.0001) and 0.64 (p = 0.0001), respectively. PL-DHA was positively associated with Bayley psychomotor and mental developmental indexes (PDI and MDI, respectively) in preterm infants. Using multiple-regression analysis, 64% (R2 = 0.639; p = 0.0001) of PDI variance was explained by 1/DHA and weight at 1 y, whereas 82% (R2 = 0.816; p = 0.0001) of MDI variance was explained by weight at 1 y, Apgar score, 1/DHA, and 1/EPA. 1/DHA was negatively correlated with PDI and MDI, whereas 1/EPA was positively correlated with MDI. The results suggest that infant formulas should contain preformed DHA, and that a too-high supply of EPA in addition to DHA might be harmful in preterm infants.

Primary hepatic B-cell lymphoma in a child.

Lymphoma arising in the liver is uncommon in adults and rare in children. A 12-year-old boy with hepatomegaly and jaundice had a calcified intrahepatic large-cell lymphoma of B-cell origin that expressed bcl-2 protein and had near-tetraploid chromosome number with a t(8;14) (q24;q32) and a homogeneously staining region (HSR). This tumor, only the fourth example of primary hepatic lymphoma in a child, has the rare finding of an HSR before treatment and is the first human lymphoma with t(8;14) that expresses bcl-2 protein. In addition, the demonstration of extensive calcification in the tumor by computed tomography scan is highly unusual for lymphoma. Lymphoma must be considered in the differential diagnosis of primary liver tumors in children and adults, especially if the serum alpha-fetoprotein level is normal.

Growth factor stimulation of hematopoietic cells leads to membrane translocation of AKT1 protein kinase.

AKT1 is the human homolog of the v-akt oncogene. AKT1 has two distinct protein domains, one serine/threonine kinase domain and one pleckstrin homology (PH) domain. We studied the expression and activity of AKT1 in hematopoietic cell lines. The expression of AKT1 was constitutive in hematopoietic cells of various stages of development. In the growth factor dependent MO7e cells, serum and growth factor starvation resulted in an early 50% fall in activity which was maintained over 24 h. Treatment of cells which growth factors or agents which induce differentiation activated AKT1. The subcellular localization of AKT1 in MO7e cells was altered as it was activated. High AKT1 kinase activity was associated with membrane fractions in stimulated cells, in contrast to the much lower AKT1 activity in membranes of cells starved of serum and growth factor for 1 h. These results demonstrate AKT1 kinase activity and its regulation by extracellular signaling factors in vivo in hematopoietic cells, and suggest that the activation of AKT1 involves intracellular translocation of the kinase from cytosol to membrane.

The activity of gamma-glutamyltransferase after bile duct ligation in guinea pig.

The activity of gamma-glutamyltransferase was studied in guinea pig after bile duct ligation. In serum, an abrupt increase in activity up to 10--20 times the normal value was found 3 h after obstruction and the mean activity over the first 3 days following the operation was some 8 times the normal value. In liver, however, a small decline in activity could be demonstrated. The administration of cycloheximide did not influence the acute increase in serum activity. Bile duct ligation caused marked increases in serum bile acid levels which initially paralleled the serum gamma-glutamyltransferase activity. It is suggested that the increased serum activity may arise from the solubilization by bile acids of liver membrane-bound enzyme.

Morbidity during the first year of life in small for gestational age infants.

Postneonatal morbidity during infancy was studied in 284 small for gestational age (SGA) and 359 non-SGA term infants. None of these babies had congenital malformations and they were born to para 1 and para 2 mothers. SGA infants had an increased risk (OR: 1.7, 95% confidence interval: 1.1-2.6) of being admitted to hospital compared with non-SGA infants. The principal cause was respiratory tract infections. Increased hospitalisation among SGA infants was a factor only if the mother was a smoker-that is, smoked cigarettes at the time of conception. Among subgroups of SGA babies, there was an increased risk for infants of non-repeaters (women without a previous SGA child) (OR: 2.4, 95% CI: 1.4-3.8) and for infants with symmetric (OR: 2.0, 95% CI: 1.2-3.3) body proportions compared with non-SGA infants. The results suggest that, beginning in early pregnancy, growth retardation may have long term consequences for subsequent infant morbidity, particularly if the mother is smoker.

Psychiatric symptoms and disorders in adolescents with low birth weight.

OBJECTIVE: To evaluate the prevalence of psychiatric symptoms and disorders associated with low birth weight.Design/study groups: A population based follow up study of 56 very low birthweight (VLBW: birth weight < or = 1500 g), 60 term small for gestational age (SGA: birth weight < 10th centile), and 83 term control (birth weight > or = 10th centile) children at 14 years of age. OUTCOME MEASURES: Schedule for affective disorders and schizophrenia for school aged children, attention deficit/hyperactivity disorder (ADHD) rating scale IV, autism spectrum screening questionnaire, and children's global assessment scale. RESULTS: VLBW adolescents had a higher prevalence of psychiatric symptoms (46%) than controls (13%) (odds ratio (OR) 5.7, 95% confidence interval (CI) 2.5 to 13.0) and more psychiatric disorders (25%) than controls (7%) (OR 4.3, 95%CI 1.5 to 12.0), especially anxiety disorders. Although 25% of the VLBW adolescents had attention problems, ADHD was diagnosed in only 7%. Four VLBW adolescents had symptoms of Asperger's disorder, and the VLBW group had a higher sum score than controls on the autism spectrum screening questionnaire. Although more SGA adolescents had psychiatric symptoms than controls (23% v 13%), the difference was not statistically significant. Results remained essentially the same when adolescents with low estimated intelligence quotient were excluded, and persisted after possible psychosocial confounders had been controlled for. CONCLUSION: VLBW, but not SGA adolescents, have a high risk of developing psychiatric symptoms and disorders by the age of 14, especially attention deficit, anxiety symptoms, and relational problems.

