[Rat bite fever in children]. / Rattenbeetziekte bij kinderen.

BACKGROUND: Worldwide, disease in children due to exposure to rats is increasing, also in the Netherlands. Not only the generally known pathogen Leptospira should be considered, also S. moniliformis, Yersinia pestis, Lymphocytic choriomeningitis virus, Hantavirus, Francisella tularensis and Pasteurella multocida are also known rat-associated zoonosis. CASE DESCRIPTION: An 12-year-old boy visited the pediatrician with fever, headache and nausea, followed by generalized erythema and arthritis. The boy had a pet rat. The patient's blood culture was positive for S. moniliformis. The patient was treated with antibiotics and made a full recovery. CONCLUSION: Just like many rat-associated diseases have 'rat-bite fever' caused by S. moniliformis an nonspecific clinical presentation. It is not necessary to have had a rat bite, to develop rat-bite fever. Better awareness and knowledge about rat related diseases should contribute to earlier diagnosis and treatment. Which is of great importance because of increased morbidity and mortality associated to rat related diseases.

The use of in-hospital guidelines for prevention of sudden unexpected postnatal collapse: A national survey.

AIM: Sudden unexpected postnatal collapse is a life-threatening event and may occur in any newborn infant. Safe skin-to-skin contact, and awareness of sudden unexpected postnatal collapse are key to its prevention. The aim of this study was to survey the presence of skin-to-skin contact and/or sudden unexpected postnatal collapse protocols in the 70 perinatal centres in the Netherlands. METHODS: We performed a survey among Dutch paediatricians to examine the safe skin-to-skin contact and sudden unexpected postnatal collapse protocols. RESULTS: We received data from 59/70 (85%) perinatal centres. At least one case of sudden unexpected postnatal collapse was reported in 35/59 (59%) of these centres. Nearly half the centres had safe skin-to-skin contact and/or sudden unexpected postnatal collapse protocols. Ultimately, 16 protocols were available for analysis. They showed considerable differences in the type of perinatal care provided. Most protocols lacked recently published insights on safe skin-to-skin contact. Besides, protocols failed to incorporate awareness of and knowledge on how to prevent sudden unexpected postnatal collapse. CONCLUSION: This study underlines the importance of drawing up uniform, multidisciplinary guidelines containing recommendations for the prevention of sudden unexpected postnatal collapse in the Netherlands.

[Infants with an unexplained event: management of brief resolved unexplained events revised]. / Zuigelingen met een kortdurend, onverklaard incident.

In this article, the new Dutch pediatric guideline Brief Resolved Unexplained Event is discussed, which replaces the old guideline Apparent Life Threatening Event. The main goal of the new guideline is identification of a group of low-risk infants who need not be admitted to the hospital and in which only limited diagnostic workup is indicated. Three fictional cases are presented to highlight the major changes in management of infants who present with an unexplained event. Application of the new guideline will likely result in less clinical admissions and diagnostic testing in these patients.

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

BACKGROUND: Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS: In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

Time-course analysis of 3-epi-25-hydroxyvitamin D3 shows markedly elevated levels in early life, particularly from vitamin D supplementation in preterm infants.

BACKGROUND: An epimeric form of 25-hydroxyvitamin D3 (25(OH)D3) has recently been detected in clinical samples, with relatively high levels in infants. Little is known on 3-epi-25(OH)D3 formation and physiological function. Our objective was to study dynamics of 3-epi-25(OH)D3 formation during infancy. METHODS: 25(OH)D3 and 3-epi-25(OH)D3 levels were measured by liquid chromatography-tandem mass spectrometry in 22 preterm (aged 34-37 wk), 15 early preterm (aged <34 wk), and 118 term infants up to 2 y of age. All infants were prescribed vitamin D 400 IU/day after the first week of life. RESULTS: At birth, 3-epi-25(OH)D3 levels were 3 (1-7) nmol/l, <10% of total 25(OH)D3. From the second week to 3 mo of age, both 25(OH)D3 and 3-epi-25(OH)D3 increased, with highest 3-epi-25(OH)D3 contribution in early preterm infants (up to 55% of total 25(OH)D3 vs. 36% in term infants, P < 0.0001). After 3 mo of age, 3-epi-25(OH)D3 normalized to <10% in all infants. CONCLUSIONS: At birth, all infants showed low contribution of 3-epi-25(OH)D3, increasing the week after starting vitamin D supplementation, until 3 mo of age. Highest levels of 3-epi-25(OH)D3 were found in early preterm infants, supporting the hypothesis that hepatic immaturity plays a role in 3-epi-25(OH)D3 formation.

Umbilical choline and related methylamines betaine and dimethylglycine in relation to birth weight.

