Maternal treatment with selective serotonin reuptake inhibitors during pregnancy and delayed neonatal adaptation: a population-based cohort study.

OBJECTIVE: Selective serotonin reuptake inhibitor (SSRI) use is common in pregnancy. It is associated with delayed neonatal adaptation. Most previous studies have not adjusted for the severity of maternal mental health disorders or examined the impact of SSRI type and dosage. We examined whether treatment with SSRIs in late pregnancy (after 20 weeks) is associated with delayed neonatal adaptation independent of maternal depression and anxiety. DESIGN, SETTING AND PATIENTS: Retrospective population-based birth cohort of 280 090 term infants born at 15 Kaiser Permanente Northern California hospitals, 2011-2019. Individual-level pharmacy, maternal, pregnancy and neonatal data were obtained from electronic medical records. EXPOSURE: Dispensed maternal SSRI prescription after 20 weeks of pregnancy. MAIN OUTCOME MEASURES: Delayed neonatal adaptation defined as a 5 min Apgar score ≤5, resuscitation at birth or admission to a neonatal intensive care unit for respiratory support. Secondary outcomes included each individual component of the primary outcome and more severe neonatal outcomes (pulmonary hypertension, hypoxic-ischaemic encephalopathy and seizures). RESULTS: 7573 (2.7%) infants were exposed to SSRIs in late pregnancy. Delayed neonatal adaptation occurred in 11.2% of exposed vs 4.4% of unexposed infants (relative risk 2.52 (95% CI 2.36 to 2.70)). After multivariable adjustment, there was an association between SSRI exposure and delayed neonatal adaptation (adjusted OR 2.14 (95% CI 1.96 to 2.32)). This association was dose dependent. Escitalopram and fluoxetine were associated with the highest risk of delayed neonatal adaptation. CONCLUSIONS: Infants exposed to SSRIs have increased risks of delayed adaptation in a type and dose-dependent relationship, pointing toward a causal relationship.

Clinical Course of Children 1 to 24 Months Old With Positive Urine Cultures Without Pyuria.

OBJECTIVE: To describe the clinical course of children with positive urine cultures without pyuria who were not given antibiotics initially, identify predictors of subsequent antibiotic treatment, and evaluate the association between subsequent treatment and urinary tract infection (UTI) within 30 days. METHODS: We conducted a multicenter retrospective cohort study of children 1 to 24 months old who had positive urine cultures without pyuria and who were not started on antibiotics upon presentation to 3 health care systems from 2010 to 2021. Outcomes included clinical status at the time urine cultures resulted, escalation of care (emergency department visit or hospitalization) and subsequent antibiotic treatment within 7 days, and subsequent UTI within 30 days of presentation. RESULTS: Of 202 included children, 61% were female and median age was 9 months. Of 151 patients with clinical status information when cultures resulted, 107 (70.8%, 95% confidence interval [CI] 62.9-77.9%) were improved. Two of 202 children (1.0%, 95% CI 0.2-4.0%) experienced care escalation. Antibiotics were started in 142 (82.2%) children, and treatment was associated with prior UTI (risk ratio [RR] 1.20, 95% CI 1.15-1.26) and lack of improvement (RR 1.22, 95% CI 1.13-1.33). Subsequent UTI was diagnosed in 2 of 164 (1.2%, 95% CI 0.1-4.3%) treated and 0 of 36 (0%, 95% CI 0-9.7%) untreated children. CONCLUSIONS: Seventy percent of children with positive urine cultures without pyuria improved before starting antibiotics; however, >80% were ultimately treated. Future research should study the impact of diagnostic stewardship interventions and various urine testing strategies to optimize the management of children evaluated for UTI.retain-->.

Perinatal Hypoxic-Ischemic Encephalopathy: Incidence Over Time Within a Modern US Birth Cohort.

BACKGROUND: Recent studies suggest that the incidence of perinatal hypoxic-ischemic encephalopathy (HIE) may be increasing in developed countries. However, this observed increase may be due to increased ascertainment and increased treatment with therapeutic hypothermia rather than an increase in disease burden. In a US population-based cross-sectional study, we determined the incidence of perinatal HIE over time. METHODS: The study population included all 289,793 live-born infants ≥35 weeks gestational age born at 15 Kaiser Permanente Northern California hospitals between 2012 and 2019. Perinatal HIE was defined as the presence of both neonatal acidosis (i.e., cord blood pH < 7 or base deficit ≥10, or base deficit ≥10 on first infant gas) and neonatal encephalopathy confirmed by medical record review. Hospital discharge diagnoses of HIE were determined by extracting International Classification of Disease diagnostic codes for HIE assigned upon hospital discharge. RESULTS: The population incidence of perinatal HIE was 1.7 per 1000. Although the incidence of perinatal HIE did not change significantly, both hospital discharge diagnoses of HIE and treatment with therapeutic hypothermia increased significantly during the study period. The sensitivity and positive predictive value of a hospital discharge diagnosis of HIE for identifying perinatal HIE confirmed by chart review were 72% and 79%, respectively. CONCLUSIONS: During the study years, the incidence of perinatal HIE remained stable despite increases in hospital discharge diagnoses of HIE and in the use of therapeutic hypothermia. Our findings underscore the importance of applying stringent diagnostic criteria when diagnosing this complex condition.

