Congenital diaphragmatic hernia: quality improvement using a maximal lung protection strategy and early surgery-improved survival.

To evaluate the effectiveness of a novel protocol, adopted in our institution, as a quality improvement project for congenital diaphragmatic hernia (CDH). A maximal lung protection (MLP) protocol was implemented in 2019. This strategy included immediate use of high-frequency oscillatory ventilation (HFOV) after birth, during the stay at the Neonatal Intensive Care Unit (NICU), and during surgical repair. HFOV strategy included low distending pressures and higher frequencies (15 Hz) with subsequent lower tidal volumes. Surgical repair was performed early, within 24 h of birth, if possible. A retrospective study of all inborn neonates prenatally diagnosed with CDH and without major associated anomalies was performed at the NICU of Schneider Children's Medical Center of Israel between 2009 and 2022. Survival rates and pulmonary outcomes of neonates managed with MLP were compared to the historical standard care cohort. Thirty-three neonates were managed with the MLP protocol vs. 39 neonates that were not. Major adverse outcomes decreased including death rate from 46 to 18% (p = 0.012), extracorporeal membrane oxygenation from 39 to 0% (p < 0.001), and pneumothorax from 18 to 0% (p = 0.013). CONCLUSION:  MLP with early surgery significantly improved survival and additional adverse outcomes of neonates with CDH. Prospective randomized studies are necessary to confirm the findings of the current study. WHAT IS KNOWN: • Ventilator-induced lung injury was reported as the main cause of mortality in neonates with congenital diaphragmatic hernia (CDH). • Conventional ventilation is recommended by the European CDH consortium as the first-line ventilation modality; timing of surgery is controversial. WHAT IS NEW: • A maximal lung protection strategy based on 15-Hz high-frequency oscillatory ventilation with low distending pressures as initial modality and early surgery significantly reduced mortality and other outcomes.

Fetal surgery using fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: a single-center experience.

PURPOSE: To provide a comprehensive report of the experience gained in the prenatal treatment of congenital diaphragmatic hernia (CDH) using fetoscopic endoluminal tracheal occlusion (FETO) following its implementation at a newly established specialized fetal medicine center. METHODS: Mothers of fetuses with severe CDH were offered prenatal treatment by FETO. RESULTS: Between 2018 and 2021, 16 cases of severe CDH underwent FETO. The median gestational age (GA) at balloon insertion was 28.4 weeks (IQR 27.8-28.6). The median GA at delivery was 37 weeks (IQR 34.4-37.8). The survival rate was 8/16 cases (50%). None of the survivors required home oxygen therapy at 6 months of age. Comparison between the survivors and deceased showed that survivors had balloon insertion 1 week earlier (27.8 vs. 28.4 weeks, p = 0.007), a higher amniotic fluid level change between pre- to post-FETO (3.4 vs 1.3, p = 0.024), a higher O/E LHR change between pre- to post-FETO (50.8 vs. 37.5, p = 0.047), and a GA at delivery that was 2 weeks later (37.6 vs. 35.4 weeks, p = 0.032). CONCLUSIONS: The survival rate at 6 months of age in cases of severe CDH treated with FETO in our center was 50%. Our new fetal medicine center matches the performance of other leading international centers.

Development of the Ontogenetic Self-Regulation Clock.

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed "the self-regulation clock" and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the "clock" circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates.

Antepartum Hemorrhage and Outcome of Very Low Birth Weight, Very Preterm Infants: A Population-Based Study.

