Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.

Adverse effect of lockdowns during the COVID-19 pandemic: increased incidence of pediatric crisis admissions due to eating disorders and adolescent intoxications.

During the COVID-19 pandemic, countries imposed (partial) lockdowns that reduced viral transmission. However, these interventions may have unfavorable effects on emotional and psychological well-being. The aim of this study was to quantify possible adverse effects of the COVID-19 pandemic on psychological wellbeing in children and adolescents. Hospital admission data between January 2017 and September 2021 from eight general hospitals in the Netherlands was collected, comparing the incidences of sub-categorized psychological diagnoses, more specifically eating disorders, intentional intoxications, accidental intoxications, and excessive crying, before (2017-2019) and during the pandemic (2020-2021). Data was summarized per month and per year, and the years 2020 and 2021 were compared to 2017-2019. The relative increase or decrease in diagnoses since the start of the pandemic was calculated. Overall pediatric hospital admissions decreased with 28% since the start of the pandemic. Non-infectious diagnoses showed a decrease of 8%. Of these non-infectious diagnoses, overall psychosocial admissions were increased (+ 9%), mostly caused by an increase in admissions for eating disorders (+ 64%) and intoxications in adolescents (+ 24%). In addition, the proportion of admissions due to psychosocial diagnoses increased post-pandemic (6% vs 4%, p < 0.001). Overall admissions for intoxications in children (- 3%) and excessive crying (- 1%) did not increase, although peaks in incidence were found at the start of the second lockdown. CONCLUSION: During the COVID-19 pandemic, admission rates for eating disorders and intentional intoxications showed a substantial increase, indicating a high burden of pediatric psychiatric diseases. WHAT IS KNOWN: • The COVID-19 pandemic has had an impact on psychosocial wellbeing in children and adolescents. WHAT IS NEW: • There was an increase in admissions due to psychosocial problems in the Netherlands in the period after the pandemic. • This was mainly caused by an increase in crisis admissions due to eating disorders and intoxications in adolescents.

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours.

Cost impact of procalcitonin-guided decision making on duration of antibiotic therapy for suspected early-onset sepsis in neonates.

BACKGROUNDS: The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. METHODS: Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. RESULTS: In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category 'infection unlikely' and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age < 37 weeks in the Czech Republic. CONCLUSIONS: Health care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category 'infection unlikely,' and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs.

The impact of lockdown on pediatric ED visits and hospital admissions during the COVID19 pandemic: a multicenter analysis and review of the literature.

The coronavirus disease 2019 pandemic has enormous impact on society and healthcare. Countries imposed lockdowns, which were followed by a reduction in care utilization. The aims of this study were to quantify the effects of lockdown on pediatric care in the Netherlands, to elucidate the cause of the observed reduction in pediatric emergency department (ED) visits and hospital admissions, and to summarize the literature regarding the effects of lockdown on pediatric care worldwide. ED visits and hospital admission data of 8 general hospitals in the Netherlands between January 2016 and June 2020 were summarized per diagnosis group (communicable infections, noncommunicable infections, (probable) infection-related, and noninfectious). The effects of lockdown were quantified with a linear mixed effects model. A literature review regarding the effect of lockdowns on pediatric clinical care was performed. In total, 126,198 ED visits and 47,648 admissions were registered in the study period. The estimated reduction in general pediatric care was 59% and 56% for ED visits and admissions, respectively. The largest reduction was observed for communicable infections (ED visits: 76%; admissions: 77%), whereas the reduction in noninfectious diagnoses was smaller (ED visits 36%; admissions: 37%). Similar reductions were reported worldwide, with decreases of 30-89% for ED visits and 19-73% for admissions.Conclusion: Pediatric ED utilization and hospitalization during lockdown were decreased in the Netherlands and other countries, which can largely be attributed to a decrease in communicable infectious diseases. Care utilization for other conditions was decreased as well, which may indicate that care avoidance during a pandemic is significant. What is Known: • The COVID-19 pandemic had enormous impact on society. • Countries imposed lockdowns to curb transmission rates, which were followed by a reduction in care utilization worldwide. What is New: • The Dutch lockdown caused a significant decrease in pediatric ED utilization and hospitalization, especially in ED visits and hospital admissions because of infections that were not caused by SARS-CoV-2. • Care utilization for noninfectious diagnoses was decreased as well, which may indicate that pediatric care avoidance during a pandemic is significant.

Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns).

BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION: Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

Deletion of the entire interferon-γ receptor 1 gene causing complete deficiency in three related patients.

PURPOSE: Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene. METHODS: Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-γ to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL-12p40) and IL-10. Expression of IFN-γR1 on the cell membrane of patients' monocytes was assessed using flow cytometry. IFNGR1 transcript was analyzed in RNA and the gene and adjacent regions were analyzed in DNA. Finally, IL22RA2 transcript levels were analyzed in whole blood cells and dendritic cells. RESULTS: There was no expression of the IFN-γR1 on the monocytes. Consistent with this finding, there was no IFN-γ response in the whole blood assay as measured by effect on LPS-induced IL-12p40, TNF and IL-10 production. A 119.227 nt homozygous deletion on chromosome 6q23.3 was identified, removing the IFNGR1 gene completely and ending 117 nt upstream of the transcription start of the IL22RA2 gene. Transcript levels of IL22RA2 were similar in patient and control. CONCLUSIONS: We identified the first large genomic deletion of IFNGR1 causing complete IFN-γR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription and, therefore, may not have any additional clinical consequence.

Validation of the pharmacokinetic model for anti- TNFα clearance in infants exposed to anti- TNFα during pregnancy.

BACKGROUND AND AIMS: ECCO guideline recommend postponing live attenuated vaccines in infants exposed to anti-Tumor Necrosis Factor alpha (anti-TNFα) in utero until drug clearance. The aim was to validate the predictive performance of the anti-TNFα clearance model. METHODS: Newborns and anti-TNFα concentrations from the prospective PETIT cohort were included. The anti-TNFα clearance model was used to predict all measured concentrations in the PETIT cohort, based on the measured cord blood concentration and the mean population clearance described in the model. Bayesian maximum a posteriori optimization was used to estimate the value of drug monitoring. Predictive capability and drug monitoring were assessed through Mean Absolute Error (MAE), Root mean Squared Prediction Error and Limits of Agreement according to Bland and Altman. RESULTS: Observed drug concentrations after birth were within the 80% prediction interval in 94% of adalimumab samples and 93% of infliximab samples. The anti-TNFα clearance model accurately predicted the concentration at six months after birth with an MAE of 0.03 (SD 0.03) µg/mL for adalimumab and 0.11 (SD 0.18) µg/mL for infliximab based on cord blood concentrations. Addition of an additional sample between 1 and 4 months after birth improved the predictive accuracy for infliximab (MAE 0.05 (SD 0.09)) but not for adalimumab. Guidance for use in clinical practice was formulated. CONCLUSIONS: The validity of the anti-TNFα clearance model is high, and hence can be used to guide clinicians regarding timing of live vaccines in infants exposed to adalimumab or infliximab in utero.

Effect of lockdowns on the epidemiology of pediatric respiratory disease-A retrospective analysis of the 2021 summer epidemic.

BACKGROUND: The imposition of lockdowns during the severe acute respiratory syndrome coronavirus-2 pandemic led to a significant decrease in pediatric care utilization in 2020. After restrictions were loosened, a surge in pediatric respiratory disease was observed in pediatric wards. The aim of this study was to quantify the effect of the lockdown(s) on the incidence of pediatric respiratory disease. METHODS: For this multicenter retrospective study, emergency department (ED) visit and admission data between January 2017 and September 2021 was collected from eight general hospitals in the Netherlands. Clinical diagnoses were extracted and categorized in groups ("communicable infectious disease," "all respiratory infections," "upper respiratory tract infection," "lower respiratory tract infection," and "asthma/preschool wheezing"). The incidence of admissions and ED visits during 2020 and 2021 was compared to the incidence in 2017-2019. RESULTS: Successive lockdowns resulted in a maximum decrease of 61% and 57% in ED visits and admissions, respectively. After loosening restrictions during the summer of 2021, a 48% overall increase in ED visits and 31% overall increase in admission numbers was observed in July compared to the average July in 2017-2019. This was explained by a 381% increase in ED visits and a 528% increase in ward admissions due to overall respiratory infections, mainly due to lower respiratory tract infections. CONCLUSIONS: Successive lockdowns in the spring and winter of 2020 and 2021 led to a decreased incidence of communicable infections, especially respiratory tract infections. The resulting lack of pediatric immunity resulted in an off-season surge in care utilization at an unexpected moment.

Increase in Invasive Group a Streptococcal Infections in Children in the Netherlands, A Survey Among 7 Hospitals in 2022.

Following an increase in notifiable invasive group A streptococcal (iGAS) infections in the Netherlands, we conducted a survey among 7 hospitals. Pediatric iGAS case numbers were 2-fold higher between July 2021 and June 2022 versus pre-COVID-19. A sharp increase occurred early 2022, most pronounced in <5 years old and for diagnoses empyema and necrotizing fasciitis. This recent pediatric iGAS surge warrants investigation and vigilance.

Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.

BACKGROUND AND AIMS: For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. METHODS: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. RESULTS: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. CONCLUSIONS: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

Machine Learning Used to Compare the Diagnostic Accuracy of Risk Factors, Clinical Signs and Biomarkers and to Develop a New Prediction Model for Neonatal Early-onset Sepsis.

BACKGROUND: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. STUDY DESIGN: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. RESULTS: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. CONCLUSIONS: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Response to Vaccination in Infants Exposed to Antitumor Necrosis Factor Alpha In Utero.

In this retrospective cohort study, the response to routinely administered Haemophilus influenzae type B vaccine, pneumococcal and pertussis vaccinations in 27 children exposed to antitumor necrosis factor alpha (anti-TNFα) during pregnancy was measured. The overall vaccination response seems comparable for children exposed to anti-TNFα and healthy infants. After primary vaccination series, inadequate response was present in some patients and might be related to exposure to anti-TNFα.

Health-related quality of life in the first 5 years of the children born to mothers with IBD does not differ from children born to healthy mothers.

OBJECTIVE: Inflammatory bowel disease (IBD) is often diagnosed in women in their reproductive years of life and therefore children are born to mothers with IBD. Health outcomes of children born to mothers with IBD seem favorable. However, little is known about the quality of life related to their health compared to children born to healthy mothers. Therefore, our first objective was to investigate the effect of having IBD during pregnancy on the health-related quality of life (HRQoL) of children born to mothers with IBD in the first 5 years of age compared to children born to healthy mothers. Secondly, we studied the effect of the different IBD related factors on the HRQoL. METHODS: We prospectively followed 264 women with IBD, who visited the preconception outpatient clinic at our tertiary health center in the Netherlands from April 2013 through November 2016. Women of children aged 1-5 years were approached to fill in a 43-item validated TNO-AZL Preschool Children Quality of Life questionnaire (TAPQOL) to assess HRQoL (Fekkes et al., 2000; Bunge et al., 2005 [1,2]). Outcomes were compared to children of mothers without IBD. RESULTS: One-hundred-eighty-two women completed the TAPQOL questionnaire. In total 182 children of mothers with IBD were included [median age 3.0 years (IQR 2-4)]. From 70 healthy mothers, 70 children were included as controls. There was no significant difference in the HRQoL between children who were and were not born to mothers with IBD (P = .18). Also, no effect of the different IBD related factors was found. CONCLUSION: In this study, we found no effect of having IBD during pregnancy on the health-related quality of life of children in the first 5 years of life.

Neonatal Meningitis and Subdural Empyema Caused by an Unusual Pathogen.

We report a case of neonatal meningitis with subdural empyema, caused by Ureaplasma parvum. In this case, diagnosis was made by genus-specific polymerase chain reaction, after regularly used diagnostic techniques failed. This unusual pathogen should be considered in cases that do not respond to therapy and/or where cultures for typical pathogens in neonatal sepsis and meningitis remain negative.

Pregnant women with inflammatory bowel disease: the effects of biologicals on pregnancy, outcome of infants, and the developing immune system.

INTRODUCTION: Relapse of inflammatory bowel disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review. Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, antitumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti-interleukin (IL)-12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search. The occurrence of unfavorable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFα, but the effects on the developing immune system are largely unknown. For anti-integrins and anti IL-12/23, the numbers of exposed pregnancies are too small to draw any conclusions. Expert commentary: Follow-up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design.

[Congenital CMV infections]. / Congenitale CMV-infecties.

Only 10-15% of neonates with congenital cytomegalovirus infection have symptoms at birth. The most common symptoms are intrauterine growth retardation, microcephaly, petechiae, jaundice, hepatosplenomegaly, intracranial abnormalities, ophthalmological abnormalities and hearing loss. Symptomatic and asymptomatic CMV infections can both have long-term effects. CMV infection during pregnancy is diagnosed using a blood test and possible testing of the amniotic fluid for viral DNA. Infection of the fetus may be prevented by treating the mother with CMV hyperimmune globulin. In the neonate a diagnosis can be made by viral culture or PCR in urine. PCR in saliva could be an alternative. Blood testing is of limited value. If symptoms of CMV infection occur in the neonate, such as petechiae, microcephaly, central nervous system abnormalities, sensorineural hearing loss or chorioretinitis, antiviral treatment should be considered. Long-term follow-up is advisable because of the possibility of delayed-onset hearing loss and chorioretinitis.