The walking man approach to interpreting the receiver operating characteristic curve and area under the receiver operating characteristic curve.

An accuracy study of a test that produces a wide range of results will often present a receiver operating characteristic (ROC) curve and report the area under the ROC curve (AUROC). The AUROC is a summary measure of how well the test discriminates between those with the condition or disease in question and those without it. A test that perfectly separates individuals with and without the condition has an AUROC of 1.0, and a test that doesn't separate them at all has an AUROC of 0.5. The AUROC is also the probability that a random individual with the condition will have a more abnormal test result than a random individual without the condition. In this Key Concepts article, we present our "walking man" approach to understanding ROC curves and the AUROC.

Research Methods: Diagnostic Test Characteristics.

The goal of a diagnostic test is to provide information on the probability of disease. In this article, we review the principles of diagnostic test characteristics, including sensitivity, specificity, positive and negative predictive value, receiver operating characteristics curves, likelihood ratios, and interval likelihood ratios. We illustrate how interval likelihood ratios optimize the information that can be obtained from test results that can take on >2 values, how they are reflected in the slope of the receiver operating characteristics curve, and how they can be easily calculated from published data.

NICU Versus Mother/Baby Unit Admission for Low-Acuity Infants Born at 35 Weeks' Gestation.

OBJECTIVES: To estimate the effect of NICU admission of low-acuity infants born at 35 weeks' gestation versus care in a mother/baby unit, on inpatient and outpatient medical outcomes. METHODS: This retrospective cohort study included 5929 low-acuity infants born at 350/7 to 356/7 weeks' gestation at 13 Kaiser Permanente Northern California hospitals with level II or level III NICUs between January 1, 2011, and December 31, 2021. Exclusion criteria included congenital anomalies and early respiratory support or antibiotics. We used multivariable regression and regression discontinuity analyses to control for confounding variables. RESULTS: Infants admitted to the NICU within 2 hours of birth (n = 862, 14.5%) had a 58 hour adjusted (98-hour unadjusted) longer length of stay. NICU admission was associated with an increased probability of a length of stay ≥96 hours (67% vs 21%; adjusted odds ratio [aOR], 4.94; 95% confidence interval [CI], 3.96-6.16). Regression discontinuity results suggested a similar (57 hour) increase in length of stay. Readmission risk, primarily for jaundice, was lower for those admitted to the NICU (3% vs 6%; aOR, 0.43; 95% CI, 0.27-0.69). Infants admitted to the NICU were slightly less likely to be receiving exclusive breast milk at 6-month follow-up (15% vs 25%; aOR, 0.73; 95% CI, 0.55-0.97; adjusted marginal risk difference -5%). CONCLUSIONS: Admitting low-acuity infants born at 35 weeks' gestation to the NICU was associated with decreased readmission, but with longer length of stay and decreased exclusive breast milk feeding at 6 months. Routine NICU admission may be unnecessary for low-acuity infants born at 35 weeks' gestation.

Technical Report: Diagnosis and Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation.

CONTEXT: Severe hyperbilirubinemia is associated with kernicterus. Informed guidance on hyperbilirubinemia management, including preventive treatment thresholds, is essential to safely minimize neurodevelopmental risk. OBJECTIVE: To update the evidence base necessary to develop the 2022 American Academy of Pediatrics clinical practice guideline for management of hyperbilirubinemia in the newborn infant ≥35 weeks' gestation. DATA SOURCE: PubMed. STUDY SELECTION: English language randomized controlled trials and observational studies. Excluded: case reports or series, nonsystematic reviews, and investigations focused on <35-weeks' gestation infants. DATA EXTRACTION: Topics addressed in the previous clinical practice guideline (2004) and follow-up commentary (2009) were updated with new evidence published through March 2022. Evidence reviews were conducted for previously unaddressed topics (phototherapy-associated adverse effects and effectiveness of intravenous immune globulin [IVIG] to prevent exchange transfusion). RESULTS: New evidence indicates that neurotoxicity does not occur until bilirubin concentrations are well above the 2004 exchange transfusion thresholds. Systematic review of phototherapy-associated adverse effects found limited and/or inconsistent evidence of late adverse effects, including cancer and epilepsy. IVIG has unclear benefit for preventing exchange transfusion in infants with isoimmune hemolytic disease, with a possible risk of harm due to necrotizing enterocolitis. LIMITATIONS: The search was limited to 1 database and English language studies. CONCLUSIONS: Accumulated evidence justified narrowly raising phototherapy treatment thresholds in the updated clinical practice guideline. Limited evidence for effectiveness with some evidence of risk of harm support the revised recommendations to limit IVIG use.

Real-World Midazolam Use and Outcomes With Out-of-Hospital Treatment of Status Epilepticus in the United States.

STUDY OBJECTIVE: Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently administered intranasally or intravenously and is dosed lower. Therefore, we used conventional and instrumental variable approaches to examine the effectiveness of midazolam in a national out-of-hospital cohort. METHODS: This retrospective cohort study of adults with status epilepticus used the ESO Data Collaborative research dataset (January 1, 2019, to December 31, 2019). The exposures were the route and dose of midazolam. We performed hierarchical logistic regression and 2-stage least squares regression using agency treatment patterns as an instrument to examine our outcomes, rescue therapy, and ventilatory support. RESULTS: There were 7,634 out-of-hospital encounters from 657 EMS agencies. Midazolam was administered intranasally in 20%, intravenously in 46%, and intramuscularly in 35% of the encounters. Compared with intramuscular administration, intranasal midazolam increased (risk difference [RD], 6.5%; 95% confidence interval [CI], 2.4% to 10.5%) and intravenous midazolam decreased (RD, -11.1%; 95% CI, -14.7% to -7.5%) the risk of rescue therapy. The differences in ventilatory support were not statistically significant (intranasal RD, -1.5%; 95% CI, -3.2% to 0.3%; intravenous RD, -0.3%; 95% CI, -1.9% to 1.2%). Higher doses were associated with a lower risk of rescue therapy (RD, -2.6%; 95% CI, -3.3% to -1.9%) and increased ventilatory support (RD, 0.4%; 95% CI, 0.1% to 0.7%). The instrumental variable analysis yielded similar results, except that dose was not associated with ventilatory support. CONCLUSION: The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.

The Effect of Readmission for Phototherapy on Early Breast Milk Feeding.

OBJECTIVES: To estimate the effect of readmission for inpatient phototherapy on parent-reported exclusive and any breast milk feeding at 2-month well-child visits. METHODS: We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥35 weeks' gestation with outpatient total serum bilirubin levels ranging from 1 mg/dL below to 2.9 mg/dL above the American Academy of Pediatrics phototherapy threshold at <15 days of age. We compared breast milk feeding at 2-month well-child visits among those readmitted and not readmitted to the hospital for phototherapy, adjusting for bilirubin and other confounding variables. RESULTS: Approximately one-quarter (26.5%) of the cohort (n = 7729) were readmitted for phototherapy. Almost half (48.5%) of the infants who were not readmitted for phototherapy received exclusively breast milk at the 2-month visit compared with slightly fewer infants who were readmitted (42.9%). In both groups of infants, most (82.2% not readmitted and 81.2% readmitted) received any breast milk. Readmission for phototherapy was associated with a lower adjusted risk of exclusive breast milk feeding (adjusted risk ratio 0.90; 95% confidence interval [CI], 0.84 to 0.96), corresponding to a marginal absolute reduction in exclusive breast milk feeding of 5.0% (95% CI, -7.9% to -2.1%). It was not associated with a reduction in any breast milk feeding (adjusted risk ratio, 1.00; 95% CI, 0.97 to 1.02). CONCLUSIONS: Infants readmitted for phototherapy were more likely to receive any formula, but no less likely to receive any breast milk at 2-month well-child visits.

Update on Phototherapy and Childhood Cancer in a Northern California Cohort.

