Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns.

OBJECTIVE: Determine association between time to regain birthweight and 2-year neurodevelopment among extremely preterm (EP) newborns. STUDY DESIGN: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating time to regain birthweight, time from birth to weight nadir, time from nadir to regain birthweight, and cumulative weight loss with 2-year corrected Bayley Scales of Infant and Toddler Development 3rd edition. RESULTS: Among n = 654 EP neonates, those with shorter nadir-to-regain had lower cognitive scores (≤1 day versus ≥8 days: -5.0 points, [CI -9.5, -0.6]) and lower motor scores (≤1 day versus ≥8 days: -4.6 points [CI -9.2, -0.03]) in adjusted stepwise forward regression modeling. Increasingly cumulative weight loss was associated with lower cognitive scores (≤-50 percent-days: -5.6, [CI -9.4, -1.8]), motor scores (≤-50 percent-days: -4.2, [CI -8.2, -0.2]); and language scores (≤-50 percent-days: -6.0, [CI -10.1, -1.9]). CONCLUSION: Faster nadir-to-regain and excessive cumulative weight loss are associated with adverse 2-year neurodevelopmental outcomes. TRIAL REGISTRATION: PENUT Trial Registration: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 . CLINICAL TRIAL REGISTRATION: This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273).

Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age.

BACKGROUND: Associations of 2-year neurodevelopmental and behavioral outcomes with growth trajectories of preterm infants are unknown. METHODS: This secondary analysis of a preterm cohort examined in-hospital and discharge to 2-year changes in anthropometric z-scores. Two-year follow-up included Bayley Scales of Infant Development (BSID-III) and Child Behavior Checklist. RESULTS: Among 590 infants, adjusted in-hospital growth was not associated with any BSID-III subscale. Occipitofrontal circumference (OFC) growth failure (GF) in-hospital was associated with increased adjusted odds of attention problems (aOR 1.65 [1.03, 2.65]), aggressive behavior (aOR 2.34 [1.12, 4.89]), and attention-deficit-hyperactivity symptoms (aOR 1.86 [1.05, 3.30]). Infants with OFC GF at 2 years had lower adjusted BSID-III language scores (-4.0 [-8.0, -0.1]), increased odds of attention problems (aOR 2.29 [1.11, 4.74]), aggressive behavior (aOR 3.09 [1.00, 9.56]), and externalizing problems (aOR 3.01 [1.07, 8.45]) compared to normal OFC growth cohort. CONCLUSION: Infants with OFC GF are at risk for neurodevelopmental and behavioral impairment. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273.

Reducing Severe Intraventricular Hemorrhage in Preterm Infants With Improved Care Bundle Adherence.

BACKGROUND AND OBJECTIVES: Intraventricular hemorrhage prevention bundles (IVHPBs) can decrease the incidence of intraventricular hemorrhage (IVH) in premature infants. Our center had a high rate of severe (grade III/IV) IVH (9.8%), and poor adherence (24%) to an IVHPB in neonates born ≤1250 g or ≤30 gestational weeks. Improvement initiatives were planned to decrease the incidence of severe IVH by 30% over 2 years. METHODS: A multidisciplinary team undertook interventions including in-service training, prompt initiation of IVHPB, revision of guidelines, and process standardization. Baseline data were collected from May 2016 to June 2018, with interventions occurring from July 2018 to May 2020. Adherence to the IVHPB was the primary process measure, and incidence of severe IVH the primary outcome measure. Control charts were used to analyze the effect of interventions on outcome. Balancing measures included use of breast milk at discharge, use of mechanical ventilation after initial resuscitation, and bronchopulmonary dysplasia. RESULTS: A total of 240 infants were assessed preintervention, and 185 during interventions. Adherence to the IVHPB improved from 24% to 88%. During this period, the incidence of severe IVH decreased from 9.8% to 2.4%, a 76% reduction from baseline. A higher adherence score was associated with reduced odds of IVH (odds ratio 0.30; 95% confidence interval 0.10-0.90, P = .03). CONCLUSIONS: Interventions focused on enhancing adherence to an IVHPB were associated with a reduced rate of severe IVH in high-risk neonates, highlighting the importance of assessing adherence to clinical guidelines.

Early Fluid and Nutritional Management of Extremely Preterm Newborns During the Fetal-To-Neonatal Transition.