Motor skills in adolescents with low birth weight.

BACKGROUND: Minor motor problems have been reported in low birthweight children, but few studies have assessed motor skills in adolescents. OBJECTIVE: To examine the prevalence of motor problems in adolescents with low birth weight. METHOD: Fifty four very low birthweight (VLBW: birth weight < or = 1500 g), 59 term small for gestational age (SGA: birth weight < 10th centile), and 83 control (birth weight > or = 10th centile at term) children were assessed with the Movement assessment battery for children (Movement ABC) at the age of 14 in a population based study. RESULTS: One in four VLBW children (odds ratio (OR) 9.3, 95% confidence interval (CI) 2.5 to 34.5) and one in six SGA children (OR 4.7, 95%CI 1.2 to 18.4) had motor problems compared with controls (3.7%). There were no sex differences in motor problems in the VLBW group, and the increased risk was consistent across the continuum of the Movement ABC. For SGA children, the increased risk of motor problems was particularly in manual dexterity in boys. CONCLUSION: VLBW and SGA adolescents have increased risk of motor problems compared with control children.

Pre- and post-natal growth in children of women who smoked in pregnancy.

Pre- and post-natal growth was studied from week 17 of pregnancy until 5 years of age in children of women who reported daily smoking at the time of conception, and compared to the growth in children of non-smokers. Fetal abdominal diameter, femur length and biparietal diameter were measured in weeks 17 and 37 of pregnancy, and weight, height and head circumference were measured at birth, and at 6, 13 and 60 months of age in 185 children of smokers and 345 children of non-smokers. Cross sectional data at birth showed that infants of smokers had lower weight and length, but similar ponderal index as infants of non-smokers and this may suggest a symmetrical growth retardation. Longitudinal growth curves indicated that the growth retardation took place in the second half of pregnancy. During the first 5 years of life, children of smokers had complete catch-up growth in weight, a partial catch-up in height, and no catch-up growth in head circumference. At 5 years, children of smokers had a higher ponderal index and skinfold thickness, suggesting that these children, on average, were more obese than children of non-smokers.

Prenatal growth in symmetric and asymmetric small-for-gestational-age infants.

We tested the hypothesis that growth retardation in symmetric small-for-gestational-age (SGA) infants may start in the first trimester of pregnancy, whereas in asymmetric SGA infants, it may start in the third trimester. We also examined if there may be a brain sparing effect in asymmetric SGA infants. Infants were classified as symmetric or asymmetric SGA infants, and 474 non-SGA infants. Intrauterine growth was assessed by prenatal ultrasonic measurements of fetal abdominal diameter, femur length and biparietal diameter at week 17, 25, 33 and 37 of gestation. Cross-sectional data as well as longitudinal growth curves suggested that growth retardation in both SGA groups started in the second trimester, and followed similar patterns until birth. Thus, our results did not support the hypothesis that symmetric and asymmetric growth retardation is associated with clear temporal differences in growth, and we found no sign of brain sparing in asymmetric compared to symmetric SGA infants.

Smoking in pregnancy and children's mental and motor development at age 1 and 5 years.

We used data from a Scandinavian prospective multicenter study to investigate if smoking in pregnancy may have an adverse effect on the child's mental and motor abilities. Eligible for enrolment were para I and 2 women with a singleton pregnancy, who resided in one of the study areas and could be registered before the 20th gestational week. Women were classified as 'smokers' or 'non-smokers' at study start. At 13 months, 376 children (124 children of smokers) were evaluated with the Bayley Scales of Infant Development. At this age, children of smokers and non-smokers performed equally well. At 5 years, 369 children (132 children of smokers) were tested with the Wechsler Preschool and Primary Scales of Intelligence Revised (WPPSI-R), and 362 children with the Peabody Developmental Motor Scales (PDMS). Children of smokers had an increased risk of getting a WPPSI-R score below the median value of the population (OR = 2.1, 95% CI: 1.2-3.3), but the risk was reduced when we adjusted for maternal education (OR = 1.6, 95% CI: 0.9-3.7). Children of smokers had an increased risk of getting a test score below the median population value on the subscale 'balance' from PDMS (OR = 1.8, 95% CI: 1.2-2.8). Thus, we found that smoking in pregnancy was associated with a small, but demonstrable adverse effect on the child's balance at 5 years, whereas the negative effect on cognitive function did not reach statistical significance, when we adjusted for the mother's level of education.