BACKGROUND: Low birth weight (LBW) is associated with increased morbidity and mortality for the newborn and risk of chronic disease in adulthood. Choline plays an essential role in the integrity of cell membranes, methylation reactions, and memory development. We examined whether choline, betaine, and dimethylglycine (DMG) concentrations were associated with LBW in Dutch women. METHODS: Blood was sampled from umbilical cords (UCs) at delivery in singleton pregnancies (n = 1,126). Maternal blood was sampled at 30-34 wk of gestational age (GA) (n = 366). We calculated birth weights standardized for GA and defined LBW as standardized birth weight ≤ 2,500 g. RESULTS: Maternal concentrations were lower as compared with UC concentrations and were not associated with birth weight. UC choline and betaine were inversely associated with birth weight (ß = -60 (-89, -31) and ß = -65 (-94, -36), respectively), whereas UC DMG was positively associated with birth weight (ß = 35 (6.1, 63)). Odds ratios for LBW were 4.12 (1.15, 14.78), 5.68 (1.24, 25.91), and 0.48 (0.09, 2.65) for the highest UC choline, betaine, and DMG quartiles, respectively, as compared with the lowest quartiles. CONCLUSION: We observed an increased risk of LBW with increased umbilical choline and betaine in venous UC blood. These results might reflect a change in choline consumption or metabolism or a disturbed placental function.

[Additional recommendations for safe sleep to prevent SIDS]. / Aanvullende adviezen voor veilig slapen ter preventie van wiegendood.

Great progress has been made in reducing the incidence of SIDS in the Netherlands, but the number of SIDS cases has remained constant in recent years. The American Academy of Pediatrics has new guidelines for safe sleep. Existing recommendations remain valid such as (a) discouraging prone- and side-sleeping; (b) encouraging parent and child to sleep in one room but not in one bed; and (c) avoiding second-hand smoke. The new recommendations include: (a) pre-term neonates born after 32 weeks should be placed in a supine position; (b) twins should not sleep in the same bed ('co-bedding'); (c) use of a pacifier is recommended once breastfeeding is well underway; and (d) use of stabilization pillows is not recommended. There should also be an emphasis on educating parents before discharging their newborn from the hospital.

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

[Congenital toxoplasmosis: severe ocular and neurological complications]. / Congenitale toxoplasmose: ernstige oculaire en neurologische complicaties.

Two infants with congenital toxoplasmosis are presented. A girl born prematurely was treated postnatally after the mother had received antimicrobial treatment during pregnancy for acute toxoplasmosis. Apart from being small for gestational age, she remained without symptoms and treatment was ceased after 13 months. A 2-month-old boy presented with hydrocephalus and chorioretinitis, consistent with congenital toxoplasmosis. Despite antimicrobial treatment, at 12 months of age he suffered from epilepsy, cerebral palsy and vision impairment. Most infants with congenital toxoplasmosis (2 per 1000 live births in the Netherlands) are asymptomatic at birth. The education of pregnant women is crucial for the prevention of congenital toxoplasmosis. Awareness of antenatal and postnatal presenting signs and symptoms is important for clinicians, because early diagnosis and treatment may minimize sequelae. Untreated, the majority of affected infants will develop chorioretinitis, deafness and/or neurological symptoms.

Maternal homocysteine and related B vitamins as risk factors for low birthweight.

OBJECTIVE: We designed a large prospective study to explore the relationship between maternal homocysteine concentrations and related B vitamins and birthweight. STUDY DESIGN: Blood was sampled from pregnant women at 30-34 weeks of gestation and their newborn infants (n = 366). RESULTS: Concentrations of all analytes were higher in umbilical cord compared with maternal samples. Birthweight was related negatively to maternal homocysteine (r = -0.12) but not related to maternal cobalamin, methylmalonic acid, and folate (r = 0.02, r = 0.06, and r = 0.04, respectively). Regression analysis revealed smoking (beta = -313; 95% confidence interval [CI], -479 to -149), gestational age (beta = 150; 95% CI, 118-182), female sex (beta = -146; 95% CI, -256 to -35), and parity (beta = 104; 95% CI, 37-171) as strong determinants of birthweight. Maternal homocysteine, cobalamin, methylmalonic acid, and folate were not determinants of birthweight in multivariate analysis. CONCLUSION: Maternal homocysteine and B vitamins are not related to birthweight in a multivariate model that was adjusted for potential confounders.

Surveillance study of apparent life-threatening events (ALTE) in the Netherlands.