During the fetal-to-neonatal transitional period, extremely preterm newborns undergo significant intrabody fluid shifts and resulting weight loss due to increased insensible fluid losses due to immature skin, kidneys, among other factors. These ongoing physiologic changes make fluid and nutritional management complex in the neonatal-to-fetal transitional time period for extremely premature newborns. However, limited literature exists to guide optimal practices for providers caring for this population. Here, we review the evidence on optimal fluid and nutritional management during the fetal-to-neonatal transition of extremely preterm newborns.

Increasing Sodium Variability in the First 96 Hours after Birth is Associated with Adverse In-Hospital Outcomes of Preterm Newborns.

Background: Neonatal intraventricular hemorrhage prevention bundles for preterm infants commonly defer daily weighing for the first 72 h, with reweighing occurring on day 4. Clinicians rely on maintaining stable sodium values as a proxy of fluid status to inform fluid management decisions over the first 96 h after birth. Yet, there exists a paucity of research evaluating whether serum sodium or osmolality are appropriate proxies for weight loss and whether increasing variability in sodium or osmolality during this early transitional period is associated with adverse in-hospital outcomes. Objectives: To evaluate whether serum sodium or osmolality change in the first 96 h after birth was associated with percent weight change from birth weight, and to assess potential associations between serum sodium and osmolality variability with in-hospital outcomes. Methods: This retrospective, cross-sectional study included neonates born at ≤30 gestational weeks or ≤1250 g. We evaluated associations between serum sodium coefficient of variation (CoV), osmolality CoV, and maximal weight loss percentage in the first 96 h after birth with in-hospital neonatal outcomes. Results: Among 205 infants, serum sodium and osmolality were poorly correlated with percent weight change in individual 24-h increments (R2 = 0.01-0.14). For every 1% increase in sodium CoV, there was an associated 2-fold increased odds of surgical necrotizing enterocolitis and 2-fold increased odds of in-hospital mortality (odds ratio, 2.07; 95% CI: 1.02, 4.54; odds ratio, 1.95; 95% CI: 1.10, 3.64, respectively). Sodium CoV was more strongly associated with outcomes than absolute sodium maximal change. Conclusions: In the first 96 h, serum sodium and osmolality are poor proxies for assessing percent weight change. Increasing variability of serum sodium is associated with later development of surgical necrotizing enterocolitis and all-cause in-hospital mortality. Prospective research is needed to evaluate whether reducing sodium variability in the first 96 h after birth, as assessed by CoV, improves newborn health outcomes.

Nonsurgical periodontal treatment during pregnancy and rates of preterm birth.

BACKGROUND: Periodontitis during pregnancy is associated with an increased risk of preterm birth (<37 weeks of gestation) or low birthweight (<2500 g) offspring. Beyond periodontal disease, the risk of preterm birth varies both by previous history of preterm birth and in association with social determinants prevalent among vulnerable and marginalized populations. This study hypothesized that the timing of periodontal treatment during pregnancy and/or social vulnerability measures modified the response to dental scaling and root planing for the treatment of periodontitis and prevention of preterm birth. OBJECTIVE: This study aimed to determine the association of timing of dental scaling and root planing for gravidae with a diagnosed periodontal disease on the rates of preterm birth or low birthweight offspring among subgroups or strata of gravidae as part of the Maternal Oral Therapy to Reduce Obstetric Risk randomized controlled trial. All participants in the study had clinically diagnosed periodontal disease and differed by the timing of the periodontal treatment (dental scaling and root planing at <24 weeks [per protocol] or after delivery) or by baseline characteristics. Although all participants met the well-accepted clinical criteria for periodontitis, not all participants acknowledged a priori that they had periodontal disease. STUDY DESIGN: This was a per-protocol analysis of data from 1455 participants of the Maternal Oral Therapy to Reduce Obstetric Risk trial evaluating dental scaling and root planing on the risk of preterm birth or low birthweight offspring. Adjusted multiple logistic regression to control for confounders was used to estimate associations comparing the timing of periodontal treatment in pregnancy to receiving treatment after pregnancy (referent control) on rates of preterm birth or low birthweight among subgroups of gravidae with known periodontal disease. Study analyses were stratified, and the associations with the following characteristics-body mass index, self-described race and ethnicity, household income, maternal education, recency of immigration, and self-acknowledgment of poor oral health, were explored. RESULTS: Dental scaling and root planing during the second or third trimester of pregnancy were associated with an increased adjusted odds ratio of preterm birth among those at the lower body mass index strata (18.5 to <25.0 kg/m2) (adjusted odds ratio, 2.21; 95% confidence interval, 1.07-4.98), but not among individuals who were overweight (body mass index of 25.0 to <30.0 kg/m2; adjusted odds ratio, 0.68; 95% confidence interval, 0.29-1.59) or obese (body mass index of ≥30 kg/m2; adjusted odds ratio, 1.26; 95% confidence interval, 0.65-2.49). There was no significant difference in pregnancy outcomes related to the other evaluated variables: self-described race and ethnicity, household income, maternal education, immigration status, or self-acknowledgment of poor oral health. CONCLUSION: In this per-protocol analysis of the Maternal Oral Therapy to Reduce Obstetric Risk trial, dental scaling and root planing had no preventive benefit against adverse obstetrical outcomes and were associated with increased odds of preterm birth among individuals at lower body mass index strata. There was no significant difference in the occurrence of preterm birth or low birthweight after dental scaling and root planing periodontitis treatment concerning other analyzed social determinants of preterm birth.