OBJECTIVE: We aimed to determine the independent effect of maternal antepartum hemorrhage (APH) on mortality and major neonatal morbidities among very low birth weight (VLBW), very preterm infants. STUDY DESIGN: A population-based cohort study of VLBW singleton infants born at 24 to 31 weeks of gestation between 1995 and 2016 was performed. Infants born with the following pregnancy associated complications were excluded: maternal hypertensive disorders, prolonged rupture of membranes, amnionitis, maternal diabetes, and small for gestational age. APH included hemorrhage due to either placenta previa or placental abruption. Univariate and multivariable logistic regression analyses were performed to assess the effect of maternal APH on mortality and major neonatal morbidities. RESULTS: The initial cohort included 33,627 VLBW infants. Following exclusions, the final study population comprised 6,235 infants of whom 2,006 (32.2%) were born following APH and 4,229 (67.8%) without APH. In the APH versus no APH group, there were higher rates of extreme prematurity (24-27 weeks of gestation; 51.6% vs. 45.3%, p < 0.0001), mortality (20.2 vs. 18.5%, p = 0.011), bronchopulmonary dysplasia (BPD, 16.1 vs. 13.0%, p = 0.004) and death or adverse neurologic outcome (37.4 vs. 34.5%, p = 0.03). In the multivariable analyses, APH was associated with significantly increased odds ratio (OR) for BPD in the extremely preterm infants (OR: 1.31, 95% confidence interval: 1.05-1.65). The OR's for mortality, adverse neurological outcomes, and death or adverse neurological outcome were not significantly increased in the APH group. CONCLUSION: Among singleton, very preterm VLBW infants, maternal APH was associated with increased odds for BPD only in extremely premature infants, but was not associated with excess mortality or adverse neonatal neurological outcomes. KEY POINTS: · Outcome of very low birth weight infants born after antepartum hemorrhage (APH) was assessed.. · APH was not associated with higher infant mortality.. · APH was not associated with adverse neurological outcome.. · APH was associated with increased bronchopulmonary dysplasia in extremely preterm infants..

Changing epidemiology and resistance patterns of pathogens causing neonatal bacteremia.

To conduct a survey of the local prevalent bacteria and antibiotic resistance in a referral tertiary neonatal intensive care unit (NICU), in order to assess the efficacy of local antibiotic policies. We reviewed all positive blood and cerebrospinal fluid cultures obtained between January 2007 and December 2017 in the NICU of Schneider Children's Medical Center of Israel. Early and late-onset bacteremia were defined as episodes occurring within or after the first 3 calendar days of life respectively. Empiric treatment included ampicillin and gentamicin or piperacillin-tazobactam and amikacin for early or late-onset bacteremia respectively. The prevalence and antibiotic resistance of the bacteria were described and compared over time. Eight hundred and twenty nine of 15,947 (5.2%) newborns had at least one episode of bacteremia; 81 had multiple episodes. The most common bacteria were Escherichia coli (32.35%) and group B Streptococcus (19.11%) or coagulase negative Staphylococcus (CoNS) (60.5%) and Klebsiella sp. (12.4%) in early or late-onset bacteremia respectively. Overall, all Gram-positive bacteria were susceptible to vancomycin and most non-CoNS to ampicillin. Nosocomial vs. vertical bacteremia had increased resistance to ampicillin and cephalosporins. Resistance of nosocomial bacteria to piperacillin-tazobactam was 22.4%, to amikacin 3.3%, and to meropenem 1.8%. Changes over time: Gram-negative bacteria had a significant increase in resistance to cotrimoxazole and piperacillin. The resistance to gentamicin doubled. Our empiric antibiotic regimen covers the most frequent isolates. Amikacin may replace gentamicin for selected sick patients in early-onset bacteremia. Piperacillin-tazobactam should be combined with amikacin until susceptibility is available.

Do Neonatal Infections Require a Positive Blood Culture?

Neonatal sepsis is a major cause of worldwide morbidity and mortality. Blood cultures are considered the gold standard for diagnosis, but results are often delayed for 24 to 48 hours, and sensitivity, although improved by modern techniques, such as automated blood cultures, is variable and affected by the bacterial load. For these reasons, empiric antibiotics are frequently administered to avoid potential devastating consequences of untreated sepsis. Unnecessary antibiotic treatment has been associated with increased mortality and other adverse outcomes; therefore, antibiotics should be discontinued as soon as sepsis has been ruled out. Negative cultures pose a challenge to clinicians, who must distinguish between real sepsis and sepsis-like conditions (noninfectious or viral) which do not require antibiotics. Focal infections with negative blood cultures do require antibiotic treatment. Ultra-low bacteremia, primary or secondary to recent antibiotic exposure, is often associated with negative cultures, and some consider a short course of empiric antibiotics sufficient for clearing of bacteremia. Biomarkers and molecular methods based on polymerase chain reaction are important add-ons to clinical signs or symptoms for establishing the diagnosis of sepsis. Other promising future potential adjuvants are metabolomics. Antibiotic stewardship should be implemented to avoid or discontinue unnecessary treatment. Prevention of infection still remains the most important step for dealing with neonatal sepsis. KEY POINTS: · Blood cultures are the gold standard diagnosis of neonatal sepsis but sometimes may be negative.. · Other bacterial, viral, and noninfectious conditions may mimic sepsis, prompting initiation of empiric antibiotic treatments.. · Since a definition of neonatal sepsis is lacking, recognizing real septic episodes may be challenging..

