Ruurd M. van Elburg

Brain development of very preterm and very low‐birthweight children in childhood and adolescence: a meta‐analysis

Aim  The aim of this article was to clarify the impact and consequences of very preterm birth (born <32wks of gestation) and/or very low birthweight ([VLBW], weighing <1500g) on brain volume development throughout childhood and adolescence.

Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites.

INTRODUCTION:The use of azathioprine (AZA) in the treatment of autoimmune diseases during pregnancy are believed to be relatively safe, particularly taking into account the potential risks for mother and fetus should the underlying disease become active due to withdrawal of this thiopurine. However, essential evidence on the safety of AZA use during pregnancy is lacking. The determination of the intrauterine exposure to maternal AZA use may provide additional and crucial insights into the safety and teratogenicity of this drug.METHODS:We describe three patients with Crohns disease and autoimmune hepatitis who were treated with AZA throughout all trimesters of their pregnancies. Thiopurine metabolites (6-thioguaninenucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)) were measured in the red blood cells (RBC) of mother and infant directly after delivery.RESULTS:The 6-TGN concentration was slightly lower in the RBC of the infant than the mother. No 6-MMP could be detected in the infant.CONCLUSION:The placenta forms a (relative) barrier to AZA and its metabolites. Intrauterine exposure to 6-TGN may be minimized by careful therapeutic drug monitoring of the mother during pregnancy.

Neonatal respiratory morbidity following elective caesarean section in term infants. A 5-year retrospective study and a review of the literature.

Respiratory morbidity is an important complication of elective caesarean section. The presence of labour preceding caesarean section reduces the risk of neonatal respiratory morbidity. Recently, it has been shown that the incidence of respiratory morbidity is lower in infants with a gestational age of at least 39(+0) weeks at elective caesarean section compared to infants with a gestational age less than 39(+0) weeks.This article describes the results of a 5-year retrospective study on the incidence of respiratory distress in term neonates delivered by elective caesarean section in relation to gestational age and provides a literature review on neonatal respiratory morbidity following elective caesarean section.

High frequency of celiac disease in Down syndrome

We screened 115 children with Down syndrome for celiac disease, using antigliadin, antiendomysium, and antireticulin serum antibodies and an intestinal permeability test. Celiac disease was diagnosed in eight children, giving a frequency of 7.0%. We recommend screening for celiac disease in all persons with Down syndrome, with the use of at least the antiendomysium antibody determination.

Nosocomial Spread of a Staphylococcus capitis Strain with Heteroresistance to Vancomycin in a Neonatal Intensive Care Unit

ABSTRACT A premature infant in a neonatal intensive care unit (NICU) developed a bloodstream infection caused by coagulase-negative staphylococci (CoNS) sensitive to vancomycin. The infection persisted for 3 weeks, despite therapy with vancomycin and replacement of all intravenous catheters. The neonate died due to necrotizing enterocolitis which developed during the ongoing sepsis. We screened this strain and 216 other strains of CoNS from cultures of blood obtained from neonates between 1997 and 2000 for heteroresistance to vancomycin. Forty-eight isolates, including the strain that caused ongoing sepsis, proved heteroresistant. All isolates were identified as Staphylococcus capitis and were identical, just as their resistant stable subcolonies were, when they were genetically fingerprinted by amplified-fragment length polymorphism analysis. The heteroresistant phenotype of this endemic strain was confirmed by population analysis. We conclude that heteroresistance to vancomycin occurs in S. capitis and might be the cause of therapeutic failures in NICUs. Moreover, heteroresistant strains can become endemic in such units.

Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease

Objective Several studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using thiopurines, in order to determine the influence of pregnancy on thiopurine metabolism and to assess intrauterine exposure of the fetus to thiopurines. Design Female patients with IBD receiving steady-state thiopurines and planning a pregnancy were prospectively enrolled. 6-Thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations were determined, combined with routine laboratory tests, before, during and after pregnancy. Thiopurine metabolites were measured in umbilical cord blood immediately after delivery. Results Thirty patients who were using azathioprine (28 patients, median dose 1.93 mg/kg) or mercaptopurine (two patients, doses 1.32 and 0.94 mg/kg) were included. During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except one born with pancytopenia and high alkaline phosphatase activity; the mother of this infant had severe pre-eclampsia. All infants had normal Apgar scores, but 60% had anaemia at birth. No major congenital abnormalities were observed. Conclusions Pregnancy has a major effect on maternal thiopurine metabolism. In utero the unborn child is exposed to 6-TGN, but not to 6-MMP. Sixty per cent of the infants were born with anaemia, which raises the question whether infants should be tested for possible anaemia immediately after birth.