Considering Risks to Researchers and Staff in Low-Resource Settings during Public Health Crises: A Proposed Conceptual Model.

Human subjects research protections have historically focused on mitigating risk of harm and promoting benefits for research participants. In many low-resource settings (LRS), complex and often severe challenges in daily living, poverty, geopolitical uprisings, sociopolitical, economic, and climate crises increase the burdens of even minimal risk research. While there has been important work to explore the scope of ethical responsibilities of researchers and research teams to respond to these wider challenges and hidden burdens in global health research, less attention has been given to the ethical dilemmas and risk experienced by frontline researcher staff as they perform research-related activities in LRS. Risks such as job insecurity, moral distress, infection, or physical harm can be exacerbated during public health crises, as recently highlighted by the COVID-19 pandemic. We highlight the layers of risk research staff face in LRS and present a conceptual model to characterize drivers of this risk, with particular attention to public health crises. A framework by which funders, institutions, principal investigators, and/or research team leaders can systematically consider these additional layers of risk to researchers and frontline staff is an important and needed addition to routine research proposals and protocol review.

Antepartum periodontitis treatment and risk of offspring screening positive for autism spectrum disorder.

BACKGROUND: To evaluate if treating maternal periodontal disease, a pro-inflammatory condition, during pregnancy (intervention) compared to after pregnancy (control) reduces the likelihood of offspring screening positive for autism spectrum disorder (ASD). METHODS: In a follow-up study to the MOTOR randomized trial, we compared rates of positive screens on the Modified Checklist for Autism in Toddlers (M-CHAT) among n = 306 two-year-old toddlers and correlated findings to maternal and cord blood pro-inflammatory interleukin-6 (IL-6). RESULTS: Toddlers in the intervention group had decreased risk of a positive M-CHAT screen (adjusted RR = 0.53, 95% CI 0.29-0.99). Toddlers screening positive compared to negative had higher mean IL-6 in cord blood (1.58 ± 1.14 vs. 1.09 ± 0.72 p = 0.001) and maternal IL-6 change from baseline (1.30 ± 0.61 vs 0.96 ± 0.62 p = 0.03). CONCLUSIONS: Treating periodontal disease during pregnancy reduced risk of a positive ASD screen. M-CHAT positivity was associated with increased IL-6 in maternal and cord blood. CLINICAL TRIAL: Trial Registration numbers: Clinicaltrials.gov NCT03423836.

Postnatal maximal weight loss, fluid administration, and outcomes in extremely preterm newborns.