[UNILATERAL MULTI-CYSTIC LUNG DISEASE IN A PRETERM INFANT].

INTRODUCTION: Cystic diseases of the lung are a rare spectrum of anomalies, commonly diagnosed prenatally. We present a case of a newborn twin, born at 29 weeks gestational. The infant was diagnosed with respiratory distress syndrome shortly after birth, treated with surfactant by the INSURE method (intubation, surfactant administration, extubation) and required only short-term non-invasive ventilation. On the 40th day of life an extensive single lung cystic disease was identified after respiratory deterioration occurred. The diagnostic approach is presented. The differential diagnosis of neonatal cystic lung disease includes congenital and acquired diseases. The most common cystic lesions presenting in the neonatal period include congenital pulmonary airway malformation (CPAM), pulmonary sequestration, bronchogenic cysts, congenital lobar emphysema and acquired lung damage resulting in cyst formation including pulmonary interstitial emphysema, damage secondary to infection disease. Follow-up showed gradual resolution of the cystic disease, supporting an acquired lung disease. The cystic lung disease may be due to barotrauma from non-invasive ventilation, unequal surfactant distribution, genetic susceptibility to the relatively mild barotrauma associated with non-invasive ventilation or a combination of these factors. The case report demonstrates that procedures considered "safe" such as non-invasive ventilation and surfactant administration may result in extensive lung damage.

Normal Point of Care Glucose Values after Birth in the Well-Baby Nursery.

OBJECTIVE: Normal initial blood glucose values in healthy newborns are not well defined and are subject to controversy. Despite substantive research, there is no single initial value of glucose that can be used with certainty of safety in newborns, and thus various protocols and cutoffs have been proposed. STUDY DESIGN: We sought to characterize the normal values of blood glucose levels in a large cohort of neonates admitted to the well-baby nursery in Shaare Zedek Medical Center. The blood glucose levels were measured with a point of care (POC) glucometer (Accu-Chek Performa) within 180 minutes after birth. RESULTS: The study population included 3,912 newborns with a mean birth weight of 3,322 ± 439 g and a mean gestational age of 39.4 ± 1.3 weeks. Sampling was performed at a median age of 73 minutes (interquartile range [IQR], 55-92 minutes). Median glucose concentration was 58 (IQR, 51-67) mg/dL, and first, third, and fifth percentiles were 34, 39, and 41 mg/dL, respectively. CONCLUSION: Our data describe the normal range of POC blood glucose levels in healthy neonates on admission to the nursery. Extreme low levels were rare.

Short- and long-term complications of in utero exposure to lamotrigine.

AIMS: The present study evaluates the effect of antenatal lamotrigine exposure, on short- and long-term paediatric outcome. METHODS: The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004-2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. In addition, the parents completed a questionnaire regarding their child's development and health up to the age of 12 years. RESULTS: No major malformations were found in the newborns. None of the newborns had significant withdrawal symptoms by Finnegan score. The children were followed-up to the age of 12 years (56.6% were 6-12 years at the time of evaluation). There were no significant findings in the incidence of neurodevelopmental disorders. CONCLUSIONS: According to our experience, lamotrigine is generally safe for pregnancy use, associated with minimal short-term complications with no long-term effects on the outcome.

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

For Debate: Does Cannabis Use by the Pregnant Mother Affect the Fetus and Newborn?