Predictive value of the Bayley Scales of Infant Development on development of very preterm/very low birth weight children: A meta-analysis

BACKGROUND AND AIMS The Bayley scales of infant development (BSID) is the most widely used measure to assess neurodevelopment of very preterm (gestational age ≤32 weeks) and very low birth weight (VLBW, ≤1500 g) infants in the first three years of life. This meta-analysis determines the predictive value of the mental developmental index (MDI) and the psychomotor developmental index (PDI)/motor composite, collectively referred to as Bayley motor scale, of the BSID-I, -II and Bayley-III for later cognitive and motor functioning in very preterm/VLBW children. METHODS Cochrane Library, PubMed, PsychINFO and CINAHL were searched for English-language peer-reviewed studies published before March 2013. Studies were included if they reported odds ratios or correlations between the MDI or Bayley motor scale scores obtained in the first three years of life, and standardized cognitive or motor assessment obtained later in life in very preterm/VLBW children. Meta-analytic methods were applied to aggregate available data. RESULTS A total of 16 studies met inclusion criteria. Across 14 studies (n=1330 children), MDI scores were strongly predictive for later cognitive functioning, r=0.61 (95% CI: 0.57-0.64), explained variance 37%, p<.001. The relationship between MDI scores and later cognitive function was not mediated by birth weight (p=.56), gestational age (p=.70), and time interval between assessments (p=.55). Across five studies (n=555 children), Bayley motor scale scores were moderately predictive for later motor function, r=0.34 (95% CI: 0.26-0.42), explained variance 12%, p<.001. CONCLUSIONS In very preterm/VLBW children, MDI scores explain 37% of the variance in later cognitive functioning, whereas Bayley motor scale scores explain 12% of later motor function. Thus a large proportion of the variance remains unexplained, underlining the importance of enhancing prediction of developmental delay in very preterm children.

Transplacental transport of IgG antibodies specific for pertussis, diphtheria, tetanus, haemophilus influenzae type b, and Neisseria meningitidis serogroup C is lower in preterm compared with term infants

Background: Maternal antibodies, transported through the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. The aim of this study was to measure the concentration of antibodies against several vaccine-preventable diseases in paired maternal and cord blood serum samples in preterm and term infants and to assess placental transfer ratios and infant antibody concentrations against vaccine-preventable diseases. Methods: Antibody concentrations specific against pertussis proteins (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae), diphtheria and tetanus toxins, and antibody concentrations specific against polysaccharides from Haemophilus influenzae type b and Neisseria meningitidis serogroup C were measured in cord blood samples from preterm (<32 weeks and 1500 g) and term infants and maternal serum samples, using a fluorescent bead-based multiplex immunoassay. Results: A total of 96 preterm and 42 term infants and their mothers were included in the study. Placental transfer ratios of antibodies against all vaccine antigens were significantly lower in preterm infants (medians varied from 0.26 to 0.86) compared with term infants (medians, 0.74–1.89; all antibodies P < 0.05). Furthermore, polysaccharide-vaccine–specific antibodies showed lower transplacental transport ratios than protein-vaccine–specific antibodies. Maternal concentrations are the most important determinants of infant antibody concentrations against vaccine-preventable diseases. Conclusions: Preterm infants benefit to a lesser extent from maternal antibodies against vaccine-preventable diseases than term infants, posing them at higher risk for infectious diseases in the first months of life.

Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study.

OBJECTIVES:Stressful events during early life have been suggested to play an important role in the development of the irritable bowel syndrome (IBS). In this study, we evaluate whether an exposure to severe wartime conditions during gestation and in early life are associated with an increased prevalence of IBS.METHODS:We assessed the prevalence of IBS using the Rome II questionnaire among 816 men and women (aged 58±1 years) who were born as term singletons in Wilhelmina Gasthuis, Amsterdam, The Netherlands around the time of World War II.RESULTS:Of a total of 816 participants, 9.6% (n=78, 52F) met the criteria for IBS. Exposure to severe wartime conditions in utero was not associated with the prevalence of IBS in adulthood (8.3%). Early-life exposure to severe wartime conditions was associated with an increased prevalence of IBS. The prevalence of IBS among individuals exposed up to 0.5 years of age, 1 year of age, and 1.5 years of age was 8.1%, 12.5%, and 15.3%, respectively. The increased IBS prevalence was not associated with an increased stress response.CONCLUSIONS:Our data indicate that exposure to severe wartime conditions in early life is associated with an increased risk of developing IBS. To what extent this is attributable to the stressful environment of war, to severe undernutrition, or to the increased prevalence of infectious diseases is, however, unclear.

Attention Problems of Very Preterm Children Compared with Age-Matched Term Controls at School-Age

OBJECTIVES To clarify the severity, specificity, and neurocognitive underpinnings of attention problems in very preterm children. STUDY DESIGN A sample of 66 preterm (<32 weeks gestation), mean (SD) age 7.5 (0.4) years, and 66 age-matched term controls participated. Symptoms of inattention were assessed using parent and teacher-rated questionnaires, and neurocognitive measures included speed and consistency in speed of information processing, lapses of attention (tau), alerting, orienting, and executive attention, as well as verbal and visuospatial working memory. Group differences were investigated using ANOVA, and Sobel tests were used to clarify the mediating role of neurocognitive impairments on attention problems. RESULTS There was a large decrease in visuospatial working memory abilities (P < .001, d = .87), and medium increases in tau (P = .002, d = 0.55) as well as parent and teacher ratings of inattention (range d = 0.40-0.56) in very preterm children compared with term peers. Tau and visuospatial working memory were significant predictors of parent (R(2) = .161, P < .001 and R(2) = .071, P = .001; respectively) and teacher (R(2) = .152, P < .001 and R(2) = .064, P = .002; respectively) ratings of inattention, and completely explained the effects of very preterm birth on attention problems. CONCLUSIONS Increased lapses of attention and poorer visuospatial working memory fully account for the attention problems in very premature children at school-age.