OBJECTIVE: Evaluate maximal weight loss (MWL) and total fluid administration (TFA) association in first week after birth with outcomes among extremely preterm (EP) newborns. STUDY DESIGN: We performed a retrospective analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating first-week MWL, TFA, and association with in-hospital outcomes. RESULTS: Among n = 883 included EP neonates, n = 842 survived ≥ 7 days and were included in outcome analyses. MWL between 5% to 15% was associated with decreased odds of necrotizing enterocolitis compared to MWL > 15% (OR 0.49, 95% CI 0.25-0.98). Average TFA > 150 mL/kg birthweight/day was associated with increased odds of necrotizing enterocolitis (OR 3.22, 95% CI 1.40-7.42) and patent ductus arteriosus requiring surgery (OR 2.14, 95% CI 1.10-4.15). CONCLUSION: MWL between 5% to 15% is a potentially optimal window of MWL. Increasing average TFA in the first week is associated with adverse neonatal outcomes. Prospective studies evaluating MWL and TFA and relationship to outcomes in EP neonates are needed. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273, https://clinicaltrials.gov/ct2/show/NCT01378273 .

Perinatal COVID-19 outcomes: evaluating the strength of current evidence.

Purpose of the Study: Viral respiratory diseases, like those caused by novel strains of influenza and Coronaviridae, have historically disproportionately affected pregnant women and conferred increased risk of adverse perinatal outcomes. Initial reports published from Wuhan, China identified only limited symptoms in pregnant women and no cases of mortality, but more recent reports from other regions of the world have reported contrasting information. The purpose of the study was to evaluate initially published cases of SARS-CoV-2 infection in pregnant women in China and compare them to subsequently published studies from the remainder of the world.Materials and Methods: This review curates 199 maternal published cases of SARS-CoV-2 infection and COVID-19 initially reported in the literature from China and contrasts them to more recent literature reporting clinical findings and outcomes of 729 selected cases from the rest of the world, including the United States.Results: Overall, initial case reports and series from China reported no cases of maternal mortality, which contrasts with subsequent reports from other regions of the world demonstrating significant morbidity and mortality can and does occur in pregnant women infected with SARS-CoV-2.Conclusion: While initial reports suggest limited risks of infection in pregnancy with SARS-CoV-2, subsequent findings have demonstrated pregnant women are at risk for severe morbidity and mortality. Case studies and series that are imperative in the early stages of a pandemic to provide data on a novel pathogen cannot be used to provide generalizable information predicting group risks.

The "Baby Moses" Law: A Case for Improving Medicolegal Education for Pediatric Trainees.

Medicolegal education is not standardized for medical student or pediatric resident trainees throughout the United States. However, trainees will inevitably face patient encounters in which knowing state and federal laws are integral in properly treating and caring for the patient. Here, we present the case of treating an abandoned infant in Texas, the Baby Moses law, and how knowing state and federal laws enhance trainees' understanding and ability to care for their patients. We then discuss the paucity of medical literature surrounding medicolegal education curricula and the need for the development of a national curriculum on medicolegal education that starts in medical school and extends throughout residency and subspecialty training.

Neonatal mortality rates and association with antenatal corticosteroids at Kamuzu Central Hospital.

OBJECTIVE: Malawi has one of the highest child mortality rates in the world, and neonates account for nearly half of all under-five mortality. No previous study has reported neonatal outcomes in Malawi over 12 months. We aimed to evaluate outcomes in the neonatal intensive care unit (NICU) at Kamuzu Central Hospital (KCH) and to determine if there was an association between increased survival and antenatal corticosteroid (ACS) exposure. STUDY DESIGN: We introduced a prospective, observational electronic database to collect 122 de-identified variables related to neonatal outcomes for all neonates admitted to the KCH NICU over 12 months. Patients with congenital anomalies were excluded. We compared neonatal mortality rates in neonates who were exposed to ACS compared to those who were not. Statistical methodology included the Wilcoxon rank sum test, Fisher's exact test, and logistic regression. RESULTS: Of 2051 neonates admitted to the KCH NICU, the overall neonatal mortality rate was 23.1% and remained similar across 12 months. Mortality was inversely related to birth weight, and outborn neonates referred to KCH had the highest mortality rate (29%). After controlling for confounding covariates, inborn infants exposed to ACS had significantly lower odds of death compared to those without exposure to ACS (adjusted odds ratio = 0.46, 95% confidence interval: 0.24-0.88, p = 0.020). CONCLUSION: Lower birth weight, outborn, and no ACS exposure were associated with increased mortality. ACS was associated with a 54% reduction in odds of mortality in inborn neonates highlighting the need for further evaluations of ACS use in resource-limited settings.

The Development of the Human Microbiome: Why Moms Matter.