Cannabis, commonly called marijuana, is often used during pregnancy, likely due to the perception that it is a "safe" drug. Changes in legislation in many countries have lead to the increased availability of this drug and to its increasing use during pregnancy, often with other concomitant exposures such as alcohol, tobacco, and other drugs. Herein, we review the medical literature regarding effects of marijuana on the fetus and newborn. Possible effects of in utero exposure to marijuana focus on fetal growth, increase in the rates of stillbirth and preterm delivery, congenital malformations, and neurodevelopmental effects on the child. Published studies for all these outcomes are inconsistent. Fetal weight growth may be somewhat decreased, but the magnitude of this decrease is no greater than 100 g. There is insufficient evidence to conclude on any effect on the stillbirth rate. Although there are some reports of a slight increase in the rate of prematurity, most reports do not support this effect. Marijuana does not appear to be a major teratogen; however, a small increased risk for some congenital birth defects may be associated with early pregnancy use. Neurodevelopmental effects have been associated with marijuana use, but it is difficult to control for the effect of confounders. Despite the lack of conclusive evidence, it is important to remember that marijuana has not been shown to be a harmless drug during pregnancy and may affect the long-term neurodevelopment of the newborn infant.

For Debate: Growth Hormone Treatment of Infants Born Small for Gestational Age should be Started at or before the First Year of Age.

Children born small for gestational age without early catch-up of somatic growth and head circumference subsequently remain short and suffer from various degrees of neurocognitive and psychological impairment. Based upon the role of growth hormone (GH) and insulin-like growth factor-I on early brain growth and maturation, we propose that GH treatment of these infants be instituted prior to their 2nd birthday.

Pregnancy outcome following maternal exposure to mirtazapine: a multicenter, prospective study.

This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5-2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04-10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6-5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group.

Cardiopulmonary exercise testing in adolescence following extremely premature birth.

BACKGROUND: Although extremely premature birth disrupts lung development, adolescent survivors of extreme prematurity show good clinical and physiologic outcomes. Cardiopulmonary limitations may not be clinically evident at rest. Data regarding exercise limitation in adolescents following preterm birth in the postsurfactant era are limited. RESEARCH QUESTION: What are the long-term effects of bronchopulmonary dysplasia (BPD) and extreme prematurity (<29 weeks) on ventilatory response during exercise in adolescents in the postsurfactant era? STUDY DESIGN AND METHODS: We followed a longitudinally recruited cohort of children aged 13-19 years who were born at a gestational age of <29 weeks (study group - SG). We compared the cardiopulmonary exercise testing (CPET) results of those with and without BPD, to their own CPET results from elementary school age (mean 9.09 ± 1.05 years). RESULTS: Thirty-seven children aged 15.73 ± 1.31 years, mean gestational age 26 weeks ( ± 1.19), completed the study. CPET parameters in adolescence were within the normal range for age, including mean V̇O2 peak of 91% predicted. The BPD and non-BPD subgroups had similar results. In the longitudinal analysis of the SG, improvement was observed in adolescence, compared with elementary school age, in breathing reserve (36.37 ± 18.99 vs. 26.58 ± 17.92, p = 0.044), tidal volume as a fraction of vital capacity achieved at maximal load (0.51 ± 0.13 vs. 0.37 ± 0.08, p < 0.001), and respiratory exchange ratio at maximal load (1.18 ± 0.13 vs. 1.11 ± 0.10, p = 0.021). INTERPRETATION: In the current cohort, adolescents born extremely premature have essentially normal ventilatory response during exercise, unrelated to BPD diagnosis. CPET results in this population improve over time.

Late-Onset Sepsis among Extremely Preterm Infants of 24-28 Weeks Gestation: An International Comparison in 10 High-Income Countries.

INTRODUCTION: Despite advances in neonatal care, late-onset sepsis remains an important cause of preventable morbidity and mortality. Neonatal late-onset sepsis rates have decreased in some countries, while in others they have not. Our objective was to compare trends in late-onset sepsis rates in 9 population-based networks from 10 countries and to assess the associated mortality within 7 days of late-onset sepsis. METHODS: We performed a retrospective population-based cohort study. Infants born at 24-28 weeks' gestation between 2007 and 2019 were eligible for inclusion. Late-onset sepsis was defined as a positive blood or cerebrospinal fluid culture. Late-onset sepsis rates were calculated for 3 epochs (2007-11, 2012-15, and 2016-19). Adjusted risk ratios (aRRs) for late-onset sepsis were calculated for each network. RESULTS: Of a total of 82,850 infants, 16,914 (20.4%) had late-onset sepsis, with Japan having the lowest rate (7.1%) and Spain the highest (44.6%). Late-onset sepsis rates decreased in most networks and remained unchanged in a few. Israel, Sweden, and Finland showed the largest decrease in late-onset sepsis rates. The aRRs for late-onset sepsis showed wide variations between networks. The rate of mortality temporally related to late-onset sepsis was 10.9%. The adjusted mean length of stay for infants with late-onset sepsis was increased by 5-18 days compared to infants with no late-onset sepsis. CONCLUSIONS: One in 5 neonates of 24-28 weeks' gestation develops late-onset sepsis. Wide variability in late-onset sepsis rates exists between networks with most networks exhibiting improvement. Late-onset sepsis was associated with increased mortality and length of stay.

Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-low-birthweight infants.

OBJECTIVE: We sought to assess the independent effect of perinatal factors on the risk for bronchopulmonary dysplasia (BPD) in very-low-birthweight infants. STUDY DESIGN: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network. Multivariable analyses identified independent risk factors for BPD. RESULTS: Of 12,139 infants surviving to a postmenstrual age of 36 weeks, 1663 (13.7%) developed BPD. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86). Stratified analysis by GA groups showed that postdelivery resuscitation had a more pronounced effect with increasing maturity. CONCLUSION: Perinatal factors and pregnancy complications were independently associated with development of BPD in very-low-birthweight infants. Most risk factors identified were consistent within GA groups.

Evaluation of the efficacy and safety of bi-daily combination therapy with pyridoxine and doxylamine for nausea and vomiting of pregnancy.

BACKGROUND: Diclectin (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many countries. OBJECTIVES: To evaluate the efficacy and safety of a simple bi-daily treatment regimen with the combination of pyridoxine (50 mg twice daily) and doxylamine (25-50 mg) as an alternative treatment for NVP. METHODS: A prospective case-controlled observational study of mother-infant pairs was conducted between February 2008 and December 2010. All women who contacted the Beilinson Teratology Information Service (BELTIS) regarding treatment of NVP were eligible for inclusion. Using data on NVP severity, treatment efficacy and outcomes, we compared the two groups of women: those treated with the combination of pyridoxine and doxylamine (treatment group, n=29) and those treated with metoclopramide (control group, n=29). RESULTS: Moderate to severe symptoms were present in 97% of the treatment group women vs. 69% of control group women (P < 0.01). Despite increased symptom severity in the treatment group, the combination regimen was efficacious: 20/29 (69%) vs. 18/25 (72%) in the treatment vs. control women respectively (P = 0.65). There were no congenital anomalies in the treatment group. Follow-up was normal for all infants. CONCLUSIONS: Bi-daily combination therapy with pyridoxine and doxylamine for NVP is safe, has comparable efficacy to metoclopramide, and is a treatment alternative in countries where Diclectin is not available. Despite symptoms warranting counseling by a teratology information service, more than a third of women do not take the suggested treatment.

Antipsychotic drugs and breastfeeding.

OBJECTIVE: The incidence of psychotic disorders during the postpartum period is higher than at any other time during a women's life and coincides with the time when breastfeeding is most recommended. As a result, safety data on use of antipsychotic drugs during lactation is essential. Our aim was to analyze the medical literature for information on antipsychotic drug use during breastfeeding and to determine the safety of their use for the exposed infant. DATA SOURCES: Medline (U.S. National Library of Medicine), LactMed (U.S. National Library of Medicine) and Reprotox (Reproductive Toxicology Center) databases were searched to identify all relevant medical literature on antipsychotic medications and lactation. The database search, updated to March, 2012, used the generic name of each antipsychotic drug in combination with the terms breastfeeding or lactation or breast-milk. STUDY SELECTION: 4 prospective studies, 12 case series, 28 case reports and 1 pharmaceutical registry were included. DATA EXTRACTION: Infant outcomes focusing on long-term outcome were summarized from all reports of breastfeeding mothers taking antipsychotic medications. Recommendations for drug use during breastfeeding were based on safety data and on pharmaco kinetic drug properties. Recommendatins were categorized as acceptable, possible under medical supervision, or, not recommended. RESULTS: Among 21 antipsychotic drugs used in clinical practice, for 7 there are no data at all regarding breastfeeding and for 6 others the data are based only on few infant exposures. Only few prospective studies assessing'use of haloperidol, chlorpromazine and olanzapine during breastfeeding were identified. Olanzapine and quetiapine were categorized as acceptable for breastfeeding. Chlorpromazine, haloperidol, risperidone and zuclopenthixol were categorized as possible for breastfeeding under medical supervision. Breastfeeding cannot be currently recommended for the following medications: aripiprazole, asenapine, chlorprothixene, clozapine, droperidol, fluphenazine, flupenthixol, iloperidone, lurasidone, paliperidone, perphenazine, pimozide, trifluoperazine, thiothixene and ziprasidone. CONCLUSIONS: With a limited number of infants exposed to antipsychotic drugs during breastfeeding, for most drugs a firm and evidence-based conclusion cannot be reached. Counseling of breastfeeding mothers should be carefully assessed. Pharmacokinetic drug characteristics, disease severity, behavioral or psychosocial alternatives, preventative interventions and possible impact of discontinuing breastfeeding on the maternal-infant relationship should all be considered.

Late-Onset Sepsis in Very Low Birth Weight Infants.

BACKGROUND AND OBJECTIVES: Late-onset sepsis is associated with significant morbidity and mortality among very low birth weight (VLBW) infants. Our objective was to determine risk factors associated with late-onset sepsis and to present temporal trends in overall and pathogen-specific rates. METHODS: Population-based study by the Israel Neonatal Network on VLBW infants (≤1500 g) born between 1995 and 2019. Late-onset sepsis required clinical symptoms and microbiologic confirmation. Bivariate and multivariable analyses were performed to identify risk factors. The study period was divided into 4 epochs. Overall and pathogen-specific late-onset sepsis rates for each epoch were compared. RESULTS: The study population comprised 31 612 VLBW infants, of whom 7423 (23.5%) had late-onset sepsis. An increased adjusted risk of late-onset sepsis was associated with gestational age <27 w (odds ratio [OR] 8.90, 95% confidence interval [CI] 7.85-10.09) and delivery room resuscitation (OR 1.43, 95% CI 1.34-1.52) and a decreased adjusted risk among infants born between 2013 and 2019 (OR 0.32, 95% CI 0.29-0.35). Late-onset sepsis rates declined from 29.5% in 1995 to 2000 to 13.0% in 2013 to 2019. Gram-negative and fungal rates decreased in all epochs, whereas gram-positive rates decreased only in the last epoch. The adjusted hazard ratios (95% CI) decreased in the 2013 to 2019 versus 1995 to 2000 epochs and were: all late-onset sepsis, 0.40 (0.37-0.43); gram-positive, 0.47 (0.37-0.59); gram- negative, 0.54 (0.48-0.61); fungal, 0.17 (0.12-0.22). CONCLUSIONS: The strongest risk factor for late-onset sepsis was gestational age <27 w. Over a 25-year period, the pathogen-specific rates of late-onset sepsis among VLBW infants decreased approximately twofold for gram-positive and gram-negative bacterial infections and sixfold for fungal infections.

Targeted fluconazole prophylaxis for high-risk very low birth weight infants.

Antifungal prophylaxis is increasingly used in very low birth weight (VLBW) infants who are at risk for severe fungal infections. Our objective was to assess the effectiveness of targeted fluconazole prophylaxis for high-risk VLBW infants. A retrospective cohort study with historical controls was performed. During the period 2007-2008, all high-risk VLBW infants (birth weight, ≤1,000 g; gestational age, ≤28 weeks; seven antimicrobial therapy or additional risk factors present) received fluconazole prophylaxis until risk factors were not present. Treated infants were compared to a gestational age- and birth weight-matched untreated cohort. Statistical analyses used univariate and multivariate analyses. The main outcome variable was a breakthrough fungal bloodstream infection (BSI). The prophylaxis cohort of 130 VLBW infants was compared to 319 control infants. The rate of fungal infections was significantly lower in the fluconazole prophylaxis group (1 of 130 vs. 19 of 319, p = 0.016); however, they did not differ in mortality (16.2 vs. 15 %, p = 0.77) or complications of prematurity. Fluconazole prophylaxis was associated with a significant decrease in candidal BSI (odds ratio, 0.05; 95 % confidence interval, 0.005-0.523). Selective vs. nonselective prophylaxis reduced the number of infants treated from 247 to 130. Conclusion Targeted fluconazole prophylaxis in VLBW infants is effective in preventing fungal infections without increasing the risk of BSI among low-risk infants.