OBJECTIVES: We aimed to reassess the relationship between phototherapy and cancer in an extended version of a previous cohort and to replicate a report from Quebec of increased cancer risk after phototherapy beginning at age 4 years. METHODS: This cohort study included 139 100 children born at ≥35 weeks' gestation from 1995 to 2017, followed through March 16, 2019, in Kaiser Permanente Northern California hospitals who had a qualifying bilirubin level from -3 mg/dL to +4.9 mg/dL from the American Academy of Pediatrics phototherapy threshold; an additional 40 780 children and 5 years of follow-up from our previous report. The exposure was inpatient phototherapy (yes or no), and the outcomes were various types of childhood cancer. We used Cox proportional hazard models, controlling for propensity-score quintiles, and allowed for time-dependent exposure effects to assess for the risk of cancer after a latent period. RESULTS: Over a mean (SD) follow-up of 8.2 (5.7) years, the crude incidence of cancer per 100 000 person-years was 25.1 among those exposed to phototherapy and 19.2 among those not exposed (233 cases of cancer). After propensity adjustment, phototherapy was not associated with any cancer (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.83-1.54), hematopoietic cancer (HR: 1.17, 95% CI: 0.74-1.83), or solid tumors (HR: 1.01, 95% CI: 0.65-1.58). We also found no association with cancer diagnoses at age ≥4 years. CONCLUSIONS: We did not confirm previous, concerning associations between phototherapy and adjusted risk of any cancer, nonlymphocytic leukemia, or brain and/or central nervous systems tumors in later childhood.

Use of Complete Blood Cell Count Components to Screen for Hereditary Spherocytosis in Neonates.

BACKGROUND AND OBJECTIVES: The neonatal hereditary spherocytosis (HS) index, defined as the mean corpuscular hemoglobin concentration divided by the mean corpuscular volume, has been proposed as a screening tool for HS in neonates. In a population of mostly white infants, an HS Index >0.36 was 97% sensitive and >99% specific. We evaluated the utility of the HS Index among a more racially and ethnically diverse population and determined if its discrimination varies with total serum bilirubin (TSB) levels. METHODS: Infants born at ≥35 weeks' gestation at 15 Kaiser Permanente Northern California hospitals from 1995 to 2015 were eligible (N = 670 272). Erythrocyte indices from the first complete blood count drawn at ≤7 days and TSB levels drawn at ≤30 days were obtained. Diagnoses of HS were confirmed via chart review. RESULTS: HS was confirmed in 79 infants, 1.2 per 10 000. HS was more common among infants of white and "other" race or ethnicity and among those with higher peak TSB levels. The area under the receiver operating characteristic curve for the HS Index was 0.84 (95% confidence interval 0.78-0.90). Likelihood ratios ranged from 10.1 for an HS Index ≥0.380 to 0.1 for an HS Index <0.310. Dichotomized at 0.36, the HS Index was 56% sensitive and 93% specific. Discrimination of the HS Index appeared best among infants with TSB levels <10 mg/dL. CONCLUSIONS: The HS Index, when obtained from a CBC drawn within the first week after birth, had only modest ability to alter the probability of HS.

Perioperative Normal Saline Administration and Delayed Graft Function in Patients Undergoing Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: Perioperative normal saline administration remains common practice during kidney transplantation. The authors hypothesized that the proportion of balanced crystalloids versus normal saline administered during the perioperative period would be associated with the likelihood of delayed graft function. METHODS: The authors linked outcome data from a national transplant registry with institutional anesthesia records from 2005 to 2015. The cohort included adult living and deceased donor transplants, and recipients with or without need for dialysis before transplant. The primary exposure was the percent normal saline of the total amount of crystalloids administered perioperatively, categorized into a low (less than or equal to 30%), intermediate (greater than 30% but less than 80%), and high normal saline group (greater than or equal to 80%). The primary outcome was the incidence of delayed graft function, defined as the need for dialysis within 1 week of transplant. The authors adjusted for the following potential confounders and covariates: transplant year, total crystalloid volume, surgical duration, vasopressor infusions, and erythrocyte transfusions; recipient sex, age, body mass index, race, number of human leukocyte antigen mismatches, and dialysis vintage; and donor type, age, and sex. RESULTS: The authors analyzed 2,515 records. The incidence of delayed graft function in the low, intermediate, and high normal saline group was 15.8% (61/385), 17.5% (113/646), and 21% (311/1,484), respectively. The adjusted odds ratio (95% CI) for delayed graft function was 1.24 (0.85 to 1.81) for the intermediate and 1.55 (1.09 to 2.19) for the high normal saline group compared with the low normal saline group. For deceased donor transplants, delayed graft function in the low, intermediate, and high normal saline group was 24% (54/225 [reference]), 28.6% (99/346; adjusted odds ratio, 1.28 [0.85 to 1.93]), and 30.8% (277/901; adjusted odds ratio, 1.52 [1.05 to 2.21]); and for living donor transplants, 4.4% (7/160 [reference]), 4.7% (14/300; adjusted odds ratio, 1.15 [0.42 to 3.10]), and 5.8% (34/583; adjusted odds ratio, 1.66 [0.65 to 4.25]), respectively. CONCLUSIONS: High percent normal saline administration is associated with delayed graft function in kidney transplant recipients.