SIDS and ALTE are different entities that somehow show some similarities. Both constitute heterogeneous conditions. The Netherlands is a low-incidence country for SIDS. To study whether the same would hold for ALTE, we studied the incidence, etiology, and current treatment of ALTE in The Netherlands. Using the Dutch Pediatric Surveillance Unit, pediatricians working in second- and third-level hospitals in the Netherlands were asked to report any case of ALTE presented in their hospital from January 2002 to January 2003. A questionnaire was subsequently sent to collect personal data, data on pregnancy and birth, condition preceding the incident, the incident itself, condition after the incident, investigations performed, monitoring or treatment initiated during admission, any diagnosis made at discharge, and treatment or parental support offered after discharge. A total of 115 cases of ALTE were reported, of which 110 questionnaires were filled in and returned (response rate 97%). Based on the national birth rate of 200,000, the incidence of ALTE amounted 0.58/1,000 live born infants. No deaths occurred. Clinical diagnoses could be assessed in 58.2%. Most frequent diagnoses were (percentages of the total of 110 cases) gastro-esophageal reflux and respiratory tract infection (37.3% and 8.2%, respectively); main symptoms were change of color and muscle tone, choking, and gagging. The differences in diagnoses are heterogeneous. In 34%, parents shook their infants, which is alarmingly high. Pre- and postmature infants were overrepresented in this survey (29.5% and 8.2%, respectively). Ten percent had recurrent ALTE. In total, 15.5% of the infants were discharged with a home monitor. In conclusion, ALTE has a low incidence in second- and third-level hospitals in the Netherlands. Parents should be systematically informed about the possible devastating effects of shaking an infant. Careful history taking and targeted additional investigations are of utmost importance.

[Multidisciplinary guidelines for 'Apparent life threatening event' (ALTE)]. / Multidisciplinaire richtlijn 'Apparent life threatening event' (ALTE).

In order to reach a consensus concerning diagnosis, support and follow-up in children with an 'apparent life threatening event' (ALTE) multidisciplinary guidelines have been developed by the Dutch Paediatric Association and the Dutch Institute for Healthcare Improvement (CBO). All children presenting as an emergency with ALTE should undergo inpatient clinical observation for 24-72 h, with at least 24 h of cardio-respiratory monitoring. Observation does not need to be continued once an explanation for the incident has been established. The most common causes of ALTE are: gastro-oesophageal reflux (31%), neurological insult (11%) and lower respiratory tract infection (8%). Results from a targeted case history and from physical and neurological examination serve as a guideline for further investigations and support, in accordance with the formulated flowchart. A complete blood-count, CRP- and glucose concentration determination, blood-gas analysis and exploratory urine analysis should be carried out in all infants admitted with an ALTE, and an acute phase urine sample should be collected and frozen for possible metabolic investigation at a later date. Routine monitoring at home is not recommended following an ALTE.

Bed-sharing in the first four months of life: a risk factor for sudden infant death.

AIM: To investigate the risk of sudden infant death in the Netherlands during bed-sharing in the first half year of life and the protective effect of breastfeeding on it. METHODS: During a 10-year period between September 1996 and September 2006 nationwide, 213 cot deaths were investigated. RESULTS AND DISCUSSION: Of 138 cot deaths of less than 6 months of age, 36 (26%) bed-shared. In a reference group of 1628 babies from infant welfare centres only 9.4% were bed-sharing in the night prior to the interview. After correction for smoking of one or both parents the odds ratio for cot death during bed-sharing with parents decreased with age from 9.1 (CI 4.2-19.4) at 1 month, to 4.0 (CI 2.3-6.7) at 2 months, to 1.7 (CI 0.9-3.4) at 3 months and to 1.3 (CI 1.0-1.6) at 4 through 5 months of age. The excess risk (OR > 1) associated with bed-sharing is itself not significantly influenced by the presence or absence of breastfeeding. CONCLUSION: Bed-sharing is a serious risk factor for sudden infant death for all babies of less than 4 months of age. From 4 months onwards bed-sharing did not contribute significantly to the risk of cot death anymore in our study.

Allergic colitis presenting within the first hours of premature life.

UNLABELLED: A prematurely born infant developed rectal blood loss several hours after birth, after his first formula feeding. Discontinuing the feeding resolved symptoms, but after resuming feeding rectal blood loss reappeared. There were no signs of necrotizing enterocolitis. Suspecting cow's milk allergy, the feeding was changed to a casein-based protein hydrolysate, without effect. Meanwhile, laboratory tests indicated cow's milk allergy. Symptoms only resolved after introducing an amino acid-based formula supporting a definite diagnosis of cow's milk-induced allergic colitis. This is the first description of a premature infant with symptoms of allergic colitis, appearing within hours after birth, suggestive of intrauterine sensitization. The exact mechanisms of sensitization remain obscure. CONCLUSION: Cow's milk-induced allergic colitis can occur after the first feed, even in a prematurely born neonate. This is most probably due to intrauterine sensitization, and should be included in the differential diagnosis of rectal blood loss.

The incidence of congenital cytomegalovirus infections in The Netherlands.

