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Item Early Brain and Abdominal Oxygenation in Extremely Low Birth Weight Infants(Springer Nature, 2022) Chock, Valerie Y.; Smith, Emily; Tan, Sylvia; Ball, M. Bethany; Das, Abhik; Hintz, Susan R.; Kirpalani, Haresh; Bell, Edward F.; Chalak, Lina F.; Cotten, C. Michael; Widness, John A.; Kennedy, Kathleen A.; Ohls, Robin K.; Seabrook, Ruth B.; Patel, Ravi M.; Laptook, Abbot R.; Mancini, Toni; Sokol, Gregory M.; Walsh, Michele C.; Yoder, Bradley A.; Poindexter, Brenda B.; Chawla, Sanjay; D’Angio, Carl T.; Higgins, Rosemary D.; Van Meurs, Krisa P.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of MedicineBackground: Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined. Methods: A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables. Results: In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001). Conclusion: Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population. Impact: Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.Item Genetic predictors of severe intraventricular hemorrhage in extremely low-birthweight infants(Springer Nature, 2021) Thornburg, Courtney D.; Erickson, Stephen W.; Page, Grier P.; Clark, Erin A. S.; DeAngelis, Margaret M.; Hartnett, M. Elizabeth; Goldstein, Ricki F.; Dagle, John M.; Murray, Jeffrey C.; Poindexter, Brenda B.; Das, Abhik; Cotten, C. Michael; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of MedicineObjective: To test associations between grades 3 or 4 (severe) intraventricular hemorrhage (IVH) and single nucleotide polymorphisms (SNPs) associated with coagulation, inflammation, angiogenesis, and organ development in an exploratory study. Study design: Extremely low-birthweight (ELBW) infants enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's (NRN) Cytokines Study were included if they had cranial ultrasound (CUS) and genotyping data available in the NRN Anonymized DNA Repository and Database. Associations between SNPs and IVH severity were tested with multivariable logistic regression analysis. Result: One hundred thirty-nine infants with severe IVH and 687 infants with grade 1 or 0 IVH were included. One thousand two hundred seventy-nine SNPs were genotyped. Thirteen were preliminarily associated with severe IVH including five related to central nervous system (CNS) neuronal and neurovascular development. Conclusion: Genetic variants for CNS neuronal and neurovascular development may be associated with severe IVH in premature infants.Item Gestational Weight Gain and Pregnancy Outcomes among Nulliparous Women(Thieme, 2021) Dude, Annie M.; Grobman, William; Haas, David; Mercer, Brian M.; Parry, Samuel; Silver, Robert M.; Wapner, Ronald; Wing, Deborah; Saade, George; Reddy, Uma; Iams, Jay; Kominiarek, Michelle A.; Obstetrics and Gynecology, School of MedicineObjective: To determine the association between total gestational weight gain and perinatal outcomes. Study design: Data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be (NuMoM2b) study were used. Total gestational weight gain was categorized as inadequate, adequate, or excessive based on the 2009 Institute of Medicine guidelines. Outcomes examined included hypertensive disorders of pregnancy, mode of delivery, shoulder dystocia, large for gestational age or small for-gestational age birth weight, and neonatal intensive care unit admission. Results: Among 8,628 women, 1,666 (19.3%) had inadequate, 2,945 (34.1%) had adequate, and 4,017 (46.6%) had excessive gestational weight gain. Excessive gestational weight gain was associated with higher odds of hypertensive disorders (adjusted odds ratio [aOR] = 2.05, 95% confidence interval [CI]: 1.78-2.36) Cesarean delivery (aOR = 1.24, 95% CI: 1.09-1.41), and large for gestational age birth weight (aOR = 1.49, 95% CI: 1.23-1.80), but lower odds of small for gestational age birth weight (aOR = 0.59, 95% CI: 0.50-0.71). Conversely, inadequate gestational weight gain was associated with lower odds of hypertensive disorders (aOR = 0.75, 95% CI: 0.62-0.92), Cesarean delivery (aOR = 0.77, 95% CI: 0.65-0.92), and a large for gestational age birth weight (aOR = 0.72, 95% CI: 0.55-0.94), but higher odds of having a small for gestational age birth weight (aOR = 1.64, 95% CI: 1.37-1.96). Conclusion: Both excessive and inadequate gestational weight gain are associated with adverse maternal and neonatal outcomes.Item Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children(Elsevier, 2017-08) Newton, Kimberly P.; Feldman, Haruna S.; Chambers, Christina D.; Wilson, Laura; Behling, Cynthia; Clark, Jeanne M.; Molleston, Jean P.; Chalasani, Naga; Sanyal, Arun J.; Fishbein, Mark H.; Lavine, Joel E.; Schwimmer, Jeffrey B.; Medicine, School of MedicineOBJECTIVES: To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD. STUDY DESIGN: A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category. RESULTS: Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P < .