The human body is cohabitated with trillions of commensal bacteria that are essential for our health. However, certain bacteria can also cause diseases in the human host. Before the microbiome can be attributed to disease risk and pathogenesis, normal acquisition and development of the microbiome must be understood. Here, we explore the evidence surrounding in utero microbial exposures and the significant of this exposure in the proper development of the fetal and neonatal microbiome. We further explore the development of the fetal and neonatal microbiome and its relationship to preterm birth, feeding practices, and mode of delivery, and maternal diet.

Clinical Importance of Placental Testing among Suspected Cases of Congenital Zika Syndrome.

Contemporaneous Zika virus (ZIKV) strains can cause congenital Zika syndrome (CZS). Current ZIKV clinical laboratory testing strategies are limited and include IgM serology (which may wane 12 weeks after initial exposure) and nucleic acid testing (NAT) of maternal serum, urine, and placenta for (+) strand ZIKV RNA (which is often transient). The objectives of this study were to determine if use of additional molecular tools, such as quantitative PCR and microscopy, would add to the diagnostic value of current standard placental ZIKV testing in cases with maternal endemic exposure and indeterminate testing. ZIKV RNA was quantified from dissected sections of placental villi, chorioamnion sections, and full cross-sections of umbilical cord in all cases examined. Quantitation with high-resolution automated electrophoresis determined relative amounts of precisely verified ZIKV (74-nt amplicons). In order to localize and visualize stable and actively replicating placental ZIKV in situ, labeling of flaviviridae glycoprotein, RNA ISH against both (+) and (⁻) ZIKV-specific ssRNA strands, and independent histologic examination for significant pathologic changes were employed. We demonstrate that the use of these molecular tools added to the diagnostic value of placental ZIKV testing among suspected cases of congenital Zika syndrome with poorly ascribed maternal endemic exposure.

Timing of gestational exposure to Zika virus is associated with postnatal growth restriction in a murine model.

BACKGROUND: Vertical transmission of Zika virus leads to infection of neuroprogenitor cells and destruction of brain parenchyma. Recent evidence suggests that the timing of infection as well as host factors may affect vertical transmission. As a result, congenital Zika virus infection may only become clinically apparent in the postnatal period. OBJECTIVE: We sought to develop an outbred mouse model of Zika virus vertical transmission to determine if the timing of gestational Zika virus exposure yields phenotypic differences at birth and through adolescence. We hypothesized that later gestational inoculations would only become apparent in adolescence. STUDY DESIGN: To better recapitulate human exposures, timed pregnant Swiss-Webster dams (n = 15) were subcutaneously inoculated with 1 × 104 plaque-forming units of first passage contemporary Zika virus HN16 strain or a mock injection on embryonic day 4, 8, or 12 with bioactive antiinterferon alpha receptor antibody administered in days preceding and proceeding inoculation. The antibody was given to prevent the robust type I interferon signaling cascade that make mice inherently resistant to Zika virus infection. At birth and adolescence (6 weeks of age) offspring were assessed for growth, brain weight, and biparietal head diameters, and Zika virus viral levels by reverse transcription-polymerase chain reaction or in situ hybridization. RESULTS: Pups of Zika virus-infected dams infected at embryonic days 4 and 8 but not 12 were growth restricted (P < .003). Brain weights were significantly smaller at birth (P = .01) for embryonic day 8 Zika virus-exposed offspring. At 6 weeks of age, biparietal diameters were smaller for all Zika virus-exposed males and females (P < .05), with embryonic day 8-exposed males smallest by biparietal diameter and growth-restriction measurements (weight >2 SD, P = .0007). All pups and adolescent mice were assessed for Zika virus infection by reverse transcription-polymerase chain reaction. Analysis of all underweight pups reveled 1 to be positive for neuronal Zika virus infection by in situ hybridization, while a second moribund animal was diffusely positive at 8 days of age by Zika virus infectivity throughout the brain, kidneys, and intestine. CONCLUSION: These findings demonstrate that postnatal effects of infection occurring at single time points continue to be detrimental to offspring in the postnatal period in a subset of littermates and subject to a window of gestational susceptibility coinciding with placentation. This model recapitulates frequently encountered clinical scenarios in nonendemic regions, including the majority of the United States, where travel-related exposure occurs in short and well-defined windows of gestation. Our low rate of infection and relatively rare evidence of congenital Zika syndrome parallels human population-based data.