Cytomegalovirus (CMV) is one of the most common causes of congenital infection without an effective treatment or an effective vaccine available to date. The emphasis has to be on preventive strategies, which rely on the epidemiological situation. The incidence of congenital CMV infections, however, is not known for The Netherlands. Therefore, a prospective virological study was carried out in a population of 7,524 pregnant women and 7,793 newborns. CMV-specific IgG antibodies were determined in cord blood by ELISA. When CMV antibodies were present, a CMV specific PCR was performed on the throat swab. A positive PCR was confirmed by urine culture. In addition, the seroepidemiology for CMV was investigated in the metropolitan region (Amsterdam and Rotterdam) which has a different ethnic composition. Congenital CMV infection was found in 7 infants (0.9 per 1,000). None had symptoms at birth or during 24 month follow-up. Carriage or CMV was 41%, with a variation between 35% and 100% depending on ethnicity. The ethnic composition in the south-eastern region was different from that in large cities, but similar to that in the rest of the country. The incidence of congenital CMV infections in The Netherlands is the lowest described to date, which does not justify special preventive policies.

Congenital cytomegalovirus infection after recurrent infection: case reports and review of the literature.

Cytomegalovirus (CMV) is one of the most common causes of congenital infections in developed countries with reported incidences varying between 0.15% and 2.0%. The effects of congenital CMV infection may vary from a congenital syndrome to an asymptomatic course. Infants that are asymptomatic at birth may still present handicaps at a later age. It is generally accepted that symptoms of congenitally infected children are more severe after primary infection than after recurrent infection. In this article, we present two case reports which demonstrate that the outcome of recurrent maternal CMV infection may be severe. In the first case, early pregnancy serology showed positive IgG and IgM, but negative IgA, whereas at the time of diagnosed fetal death, 5 weeks later, there was only positive IgG. The second case showed positive IgG and negative IgM and IgA both in early pregnancy and after delivery. Since in both cases CMV was isolated from several organs, these findings are compatible with recurrent rather than primary CMV infection. In the reported patients, fetal death and necrotising enterocolitis occurred after a congenital CMV infection, with mothers having pre-existing immunity to CMV. In conclusion, these case reports and review of the literature emphasise that the outcome of recurrent maternal CMV infection may be severe and that congenital CMV infection should be considered in cases of pregnancy loss and necrotising enterocolitis with recurrent maternal CMV infection.

A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency.

Mitochondrial beta-oxidation of long-chain fatty acids requires the concerted action of three tightly integrated membrane-bound enzymes (carnitine palmitoyltransferase I and II and carnitine/acylcarnitine translocase) that transport them into mitochondria. Neonatal onset of carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive, often lethal disorder of this transport. We describe a novel splice-site mutation in the CPT II gene, found in a Moroccan family, of which four out of five children have died from the neonatal form of CPT II deficiency. Mutation detection studies at the mRNA level in the CPT II gene implied that the affected children were homozygous for the previously reported 534T insertion followed by a 25-bp deletion (encompassing bases 534-558). Studies of genomic DNA, however, revealed all patients to be compound heterozygous for this 534T ins/del 25 mutation, and for a new g-->a splice-site mutation in the splice-acceptor site of intron 2. Because of these findings, prenatal diagnosis was performed in chorionic villi of three new pregnancies. This did not reveal new compound heterozygous genotypes, and, after uneventful pregnancies, all children appeared to be healthy. The new mutation is the first splice-site mutation ever identified in CPT II deficiency. The fact that it was not discovered in the patient's cDNA makes this study another example of the incompleteness of mutation detection at the mRNA level in cases where a mutation leads to aberrant splicing or nonsense-mediated messenger decay.

Seroprevalences of herpes simplex virus type 1 and type 2 among pregnant women in the Netherlands.

BACKGROUND: In the Netherlands 73% of cases of neonatal herpes are caused by herpes simplex virus type 1 (HSV-1), whereas in the United States a majority are caused by HSV type 2 (HSV-2). GOAL To understand this difference we undertook a seroepidemiological study on the prevalence of HSV-1 and HSV-2 among pregnant women. STUDY DESIGN: Type-specific antibodies to HSV-1 and HSV-2 were detected by enzyme-linked immunosorbent assay (ELISA) in serum samples from 1,507 pregnant women in Amsterdam, Rotterdam, and Nijmegen. RESULTS: The prevalence of HSV-1 was 61% in Nijmegen, 73% in Amsterdam, and 75% in Rotterdam. The prevalence of HSV-2 was 11% in Nijmegen, 35% in Amsterdam, and 27% in Rotterdam. CONCLUSION: The seroprevalence of HSV-1 and HSV-2 antibodies among pregnant women in the Netherlands shows significant geographical differences, which were attributed to ethnical variation. However, the epidemiologic differences did not correlate with the incidence of neonatal herpes in the Netherlands.