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62). CONCLUSION: Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.Item Marijuana use, fetal growth, and uterine artery Dopplers(Taylor & Francis, 2022) Bruno, Ann M.; Blue, Nathan R.; Allshouse, Amanda A.; Haas, David M.; Shanks, Anthony L.; Grobman, William A.; Simhan, Hyagriv; Reddy, Uma M.; Silver, Robert M.; Metz, Torri D.; Obstetrics and Gynecology, School of MedicineObjective: Marijuana (MJ) use is associated with adverse effects on fetal growth. We aimed to investigate the timing of suboptimal fetal growth onset in MJ-exposed pregnancies. In addition, we aimed to explore the relationship between MJ-exposure and both abnormal uterine artery (UtA) Doppler parameters and small for gestational age (SGA). Study design: This was a secondary analysis of a prospective multicenter cohort that enrolled nulliparous individuals delivering non-anomalous fetuses beyond 20 weeks' gestation. Marijuana exposure was ascertained by self-report or clinical urine toxicology testing. Ultrasound estimated fetal weights (EFWs) were assessed in participants at both 16w0d-21w6d and 22w0d-29w6d. EFWs and birth weight (BW) were converted to weight percentiles (wPCT). EFW and BW wPCTs were calculated using population-based standards. Additionally, a customized standard designed to be applicable to both EFWs and BWs within the same model was also used to allow for EFW to BW percentile trajectories. The primary outcome, longitudinal wPCT, was compared between individuals with and without MJ use in a linear mixed-effects regression model adjusting for tobacco. For modeling, wPCT was smoothed across gestational age; MJ was estimated as an intercept and linear difference in the slope of gestational age. UtA Doppler notching, resistance index (RI), and pulsatility index (PI) at 16w0d-21w6d were compared using t-test and χ2. SGA at delivery was also compared. Results: Nine thousand one hundred and sixty-three individuals met inclusion criteria; 136 (1.5%) used MJ during pregnancy. Individuals who used MJ were more likely to be younger, identify as non-Hispanic Black, and have had less education. Fetuses exposed to MJ had lower wPCT beginning at 28 weeks using population-based and customized standards, when compared to those without exposure. UtA notching, PI, and RI were similar between groups. SGA was more frequent in neonates exposed to MJ using both population-based (22 vs. 9%, p<.001) and customized (25 vs. 14%, p<.001) curves. Conclusions: MJ-exposed fetuses were estimated to be smaller than unexposed fetuses starting at 28 weeks' gestation across both growth standards without a difference in UtA Doppler parameters.Item Regional trends in birth weight in low- and middle-income countries 2013–2018(BMC, 2020-12-17) Marete, Irene; Ekhaguere, Osayame; Bann, Carla M.; Bucher, Sherri L.; Nyongesa, Paul; Patel, Archana B.; Hibberd, Patricia L.; Saleem, Sarah; Goldenberg, Robert L.; Goudar, Shivaprasad S.; Derman, Richard J.; Garces, Ana L.; Krebs, Nancy F.; Chomba, Elwyn; Carlo, Waldemar A.; Lokangaka, Adien; Bauserman, Melissa; Koso‑Thomas, Marion; Moore, Janet L.; McClure, Elizabeth M.; Esamai, Fabian; Pediatrics, School of MedicineBackground: Birth weight (BW) is a strong predictor of neonatal outcomes. The purpose of this study was to compare BWs between global regions (south Asia, sub-Saharan Africa, Central America) prospectively and to determine if trends exist in BW over time using the population-based maternal and newborn registry (MNHR) of the Global Network for Women'sand Children's Health Research (Global Network). Methods: The MNHR is a prospective observational population-based registryof six research sites participating in the Global Network (2013-2018), within five low- and middle-income countries (Kenya, Zambia, India, Pakistan, and Guatemala) in threeglobal regions (sub-Saharan Af rica, south Asia, Central America). The birth weights were obtained for all infants born during the study period. This was done either by abstracting from the infants' health facility records or from direct measurement by the registry staff for infants born at home. After controlling for demographic characteristics, mixed-effect regression models were utilized to examine regional differences in birth weights over time. Results: The overall BW meanswere higher for the African sites (Zambia and Kenya), 3186 g (SD 463 g) in 2013 and 3149 g (SD 449 g) in 2018, ascompared to Asian sites (Belagavi and Nagpur, India and Pakistan), 2717 g (SD450 g) in 2013 and 2713 g (SD 452 g) in 2018. The Central American site (Guatemala) had a mean BW intermediate between the African and south Asian sites, 2928 g (SD 452) in 2013, and 2874 g (SD 448) in 2018. The low birth weight (LBW) incidence was highest in the south Asian sites (India and Pakistan) and lowest in the African sites (Kenya and Zambia). The size of regional differences varied somewhat over time with slight decreases in the gap in birth weights between the African and Asian sites and slight increases in the gap between the African and Central American sites. Conclusions: Overall, BWmeans by global region did not change significantly over the 5-year study period. From 2013 to 2018, infants enrolled at the African sites demonstrated the highest BW means overall across the entire study period, particularly as compared to Asian sites. The incidence of LBW was highest in the Asian sites (India and Pakistan) compared to the African and Central American sites. Trial registration The study is registered at clinicaltrials.gov. ClinicalTrial.gov Trial Registration: NCT01073475.Item Three essays on the impact of political and economic shocks during childhood on health outcomes : evidence from developing countries(2016-11-07) Hawash, Ronia Ahmed; Royalty, Anne; Osili, Una; Gupta, Sumedha; Wessel, JenniferThe dissertation consists of three essays which attempt to capture causal relationships between shocks during childhood and before birth, and later health outcomes. Exogenous shocks such as the experiences of war and political upheaval are treated as natural experiments which minimize problems of endogeneity and selection that are present in most association studies. The first essay examines how exposure to civil war during childhood affects females’ outcomes including age at first marriage, fertility, and second generation infant mortality using the Biafra war which took place in Nigeria between years 1967 and 1970. The study uses difference-in-difference analysis to show that females that witnessed war during early adolescence got married younger than their peers not exposed to the war, and were more likely to have higher fertility and second-generation infant mortality. The second essay uses the same shock, the Biafra war, to test if males’ and females’ exposure to community-level violence results in higher risk of experiencing domestic violence in their marital relationships in the long-run. The study conducts difference-in-difference analysis on females and males separately to show that the males’ exposure to the war at ages 13 and older is the main mechanism behind females being victims of domestic violence in the long-run. The third essay examines the impact of acute prenatal stress on birth weight using the 2011 Egyptian revolution fatalities as an indicator for exposure to violence and stressful events. Results show that higher prenatal stress resulting from political conflict during the first and second trimesters of pregnancy has a significant negative impact on birth weight. This finding is robust to restricting the sample to siblings’ data and using mother fixed effects, suggesting that neither observable nor unobservable characteristics of mothers are driving the results.Item Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS)(American Medical Association, 2023-09-05) Chock, Valerie Y.; Kirpalani, Haresh; Bell, Edward F.; Tan, Sylvia; Hintz, Susan R.; Ball, M. Bethany; Smith, Emily; Das, Abhik; Loggins, Yvonne C.; Sood, Beena G.; Chalak, Lina F.; Wyckoff, Myra H.; Kicklighter, Stephen D.; Kennedy, Kathleen A.; Patel, Ravi M.; Carlo, Waldemar A.; Johnson, Karen J.; Watterberg, Kristi L.; Sánchez, Pablo J.; Laptook, Abbot R.; Seabrook, Ruth B.; Cotten, C. Michael; Mancini, Toni; Sokol, Gregory M.; Ohls, Robin K.; Hibbs, Anna Maria; Poindexter, Brenda B.; Reynolds, Anne Marie; DeMauro, Sara B.; Chawla, Sanjay; Baserga, Mariana; Walsh, Michele C.; Higgins, Rosemary D.; Van Meurs, Krisa P.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of MedicineImportance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, setting, and participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main outcomes and measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia.