Antibiotic Exposure and Growth Patterns in Preterm, Very Low Birth Weight Infants

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Pyle, Joseph B. Cantey, L. Steven Brown, Roy Heyne, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-106896/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jan, 2021 Read the published version in Maternal Health, Neonatology and Perinatology → Version 1 posted 12 You are reading this latest preprint version Abstract Background. Antibiotic exposure in term infants has been associated with later obesity. Premature, very-low-birth-weight (birth weight ≤1500 grams) infants in the neonatal intensive care unit frequently are exposed to antibiotics. Our hypothesis was that in preterm infants, there is a positive linear and dose-dependent relationship between antibiotic exposure and growth from birth through 12 months’ corrected age. Methods . Retrospective analysis of prospectively collected data of all antibiotic use among inborn, preterm (≤32 weeks’ gestation), very-low-birth-weight infants admitted to the neonatal intensive care unit at Parkland Memorial Hospital and followed in the Low Birth Weight Clinic at Children’s Medical Center, Dallas, TX. Antibiotic use was quantified by days of therapy which was compared with weight and length parameters at birth, 36 weeks’ postmenstrual age, and 2, 4, 6, and 12 months’ corrected age. The change in weight and length z-scores from birth to all subsequent age points was calculated. Stepwise multivariate regression analysis was performed for weight, length, and weight-for-length delta z-scores at each age point. Results . During the 18-month study, 161 infants received a median of 11 (IQR, 5.5-19.5) antibiotic days of therapy which was not associated with weight or length delta z-scores from birth through 12 months’ corrected age. Conclusion . Association of prolonged antibiotic use and neonatal morbidities and mortality may override the potential association with increased weight gain in the NICU and beyond. Maternal & Fetal Medicine Very low birth weight neonate antibiotic obesity stewardship Background Antibiotic exposure in early infancy has been associated with later obesity, presumably from alteration of the intestinal microbiome that leads to modulation of host metabolism. ( 1 , 2 ) Antibiotic therapy also may result in long-lasting perturbations of metabolic pathways, thereby increasing the risk for metabolic syndrome and increased adiposity in adult life. ( 3 – 5 ) Although such outcomes have been associated with low birth weight, ( 6 – 8 ) the impact of antibiotic exposure in the neonatal intensive care unit (NICU) on growth among preterm infants is not known. Therefore, the objective of this study was to determine the effect of antibiotic use on weight and growth patterns in preterm, very-low-birth-weight (VLBW, birth weight ≤ 1500 grams) infants in the NICU. We hypothesized that during a period of critical bacterial microbiome development, there is a positive linear and dose-dependent relationship between antibiotic exposure and growth from birth through 12 months corrected age. Methods This study was a retrospective analysis of prospectively collected data of all antibiotic use among inborn, preterm (≤ 32 weeks’ gestation), and VLBW infants admitted to the NICU at Parkland Memorial Hospital, Dallas, TX, from 7/1/2011 to 12/31/2012 and subsequently followed in the Low Birth Weight Follow-up Clinic at Children’s Medical Center (CMC), Dallas as their medical home. Antibiotic use was quantified by days of therapy (DOT) which was determined by multiplying the number of antibiotic doses by the dosing interval, then dividing by 24 hours (i.e., 4 doses of ampicillin administered every 8 hours = 1.33 DOT). ( 9 ) DOT were compared with weight and length parameters that were obtained at birth, 36 weeks’ postmenstrual age, and approximately 2, 4, 6, and 12 months’ corrected age. Pertinent clinical, laboratory, microbiologic, and outcome data were collected on all infants from the electronic health record. Severity of illness was calculated for all infants using the Clinical Risk Index for Babies (CRIB)-II score, a validated risk-adjustment instrument for prediction of mortality among VLBW infants that incorporates gestational age, birth weight, gender, temperature on admission, and initial base deficit. ( 10 ) CRIB-II scores range from 0–27 with higher scores predictive of greater mortality risk. For example, scores of 0, 5, 10, and 15 predict a mortality risk of 0.2%, 1.4%, 12.2%, and 56.8%, respectively. The daily weight of each infant was obtained by the bedside nurse and weekly length measurement was performed by the NICU dieticians using a standardized measuring board. In addition, the following data were obtained on each infant during the NICU stay: total number of days that the infant was NPO which was defined as ≤ 1 feeding per 24-hour period, total number of days that the infant received total parenteral nutrition, and the caloric density of enteral feeds that the infant received at 36 weeks’ postmenstrual age. A standardized feeding protocol was utilized throughout the study period, and there was no use of donor human milk. Intrauterine growth restriction (IUGR) was defined as a ponderal index < 10% for gestational age ( 11 ) while small for gestational age was defined as birth weight < 10%. Sepsis was defined as a positive culture of a clinically relevant bacterial or fungal pathogen from a normally sterile site and for which the infant received an antimicrobial agent for ≥ 5 days. ( 12 ) Sepsis was considered to be early or late-onset if it occurred at ≤ or > 72 hours postnatal age, respectively. Bronchopulmonary dysplasia (BPD) was defined as need for oxygen at 36 weeks’ postmenstrual age. ( 13 ) The diagnosis of a patent ductus arteriosus (PDA) required confirmation by echocardiography and treatment with indomethacin or surgical closure. Necrotizing enterocolitis (NEC) was defined as modified Bell stage IIa or greater. ( 14 ) Weight and length z-scores at birth and 36 weeks’ postmenstrual age were calculated using the 2013 Fenton growth chart. ( 15 ) The WHO Anthropometric calculator was used to calculate weight-for-length z-scores, adjusted for gestational age, from weight and length measurements obtained on follow-up visits at 1–3 months, 3–5 months, 5–8 months, and 10–14 months chronologic age, which corresponded to pediatric care provider visits at approximately 2, 4, 6, and 12 months corrected age. ( 16 ) The change in weight z-score and length-z-score from birth to 36 weeks postmenstrual age, and birth to 2, 4, 6, and 12 months corrected age was then calculated. Statistical analyses . Descriptive analyses, including mean and standard deviation or median and interquartile range, were performed as indicated. All tests were two-tailed, and a p-value < 0.05 was considered significant. Univariate linear regression was used to evaluate the relationship between change in z-score for weight and length from birth to each subsequent age point and demographic and clinical variables, including days of antibiotic therapy. A stepwise multivariate regression model was performed for weight, length and weight-for-length delta z-scores at each age point. Pearson correlations were calculated for all variables; p-value < 0.05 was considered significant. To control for severity of illness, bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, and late onset sepsis were included in the multivariate analysis. Post hoc power analysis showed that a sample size of 126 patients produced a two-sided confidence interval with a lower limit of 0.13 and an upper limit of 0.45 when the sample correlation was 0.30. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center with waiver of informed consent. Results During the 18-month study period, 187 inborn, preterm, VLBW infants were admitted to the NICU. Of these 187 infants, 23 died and 3 were transferred to the cardiovascular intensive care unit at CMC before 36 weeks’ postmenstrual age and were excluded from the study. The clinical characteristics of the remaining 161 infants are shown in Table 1 . The majority of infants were singleton, born by cesarean delivery, appropriate for gestational age, and did not have PDA, NEC, BPD, or late-onset sepsis. None of the infants had early-onset sepsis. Of the 161 infants, 157 received at least 48 hours of antibiotics and the median antibiotic DOT received was 11 (IQR, 5.5–19.5). Table 1 Characteristics of the study population Number of infants 161 Gestational age (weeks, mean ± SD) 28.5 ± 1.97 Delivery by caesarean section 124 (77%) Singleton, twin, triplet gestation 117 (73%), 39 (24%), 5 (3%) Male gender 81 (50%) Birth weight (grams; mean ± SD) 1130 ± 229 Birth length (cm; mean ± SD) 37 ± 3 Ponderal index (mean ± SD) 2.22 ± 0.28 Intrauterine growth restriction 14 (9%) Small for gestational age 9 (6%) CRIB-II score (mean ± SD) 7.4 ± 2.9 Antibiotic exposure (median; IQR)* 11 (5.5–19.5) Bronchopulmonary dysplasia 29 (18%) Patent ductus arteriosus 40 (25%) Necrotizing enterocolitis (Bell stage ≥ 2) 8 (5%) Late-onset sepsis 1 episode, 19 (12%); 2 episodes, 9 (6%) SD, standard deviation; cm, centimeter; IQR, interquartile range *Antibiotic exposure defined as days of therapy (DOT). Of the 161 infants, 155 (96%) had at least 1 follow-up visit to the CMC Low Birth Weight Follow-up clinic. Complete weight and length data were available for 151 (94%) infants at ∼2-month visit, 134 (83%) infants at ∼4 months, 136 (84%) infants at ∼6 months, and 129 (80%) infants at ∼12 months. Weight alone was available for an additional 1 infant at 2 months, 1 infant at 4 months, 3 infants at 6 months, and 1 infant at 12 months. The weight and length z-scores at birth were within the standard range for gestational age by the Fenton curves, with the average weight and length z-scores being 0.074 ± 0.91 and 0.096 ± 0.93, respectively. The weight and length z-scores decreased by an entire standard deviation from birth to 36 weeks corrected age, to -0.98 ± 0.92 and − 1.18 ± 0.82, respectively. After 36 weeks corrected age, there was a steady increase toward a normal average z-score of zero for both weight and length, although the length z-score remained lower than the weight z-score. At 2 months corrected age, there was an elevated weight-for-length z-score of 0.997 ± 1.08 but by 12 months corrected age, the average weight-for-length z-score approached zero. Univariate linear regression was performed to evaluate the impact of antibiotic exposure as well as demographic features and clinical diagnoses on growth patterns (Table 2 , 3 ). There was a negative correlation between antibiotic exposure and weight delta z-score at only 36 weeks and 2 months corrected age. A negative correlation with weight z-scores also was seen at 36 weeks corrected age in males, at 2 months corrected age for late-onset sepsis, at 36 weeks, 2 months, and 4 months for total days of TPN, and at 36 weeks and 2 months for total days NPO. CRIB-II score and BPD had a negative relationship with change in weight z-score at multiple time points (Table 2 ). A positive correlation with weight z-scores was seen in infants who were SGA, especially at 4, 6, and 12 months corrected ages. Gestational age showed a persistently strong positive correlation with weight delta z-score, indicating that infants born later in gestation had improved catch-up weight gain through the first-year post-term. Table 2 Weight delta z-scores from birth to subsequent age points by univariate linear regression analysis # Weight Delta Z-score at Age of Evaluation ∼36 weeks ∼2 months ∼4 months ∼6 months ∼12 months No. of infants 161 151 134 136 129 Gestational age 0.274* 0.477* 0.446* 0.445* 0.479* Mode of delivery 0.270* + 0.177* + 0.121 0.130 0.111 Multiple gestation 0.091 0.081 0.034 0.022 0.025 Gender -0.208** ♦ -0.111 -0.072 -0.091 -0.040 IUGR 0.052 0.194* 0.163 0.164 0.162 SGA 0.059 0.078 0.191* 0.247* 0.250* CRIB-II score -0.206** -0.379** -0.334** -0.310** -0.321** Antibiotic exposure -0.375* -0.295* -0.151 -0.080 -0.119 BPD -0.294** -0.262** -0.195** -0.127 -0.209** PDA -0.138 -0.107 -0.077 -0.053 -0.112 NEC -0.174 -0.023 0.051 0.069 0.035 Late-onset sepsis -0.074 -0.192** -0.129 -0.052 -0.075 TPN (total days) -0.397** -0.356** -0.206** -0.131 -0.127 Total days of NPO -0.367** -1.313** -0.177 -0.092 -0.109 Caloric density (36 weeks, kcal/ounce) -0.024 0.066 0.022 0.018 0.006 IUGR, intrauterine growth restriction; SGA, small for gestational age; CRIB, Clinical Risk Index for Babies; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition; NPO, nothing per oral # Pearson correlation * Positive correlation, P < 0.05 + Positive correlation with delivery by caesarean section ** Negative correlation, P < 0.05 ♦ Negative correlation with male gender Table 3 Length delta z-score from birth to subsequent age points by univariate linear regression analysis # Length Delta Z-score at Age of Evaluation ∼36 weeks ∼2 months ∼4 months ∼6 months ∼12 months No. of infants 161 151 134 136 129 Gestational age 0.042 0.281* 0.329* 0.222* 0.251* Delivery mode 0.159* + 0.191* + 0.118 0.052 0.073 Multiple gestation 0.015 0.076 0.061 0.042 0.086 Gender -0.069 -0.116 -0.014 -0.018 -0.016 IUGR 0.253** 0.091 0.041 0.070 0.043 SGA 0.106 0.039 0.219* 0.283* 0.291* CRIB-II score 0.263 0.244** 0.232** 0.130 0.118 Antibiotic exposure 0.021 -0.144 -0.092 -0.040 -0.077 BPD -0.120 -0.216** -0.217** -0.138 -0.130 PDA -0.153 -0.171** -0.151 0.008 0.018 NEC -0.020 0.015 -0.002 0.073 0.003 Late-onset sepsis 0.244* -0.019 -0.056 -0.049 0.007 TPN (total days) 0.033 -0.216** -0.159 -0.073 -0.112 Caloric density (36 weeks, kcal/ounce) -0.070 0.003 0.012 0.015 0.081 IUGR, intrauterine growth restriction; SGA, small for gestational age; CRIB, Clinical Risk Index for Babies; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition; NPO, nothing per oral # Pearson correlation *Positive correlation, P < 0.05 + Positive correlation with delivery by caesarean section **Negative correlation, P < 0.05 Factors associated with a change in length z-score from birth to each subsequent age-point also were assessed. Antibiotic exposure had no relationship with length delta z-score at any age point. IUGR, CRIB-II score, BPD, PDA and total days of TPN all showed small negative relationships for at least one of the early age points: 36 weeks, 2 months and/or 4 months corrected age. Gestational age and SGA had a positive relationship with length delta z-score at all age points except 36 weeks’ corrected age, indicating that infants born at older gestational ages or SGA had improved catch-up growth over the first year of age. Stepwise multivariate regression analysis was performed to predict weight delta z-scores from birth to each subsequent age point using the variables that were significant on at least one time point by univariate analysis (antibiotic exposure, gestational age, gender, delivery mode, IUGR, SGA, CRIB-II score, BPD, late-onset sepsis, total days of TPN, and total days NPO; Table 4). Antibiotic exposure was not associated with weight delta z-scores at any age point in the multivariate model. The strongest positive predictor for weight at all age points was length with the converse also true. Gestational age remained a moderate predictor of weight but not length. Total duration of TPN was a strong negative predictor for weight delta z-score from birth to 36 weeks’ corrected age. The change in z-score for weight, length, and weight-for-length between each consecutive age point had no significant predictors (data not shown). Table 4. Weight (a) and length (b) delta z-scores from birth to subsequent age points by stepwise multivariate regression analysis # a) The total days of parenteral nutrition showed a strong negative correlation with weight z-scores at 36 weeks’ postmenstrual age, while positive associations were seen with gestational age, length, and IUGR status. Antibiotic exposure was not significant at any time point. P-value was ≤ 0.05 for all displayed z-score values. Delta Weight z-Score ∼36 weeks ∼2 months ∼4 months ∼6 months ∼12 months No. of infants 161 151 134 136 129 Length 0.359 0.476 0.562 0.599 0.606 Gestational age - 0.346 0.242 0.272 0.316 IUGR 0.137 0.174 0.138 0.151 0.119 Total parenteral nutrition (total days) -0.349 - - - - Delivery mode 0.174 - - - - Late-onset sepsis - -0.153 - - - PDA - 0.143 - - - b) Positive associations were seen with the length delta z-score and late-onset sepsis (p<0.05). Delta Length z-Score ∼36 weeks ∼2 months ∼4 months ∼6 months ∼12 months Weight delta z-score 0.444 0.568 0.644 0.674 0.701 Late-onset sepsis 0.152 - - - - # Pearson correlation Discussion Unlike other studies that have associated antibiotic use in term infants, older children, and animals with increased weight, length, and BMI, ( 1 , 2 , 17 – 19 ) there was no correlation between antibiotic exposure and changes in weight or length z-scores from birth through 12 months corrected age among preterm VLBW infants in the NICU in this study. The strongest predictor of increased weight gain at all age points was higher gestational age, a finding that remained significant after controlling for severity of illness and clinical factors. This study also demonstrated the overall poor weight and length gain for VLBW infants when compared to in-utero growth patterns, but the only variable associated with a significant negative change in weight z-scores was duration of TPN use. The substantial decrease in weight and length percentiles during the NICU hospitalization is a well-documented phenomenon in premature infants, and it is believed to be due to inadequate nutritional intake in combination with co-morbidities such as BPD, NEC, late-onset sepsis, and PDA which increase metabolic demand. ( 20 , 21 ) Inadequate nutrition leading to poor growth in VLBW infants has been associated with neurodevelopmental impairment. ( 20 , 22 ) Both SGA and appropriate for gestational age VLBW infants who are below the 10th percentile for height or weight at 2 years of age have significantly lower mental development (MDI) and psychomotor development indices (PDI) scores as well as higher rates of cerebral palsy. ( 23 ) Ehrenkranz et al. ( 20 ) demonstrated that in-hospital growth velocity was associated significantly with growth after discharge, cerebral palsy, MDI < 70, and PDI < 70 at 18–22 months corrected age. Despite antibiotics being among the most frequently prescribed medications in the NICU, ( 24 ), ( 25 , 26 ) they did not augment either the weight or length of preterm infants in this study. Similarly, the lack of improved or rapid weight gain in our patients makes the contribution of antibiotics to development of metabolic syndrome unlikely. ( 27 ) The lack of correlation between antibiotic exposure and weight gain may be due to low overall use of antibiotic therapy as measured by DOT or the type of antibiotics used. ( 1 , 28 , 29 ), We previously have shown that antibiotic DOT was significantly less in the study inborn NICU at PMH than in our Level 4 outborn NICU at CMC, although comparison with other similar inborn NICUs has not been performed. ( 9 , 30 , 31 ) The more common use of ampicillin and gentamicin than the third-generation cephalosporin and carbapenem agents may have affected the results of this study. It would be important to determine whether similar findings are seen in NICUs with higher antibiotic use and exposure to broader spectrum antimicrobial agents. One of the limitations of this study is its retrospective analysis, although the information on antibiotic use was obtained prospectively and included every agent used during the study period. Moreover, the optimal metric to study antibiotic use in the NICU is not known, and it is possible that other measures may yield different results. However, DOT has been used in adult and neonatal populations and encompasses not only the days that the infant received antibiotic therapy, but the quantity utilized. The study also did not account for antibiotic therapy that the infant may have received after discharge from the NICU. Another limitation was that complete weight and length data were available for only 84% and 80% of infants at ∼6 and 12 months corrected age, respectively, and longer follow-up may be necessary to detect alterations in growth percentiles especially with respect to obesity. In addition, there currently is no universally accepted and validated measure for body mass index, weight-for-length, or ponderal index in the neonatal population. ( 32 ) Strengths of the study include use of a standardized protocol for initiation and advancement of enteral feeds as well as TPN use throughout the study period that should minimize the effect of clinician variability on overall growth patterns. However, information on such variables as timing of initial enteral feeding, use of maternal milk or formula, and composition of TPN was not addressed. Conclusion In conclusion, among the study population of VLBW infants ≤ 32 weeks’ gestational age, the study hypothesis of a linear and dose-dependent relationship between antibiotic exposure and weight or length z-scores from birth through 12 months corrected age was not confirmed. The previously described negative association of prolonged antibiotic use and increased risk of NEC, late-onset sepsis, BPD, retinopathy of prematurity, invasive fungal disease, neurodevelopmental impairment, and death likely override any potential benefit with improved weight gain in the NICU and beyond. ( 33 – 39 ) Abbreviations NICU, neonatal intensive care unit; VLBW, very low birth weight; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; TPN, total parenteral nutrition; NPO, nothing per os; PMA, post menstrual age; VLBW, very-low-birth-weight; PMH, Parkland Memorial Hospital; CMC, Children’s Medical Center Declarations Ethics approval: The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center with a waiver of informed consent. Consent for Publication: not applicable Availability of Data and Materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests: The authors declare that they have no competing interests. Funding: This work was supported by a Gerber Novice Researcher Award (#5200762201) to Joseph B. Cantey. The Gerber Foundation had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The other authors have no financial relationships relevant to this article to disclose. Authors’ Contributions: 1) AKP assisted with the study design and data collection, drafted the initial manuscript, and approved the final manuscript as submitted. 2) JBC designed the study, assisted throughout the data collection process, reviewed and revised the manuscript, and approved the final manuscript as submitted. 3) LSB performed the statistical analyses, reviewed and edited the manuscript, and approved the final manuscript as submitted. 4) RH , EH , AH , EMB , and CSL contributed to conceptualization and design of the study, reviewed and edited the manuscript, and approved the final manuscript as submitted. 5) PSW assisted with data collection, reviewed and edited the manuscript, and approved the final manuscript as submitted. 6) PJS supervised all stages of study conceptualization, design, data collection, critical manuscript editing, and approved the final manuscript as submitted. Acknowledgements: The authors thank John Gard, PharmD, Melody Bush, RPh, Sara Mureeba, PharmD, and Sheeba Tharayil, PharmD of the Parkland Memorial Hospital NICU pharmacy for assistance with this study and their dedication to antimicrobial stewardship efforts. References Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 2014;168(11):1063-9. Ajslev TA, Andersen CS, Gamborg M, Sorensen TI, Jess T. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes (Lond). 2011;35(4):522-9. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705-21. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, et al. 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Clin Perinatol. 2012;39(1):61-8. Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK, Jr., Smith PB, et al. Medication use in the neonatal intensive care unit. Am J Perinatol. 2014;31(9):811-21. Kerkhof GF, Willemsen RH, Leunissen RW, Breukhoven PE, Hokken-Koelega AC. Health profile of young adults born preterm: negative effects of rapid weight gain in early life. J Clin Endocrinol Metab. 2012;97(12):4498-506. Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics. 2015;135(4):617-26. Rajpal DK, Klein JL, Mayhew D, Boucheron J, Spivak AT, Kumar V, et al. Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models. PLoS One. 2015;10(12):e0145499. Shipp KD, Chiang T, Karasick S, Quick K, Nguyen ST, Cantey JB. Antibiotic Stewardship Challenges in a Referral Neonatal Intensive Care Unit. Am J Perinatol. 2016;33(5):518-24. Cantey JB, Wozniak PS, Pruszynski JE, Sanchez PJ. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. Lancet Infect Dis. 2016;16(10):1178-84. Olsen IE, Lawson ML, Ferguson AN, Cantrell R, Grabich SC, Zemel BS, et al. BMI Curves for Preterm Infants. Pediatrics. 2015. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr. 2011;159(5):720-5. Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sanchez PJ, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009;123(1):58-66. Cantey JB, Pyle AK, Wozniak PS, Hynan LS, Sanchez PJ. Early Antibiotic Exposure and Adverse Outcomes in Preterm, Very Low Birth Weight Infants. J Pediatr. 2018;203:62-7. Novitsky A, Tuttle D, Locke RG, Saiman L, Mackley A, Paul DA. Prolonged early antibiotic use and bronchopulmonary dysplasia in very low birth weight infants. Am J Perinatol. 2015;32(1):43-8. Ting JY, Roberts A, Sherlock R, Ojah C, Cieslak Z, Dunn M, et al. Duration of Initial Empirical Antibiotic Therapy and Outcomes in Very Low Birth Weight Infants. Pediatrics. 2019;143(3). Ting JY, Synnes A, Roberts A, Deshpandey A, Dow K, Yoon EW, et al. Association Between Antibiotic Use and Neonatal Mortality and Morbidities in Very Low-Birth-Weight Infants Without Culture-Proven Sepsis or Necrotizing Enterocolitis. JAMA Pediatr. 2016;170(12):1181-7. Ting JY, Synnes A, Roberts A, Deshpandey AC, Dow K, Yang J, et al. Association of Antibiotic Utilization and Neurodevelopmental Outcomes among Extremely Low Gestational Age Neonates without Proven Sepsis or Necrotizing Enterocolitis. Am J Perinatol. 2018;35(10):972-8. Cite Share Download PDF Status: Published Journal Publication published 29 Jan, 2021 Read the published version in Maternal Health, Neonatology and Perinatology → Version 1 posted Review # 4 received at journal 30 Nov, 2020 Review # 2 received at journal 29 Nov, 2020 Review # 1 received at journal 27 Nov, 2020 Reviewer # 4 agreed at journal 18 Nov, 2020 Reviewer # 2 agreed at journal 16 Nov, 2020 Reviewer # 3 agreed at journal 16 Nov, 2020 Reviewers invited by journal 16 Nov, 2020 Reviewer # 1 agreed at journal 16 Nov, 2020 Editor assigned by journal 12 Nov, 2020 Submission checks completed at journal 12 Nov, 2020 Editor invited by journal 12 Nov, 2020 First submitted to journal 08 Nov, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-106896","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":4728647,"identity":"46171c49-605b-4d68-8672-dbb955dc12e8","order_by":0,"name":"Alaina K. Pyle","email":"","orcid":"","institution":"Connecticut Children's Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alaina","middleName":"K.","lastName":"Pyle","suffix":""},{"id":4728648,"identity":"5617d9f1-9790-4f40-9e0d-ad5923dbd0f3","order_by":1,"name":"Joseph B. Cantey","email":"","orcid":"","institution":"University of Texas UTHSCSA: The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"B.","lastName":"Cantey","suffix":""},{"id":4728649,"identity":"d01322a7-4ccb-41ea-8c58-7505cbfe6b52","order_by":2,"name":"L. Steven Brown","email":"","orcid":"","institution":"Parkland Health and Hospital System","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"L.","middleName":"Steven","lastName":"Brown","suffix":""},{"id":4728650,"identity":"44052244-72a8-43e0-99bd-4e9bedf855af","order_by":3,"name":"Roy Heyne","email":"","orcid":"","institution":"University of Texas Southwestern Department of Pediatrics","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Roy","middleName":"","lastName":"Heyne","suffix":""},{"id":4728651,"identity":"df989b5f-3534-4083-b185-275a9e9eee8e","order_by":4,"name":"Phillip S. Wozniak","email":"","orcid":"","institution":"The Ohio State University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Phillip","middleName":"S.","lastName":"Wozniak","suffix":""},{"id":4728652,"identity":"1bb9dde2-9901-499b-bd8e-1282dd722908","order_by":5,"name":"Elizabeth Heyne","email":"","orcid":"","institution":"Children's Medical Center of Dallas: Children's Health Children's Medical Center Dallas","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"","lastName":"Heyne","suffix":""},{"id":4728653,"identity":"152d05c9-a29d-43a0-9abe-f5579d5a9015","order_by":6,"name":"Amy Holcombe","email":"","orcid":"","institution":"Children's Medical Center Dallas","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amy","middleName":"","lastName":"Holcombe","suffix":""},{"id":4728654,"identity":"695d9abd-cac4-4d84-8ec7-5944ac867ec6","order_by":7,"name":"Elizabeth M. Brammer","email":"","orcid":"","institution":"Parkland Hospital: Parkland Health and Hospital System","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"M.","lastName":"Brammer","suffix":""},{"id":4728655,"identity":"0d99b427-7702-41b4-9a21-1fd0d978bed4","order_by":8,"name":"Cheryl S. Lair","email":"","orcid":"","institution":"Parkland Memorial Hospital: Parkland Health and Hospital System","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cheryl","middleName":"S.","lastName":"Lair","suffix":""},{"id":4728656,"identity":"bee441e7-ba3f-470f-a888-c7d94b8a74f0","order_by":9,"name":"Pablo J Sanchez","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-2437-1247","institution":"Nationwide Children's Hospital - The Ohio State University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"J","lastName":"Sanchez","suffix":""}],"badges":[],"createdAt":"2020-11-12 11:25:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-106896/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-106896/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40748-021-00126-6","type":"published","date":"2021-01-29T15:02:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":13616631,"identity":"25926287-e5c2-4680-be2c-db32da3eae55","added_by":"auto","created_at":"2021-09-17 06:50:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":590979,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-106896/v1/5c71f444-cba0-482a-b630-40fdcefef397.pdf"}],"financialInterests":"","formattedTitle":"Antibiotic Exposure and Growth Patterns in Preterm, Very Low Birth Weight Infants","fulltext":[{"header":"Background","content":" \u003cp\u003eAntibiotic exposure in early infancy has been associated with later obesity, presumably from alteration of the intestinal microbiome that leads to modulation of host metabolism.\u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e Antibiotic therapy also may result in long-lasting perturbations of metabolic pathways, thereby increasing the risk for metabolic syndrome and increased adiposity in adult life.\u003csup\u003e(\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/sup\u003e Although such outcomes have been associated with low birth weight,\u003csup\u003e(\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e the impact of antibiotic exposure in the neonatal intensive care unit (NICU) on growth among preterm infants is not known. Therefore, the objective of this study was to determine the effect of antibiotic use on weight and growth patterns in preterm, very-low-birth-weight (VLBW, birth weight\u0026thinsp;\u0026le;\u0026thinsp;1500 grams) infants in the NICU. We hypothesized that during a period of critical bacterial microbiome development, there is a positive linear and dose-dependent relationship between antibiotic exposure and growth from birth through 12 months corrected age.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eThis study was a retrospective analysis of prospectively collected data of all antibiotic use among inborn, preterm (\u0026le;\u0026thinsp;32 weeks\u0026rsquo; gestation), and VLBW infants admitted to the NICU at Parkland Memorial Hospital, Dallas, TX, from 7/1/2011 to 12/31/2012 and subsequently followed in the Low Birth Weight Follow-up Clinic at Children\u0026rsquo;s Medical Center (CMC), Dallas as their medical home. Antibiotic use was quantified by days of therapy (DOT) which was determined by multiplying the number of antibiotic doses by the dosing interval, then dividing by 24 hours (i.e., 4 doses of ampicillin administered every 8 hours\u0026thinsp;=\u0026thinsp;1.33 DOT).\u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e DOT were compared with weight and length parameters that were obtained at birth, 36 weeks\u0026rsquo; postmenstrual age, and approximately 2, 4, 6, and 12 months\u0026rsquo; corrected age.\u003c/p\u003e \u003cp\u003ePertinent clinical, laboratory, microbiologic, and outcome data were collected on all infants from the electronic health record. Severity of illness was calculated for all infants using the Clinical Risk Index for Babies (CRIB)-II score, a validated risk-adjustment instrument for prediction of mortality among VLBW infants that incorporates gestational age, birth weight, gender, temperature on admission, and initial base deficit.\u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/sup\u003e CRIB-II scores range from 0\u0026ndash;27 with higher scores predictive of greater mortality risk. For example, scores of 0, 5, 10, and 15 predict a mortality risk of 0.2%, 1.4%, 12.2%, and 56.8%, respectively. The daily weight of each infant was obtained by the bedside nurse and weekly length measurement was performed by the NICU dieticians using a standardized measuring board. In addition, the following data were obtained on each infant during the NICU stay: total number of days that the infant was NPO which was defined as \u0026le;\u0026thinsp;1 feeding per 24-hour period, total number of days that the infant received total parenteral nutrition, and the caloric density of enteral feeds that the infant received at 36 weeks\u0026rsquo; postmenstrual age. A standardized feeding protocol was utilized throughout the study period, and there was no use of donor human milk.\u003c/p\u003e \u003cp\u003eIntrauterine growth restriction (IUGR) was defined as a ponderal index\u0026thinsp;\u0026lt;\u0026thinsp;10% for gestational age\u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/sup\u003e while small for gestational age was defined as birth weight\u0026thinsp;\u0026lt;\u0026thinsp;10%. Sepsis was defined as a positive culture of a clinically relevant bacterial or fungal pathogen from a normally sterile site and for which the infant received an antimicrobial agent for \u0026ge;\u0026thinsp;5 days.\u003csup\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/sup\u003e Sepsis was considered to be early or late-onset if it occurred at \u0026le;\u0026thinsp;or \u0026gt;\u0026thinsp;72 hours postnatal age, respectively. Bronchopulmonary dysplasia (BPD) was defined as need for oxygen at 36 weeks\u0026rsquo; postmenstrual age.\u003csup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e The diagnosis of a patent ductus arteriosus (PDA) required confirmation by echocardiography and treatment with indomethacin or surgical closure. Necrotizing enterocolitis (NEC) was defined as modified Bell stage IIa or greater.\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWeight and length z-scores at birth and 36 weeks\u0026rsquo; postmenstrual age were calculated using the 2013 Fenton growth chart.\u003csup\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/sup\u003e The WHO Anthropometric calculator was used to calculate weight-for-length z-scores, adjusted for gestational age, from weight and length measurements obtained on follow-up visits at 1\u0026ndash;3 months, 3\u0026ndash;5 months, 5\u0026ndash;8 months, and 10\u0026ndash;14 months chronologic age, which corresponded to pediatric care provider visits at approximately 2, 4, 6, and 12 months corrected age.\u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e The change in weight z-score and length-z-score from birth to 36 weeks postmenstrual age, and birth to 2, 4, 6, and 12 months corrected age was then calculated.\u003c/p\u003e \u003cp\u003e \u003cem\u003eStatistical analyses\u003c/em\u003e. Descriptive analyses, including mean and standard deviation or median and interquartile range, were performed as indicated. All tests were two-tailed, and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. Univariate linear regression was used to evaluate the relationship between change in z-score for weight and length from birth to each subsequent age point and demographic and clinical variables, including days of antibiotic therapy. A stepwise multivariate regression model was performed for weight, length and weight-for-length delta z-scores at each age point. Pearson correlations were calculated for all variables; p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. To control for severity of illness, bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, and late onset sepsis were included in the multivariate analysis. Post hoc power analysis showed that a sample size of 126 patients produced a two-sided confidence interval with a lower limit of 0.13 and an upper limit of 0.45 when the sample correlation was 0.30.\u003c/p\u003e \u003cp\u003eThe study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center with waiver of informed consent.\u003c/p\u003e "},{"header":"Results","content":" \u003cp\u003eDuring the 18-month study period, 187 inborn, preterm, VLBW infants were admitted to the NICU. Of these 187 infants, 23 died and 3 were transferred to the cardiovascular intensive care unit at CMC before 36 weeks\u0026rsquo; postmenstrual age and were excluded from the study. The clinical characteristics of the remaining 161 infants are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The majority of infants were singleton, born by cesarean delivery, appropriate for gestational age, and did not have PDA, NEC, BPD, or late-onset sepsis. None of the infants had early-onset sepsis. Of the 161 infants, 157 received at least 48 hours of antibiotics and the median antibiotic DOT received was 11 (IQR, 5.5\u0026ndash;19.5).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of infants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational age (weeks, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDelivery by caesarean section\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 (77%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSingleton, twin, triplet gestation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 (73%), 39 (24%), 5 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale gender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirth weight (grams; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1130\u0026thinsp;\u0026plusmn;\u0026thinsp;229\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirth length (cm; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePonderal index (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntrauterine growth restriction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmall for gestational age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRIB-II score (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntibiotic exposure (median; IQR)*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (5.5\u0026ndash;19.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBronchopulmonary dysplasia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatent ductus arteriosus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNecrotizing enterocolitis (Bell stage\u0026thinsp;\u0026ge;\u0026thinsp;2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate-onset sepsis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 episode, 19 (12%); 2 episodes, 9 (6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eSD, standard deviation; cm, centimeter; IQR, interquartile range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Antibiotic exposure defined as days of therapy (DOT).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf the 161 infants, 155 (96%) had at least 1 follow-up visit to the CMC Low Birth Weight Follow-up clinic. Complete weight and length data were available for 151 (94%) infants at \u0026sim;2-month visit, 134 (83%) infants at \u0026sim;4 months, 136 (84%) infants at \u0026sim;6 months, and 129 (80%) infants at \u0026sim;12 months. Weight alone was available for an additional 1 infant at 2 months, 1 infant at 4 months, 3 infants at 6 months, and 1 infant at 12 months.\u003c/p\u003e \u003cp\u003eThe weight and length z-scores at birth were within the standard range for gestational age by the Fenton curves, with the average weight and length z-scores being 0.074\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91 and 0.096\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93, respectively. The weight and length z-scores decreased by an entire standard deviation from birth to 36 weeks corrected age, to -0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92 and \u0026minus;\u0026thinsp;1.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82, respectively. After 36 weeks corrected age, there was a steady increase toward a normal average z-score of zero for both weight and length, although the length z-score remained lower than the weight z-score. At 2 months corrected age, there was an elevated weight-for-length z-score of 0.997\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08 but by 12 months corrected age, the average weight-for-length z-score approached zero.\u003c/p\u003e \u003cp\u003eUnivariate linear regression was performed to evaluate the impact of antibiotic exposure as well as demographic features and clinical diagnoses on growth patterns (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was a negative correlation between antibiotic exposure and weight delta z-score at only 36 weeks and 2\u0026nbsp;months corrected age. A negative correlation with weight z-scores also was seen at 36 weeks corrected age in males, at 2\u0026nbsp;months corrected age for late-onset sepsis, at 36 weeks, 2 months, and 4\u0026nbsp;months for total days of TPN, and at 36 weeks and 2\u0026nbsp;months for total days NPO. CRIB-II score and BPD had a negative relationship with change in weight z-score at multiple time points (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A positive correlation with weight z-scores was seen in infants who were SGA, especially at 4, 6, and 12\u0026nbsp;months corrected ages. Gestational age showed a persistently strong positive correlation with weight delta z-score, indicating that infants born later in gestation had improved catch-up weight gain through the first-year post-term.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eWeight delta z-scores from birth to subsequent age points by univariate linear regression analysis\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eWeight Delta Z-score at Age of Evaluation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;36 weeks\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;2 months\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;4 months\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;6 months\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;12 months\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo. of infants\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.274*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.477*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.446*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.445*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.479*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMode of delivery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.270*\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.177*\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultiple gestation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.208**\u003csup\u003e\u0026diams;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIUGR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.194*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSGA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.191*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.247*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.250*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRIB-II score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.206**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.379**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.334**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.310**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.321**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntibiotic exposure\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.375*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.295*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.119\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBPD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.294**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.262**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.195**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.209**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePDA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNEC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate-onset sepsis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.192**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTPN (total days)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.397**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.356**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.206**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal days of NPO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.367**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.313**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCaloric density (36 weeks, kcal/ounce)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eIUGR, intrauterine growth restriction; SGA, small for gestational age; CRIB, Clinical Risk Index for Babies; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition; NPO, nothing per oral\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e#\u003c/b\u003e\u003c/sup\u003e Pearson correlation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e* Positive correlation, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e+\u003c/sup\u003e Positive correlation with delivery by caesarean section\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e** Negative correlation, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026diams;\u003c/sup\u003e Negative correlation with male gender\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLength delta z-score from birth to subsequent age points by univariate linear regression analysis\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eLength Delta Z-score at Age of Evaluation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;36 weeks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;2 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;4 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026sim;12 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo. of infants\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.281*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.329*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.222*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.251*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDelivery mode\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.159*\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.191*\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultiple gestation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.086\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIUGR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.253**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSGA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.219*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.283*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.291*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRIB-II score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.244**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.232**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntibiotic exposure\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBPD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.216**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.217**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePDA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.171**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNEC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate-onset sepsis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.244*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTPN (total days)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.216**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCaloric density (36 weeks, kcal/ounce)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.081\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eIUGR, intrauterine growth restriction; SGA, small for gestational age; CRIB, Clinical Risk Index for Babies; BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition; NPO, nothing per oral\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e#\u003c/b\u003e\u003c/sup\u003e Pearson correlation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Positive correlation, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e+\u003c/sup\u003e Positive correlation with delivery by caesarean section\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e**Negative correlation, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFactors associated with a change in length z-score from birth to each subsequent age-point also were assessed. Antibiotic exposure had no relationship with length delta z-score at any age point. IUGR, CRIB-II score, BPD, PDA and total days of TPN all showed small negative relationships for at least one of the early age points: 36 weeks, 2\u0026nbsp;months and/or 4\u0026nbsp;months corrected age. Gestational age and SGA had a positive relationship with length delta z-score at all age points except 36 weeks\u0026rsquo; corrected age, indicating that infants born at older gestational ages or SGA had improved catch-up growth over the first year of age.\u003c/p\u003e \u003cp\u003eStepwise multivariate regression analysis was performed to predict weight delta z-scores from birth to each subsequent age point using the variables that were significant on at least one time point by univariate analysis (antibiotic exposure, gestational age, gender, delivery mode, IUGR, SGA, CRIB-II score, BPD, late-onset sepsis, total days of TPN, and total days NPO; Table\u0026nbsp;4). Antibiotic exposure was not associated with weight delta z-scores at any age point in the multivariate model. The strongest positive predictor for weight at all age points was length with the converse also true. Gestational age remained a moderate predictor of weight but not length. Total duration of TPN was a strong negative predictor for weight delta z-score from birth to 36 weeks\u0026rsquo; corrected age. The change in z-score for weight, length, and weight-for-length between each consecutive age point had no significant predictors (data not shown).\u003c/p\u003e \n\u003cp\u003e\u003cstrong\u003eTable 4. Weight (a) and length (b) delta z-scores from birth to subsequent age points by stepwise multivariate regression analysis\u003csup\u003e#\u003c/sup\u003e \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea)\u003c/strong\u003e The total days of parenteral nutrition showed a strong negative correlation with weight z-scores at 36 weeks\u0026rsquo; postmenstrual age, while positive associations were seen with gestational age, length, and IUGR status. Antibiotic exposure was not significant at any time point. P-value was \u0026le; 0.05 for all displayed z-score values.\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 70px;\" rowspan=\"2\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" colspan=\"5\" width=\"71%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDelta Weight z-Score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;36 weeks\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;2 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;4 months \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;6 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;12 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo. of infants\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e161\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e151\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e134\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e129\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eLength\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.359\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.476\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.562\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.599\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e0.606\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eGestational age\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.346\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.242\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.272\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e0.316\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eIUGR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.137\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.174\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.138\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.151\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e0.119\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal parenteral nutrition (total days)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-0.349\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDelivery mode\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.174\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eLate-onset sepsis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-0.153\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003ePDA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e0.143\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"15%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eb)\u0026nbsp;\u003c/strong\u003ePositive associations were seen with the length delta z-score and late-onset sepsis (p\u0026lt;0.05).\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"29%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"70%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDelta Length z-Score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;36 weeks\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;2 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;4 months \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;6 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"15%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026sim;12 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003e\u003cstrong\u003eWeight delta z-score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e0.444\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e0.568\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e0.644\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e0.674\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"15%\"\u003e\n\u003cp\u003e0.701\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003e\u003cstrong\u003eLate-onset sepsis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e0.152\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"13%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"14%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"15%\"\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e#\u003c/sup\u003e\u003c/strong\u003e Pearson correlation\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eUnlike other studies that have associated antibiotic use in term infants, older children, and animals with increased weight, length, and BMI, \u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/sup\u003e there was no correlation between antibiotic exposure and changes in weight or length z-scores from birth through 12 months corrected age among preterm VLBW infants in the NICU in this study. The strongest predictor of increased weight gain at all age points was higher gestational age, a finding that remained significant after controlling for severity of illness and clinical factors. This study also demonstrated the overall poor weight and length gain for VLBW infants when compared to in-utero growth patterns, but the only variable associated with a significant negative change in weight z-scores was duration of TPN use.\u003c/p\u003e \u003cp\u003eThe substantial decrease in weight and length percentiles during the NICU hospitalization is a well-documented phenomenon in premature infants, and it is believed to be due to inadequate nutritional intake in combination with co-morbidities such as BPD, NEC, late-onset sepsis, and PDA which increase metabolic demand.\u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/sup\u003e Inadequate nutrition leading to poor growth in VLBW infants has been associated with neurodevelopmental impairment.\u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/sup\u003e Both SGA and appropriate for gestational age VLBW infants who are below the 10th percentile for height or weight at 2\u0026nbsp;years of age have significantly lower mental development (MDI) and psychomotor development indices (PDI) scores as well as higher rates of cerebral palsy.\u003csup\u003e(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/sup\u003e Ehrenkranz et al.\u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e demonstrated that in-hospital growth velocity was associated significantly with growth after discharge, cerebral palsy, MDI\u0026thinsp;\u0026lt;\u0026thinsp;70, and PDI\u0026thinsp;\u0026lt;\u0026thinsp;70\u0026nbsp;at 18\u0026ndash;22\u0026nbsp;months corrected age. Despite antibiotics being among the most frequently prescribed medications in the NICU, \u003csup\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/sup\u003e they did not augment either the weight or length of preterm infants in this study. Similarly, the lack of improved or rapid weight gain in our patients makes the contribution of antibiotics to development of metabolic syndrome unlikely.\u003csup\u003e(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe lack of correlation between antibiotic exposure and weight gain may be due to low overall use of antibiotic therapy as measured by DOT or the type of antibiotics used.\u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e),\u003c/sup\u003e We previously have shown that antibiotic DOT was significantly less in the study inborn NICU at PMH than in our Level 4 outborn NICU at CMC, although comparison with other similar inborn NICUs has not been performed.\u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/sup\u003e The more common use of ampicillin and gentamicin than the third-generation cephalosporin and carbapenem agents may have affected the results of this study. It would be important to determine whether similar findings are seen in NICUs with higher antibiotic use and exposure to broader spectrum antimicrobial agents.\u003c/p\u003e \u003cp\u003eOne of the limitations of this study is its retrospective analysis, although the information on antibiotic use was obtained prospectively and included every agent used during the study period. Moreover, the optimal metric to study antibiotic use in the NICU is not known, and it is possible that other measures may yield different results. However, DOT has been used in adult and neonatal populations and encompasses not only the days that the infant received antibiotic therapy, but the quantity utilized. The study also did not account for antibiotic therapy that the infant may have received after discharge from the NICU. Another limitation was that complete weight and length data were available for only 84% and 80% of infants at \u0026sim;6 and 12 months corrected age, respectively, and longer follow-up may be necessary to detect alterations in growth percentiles especially with respect to obesity. In addition, there currently is no universally accepted and validated measure for body mass index, weight-for-length, or ponderal index in the neonatal population.\u003csup\u003e(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/sup\u003e Strengths of the study include use of a standardized protocol for initiation and advancement of enteral feeds as well as TPN use throughout the study period that should minimize the effect of clinician variability on overall growth patterns. However, information on such variables as timing of initial enteral feeding, use of maternal milk or formula, and composition of TPN was not addressed.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, among the study population of VLBW infants\u0026thinsp;\u0026le;\u0026thinsp;32 weeks\u0026rsquo; gestational age, the study hypothesis of a linear and dose-dependent relationship between antibiotic exposure and weight or length z-scores from birth through 12 months corrected age was not confirmed. The previously described negative association of prolonged antibiotic use and increased risk of NEC, late-onset sepsis, BPD, retinopathy of prematurity, invasive fungal disease, neurodevelopmental impairment, and death likely override any potential benefit with improved weight gain in the NICU and beyond.\u003csup\u003e(\u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37 CR38\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eNICU, neonatal intensive care unit; VLBW, very low birth weight; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; TPN, total parenteral nutrition; NPO, nothing per os; PMA, post menstrual age; VLBW, very-low-birth-weight; PMH, Parkland Memorial Hospital; CMC, Children\u0026rsquo;s Medical Center\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval: \u003c/strong\u003eThe study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center with a waiver of informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication: \u003c/strong\u003enot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials: \u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests: \u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by a Gerber Novice Researcher Award (#5200762201) to Joseph B. Cantey. The Gerber Foundation had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The other authors have no financial relationships relevant to this article to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1) AKP\u003c/strong\u003e assisted with the study design and data collection, drafted the initial manuscript, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2) JBC\u003c/strong\u003e designed the study, assisted throughout the data collection process, reviewed and revised the manuscript, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3) LSB\u003c/strong\u003e performed the statistical analyses, reviewed and edited the manuscript, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4) RH\u003c/strong\u003e, \u003cstrong\u003eEH\u003c/strong\u003e, \u003cstrong\u003eAH\u003c/strong\u003e, \u003cstrong\u003eEMB\u003c/strong\u003e, and \u003cstrong\u003eCSL\u003c/strong\u003e contributed to conceptualization and design of the study, reviewed and edited the manuscript, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5) PSW\u003c/strong\u003e assisted with data collection, reviewed and edited the manuscript, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6) PJS\u003c/strong\u003e supervised all stages of study conceptualization, design, data collection, critical manuscript editing, and approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eThe authors thank John Gard, PharmD, Melody Bush, RPh, Sara Mureeba, PharmD, and Sheeba Tharayil, PharmD of the Parkland Memorial Hospital NICU pharmacy for assistance with this study and their dedication to antimicrobial stewardship efforts.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 2014;168(11):1063-9.\u003c/li\u003e\n\u003cli\u003eAjslev TA, Andersen CS, Gamborg M, Sorensen TI, Jess T. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes (Lond). 2011;35(4):522-9.\u003c/li\u003e\n\u003cli\u003eCox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705-21.\u003c/li\u003e\n\u003cli\u003eCho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012;488(7413):621-6.\u003c/li\u003e\n\u003cli\u003eBarker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. 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Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics. 2006;117(6):1979-87.\u003c/li\u003e\n\u003cli\u003eTripathi N, Cotten CM, Smith PB. Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol. 2012;39(1):61-8.\u003c/li\u003e\n\u003cli\u003eHsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK, Jr., Smith PB, et al. Medication use in the neonatal intensive care unit. Am J Perinatol. 2014;31(9):811-21.\u003c/li\u003e\n\u003cli\u003eKerkhof GF, Willemsen RH, Leunissen RW, Breukhoven PE, Hokken-Koelega AC. Health profile of young adults born preterm: negative effects of rapid weight gain in early life. J Clin Endocrinol Metab. 2012;97(12):4498-506.\u003c/li\u003e\n\u003cli\u003eSaari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics. 2015;135(4):617-26.\u003c/li\u003e\n\u003cli\u003eRajpal DK, Klein JL, Mayhew D, Boucheron J, Spivak AT, Kumar V, et al. Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models. PLoS One. 2015;10(12):e0145499.\u003c/li\u003e\n\u003cli\u003eShipp KD, Chiang T, Karasick S, Quick K, Nguyen ST, Cantey JB. Antibiotic Stewardship Challenges in a Referral Neonatal Intensive Care Unit. Am J Perinatol. 2016;33(5):518-24.\u003c/li\u003e\n\u003cli\u003eCantey JB, Wozniak PS, Pruszynski JE, Sanchez PJ. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. Lancet Infect Dis. 2016;16(10):1178-84.\u003c/li\u003e\n\u003cli\u003eOlsen IE, Lawson ML, Ferguson AN, Cantrell R, Grabich SC, Zemel BS, et al. BMI Curves for Preterm Infants. Pediatrics. 2015.\u003c/li\u003e\n\u003cli\u003eKuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr. 2011;159(5):720-5.\u003c/li\u003e\n\u003cli\u003eCotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sanchez PJ, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009;123(1):58-66.\u003c/li\u003e\n\u003cli\u003eCantey JB, Pyle AK, Wozniak PS, Hynan LS, Sanchez PJ. Early Antibiotic Exposure and Adverse Outcomes in Preterm, Very Low Birth Weight Infants. J Pediatr. 2018;203:62-7.\u003c/li\u003e\n\u003cli\u003eNovitsky A, Tuttle D, Locke RG, Saiman L, Mackley A, Paul DA. Prolonged early antibiotic use and bronchopulmonary dysplasia in very low birth weight infants. Am J Perinatol. 2015;32(1):43-8.\u003c/li\u003e\n\u003cli\u003eTing JY, Roberts A, Sherlock R, Ojah C, Cieslak Z, Dunn M, et al. Duration of Initial Empirical Antibiotic Therapy and Outcomes in Very Low Birth Weight Infants. Pediatrics. 2019;143(3).\u003c/li\u003e\n\u003cli\u003eTing JY, Synnes A, Roberts A, Deshpandey A, Dow K, Yoon EW, et al. Association Between Antibiotic Use and Neonatal Mortality and Morbidities in Very Low-Birth-Weight Infants Without Culture-Proven Sepsis or Necrotizing Enterocolitis. JAMA Pediatr. 2016;170(12):1181-7.\u003c/li\u003e\n\u003cli\u003eTing JY, Synnes A, Roberts A, Deshpandey AC, Dow K, Yang J, et al. Association of Antibiotic Utilization and Neurodevelopmental Outcomes among Extremely Low Gestational Age Neonates without Proven Sepsis or Necrotizing Enterocolitis. Am J Perinatol. 2018;35(10):972-8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"maternal-health-neonatology-and-perinatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mhnp","sideBox":"Learn more about [Maternal Health, Neonatology and Perinatology](http://mhnpjournal.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mhnp/default.aspx","title":"Maternal Health, Neonatology and Perinatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Very low birth weight, neonate, antibiotic, obesity, stewardship","lastPublishedDoi":"10.21203/rs.3.rs-106896/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-106896/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground.\u003c/strong\u003e Antibiotic exposure in term infants has been associated with later obesity.\u0026nbsp;Premature, very-low-birth-weight (birth weight ≤1500 grams) infants in the neonatal intensive care unit frequently are exposed to antibiotics.\u0026nbsp;Our hypothesis was that in preterm infants, there is a positive linear and dose-dependent relationship between antibiotic exposure and growth from birth through 12 months’ corrected age.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e. Retrospective analysis of prospectively collected data of all antibiotic use among inborn, preterm (≤32 weeks’ gestation), very-low-birth-weight infants admitted to the neonatal intensive care unit at Parkland Memorial Hospital and followed in the Low Birth Weight Clinic at Children’s Medical Center, Dallas, TX.\u0026nbsp;Antibiotic use was quantified by days of therapy which was compared with weight and length parameters at birth, 36 weeks’ postmenstrual age, and 2, 4, 6, and 12 months’ corrected age. \u0026nbsp;The change in weight and length z-scores from birth to all subsequent age points was calculated.\u0026nbsp;Stepwise multivariate regression analysis was performed for weight, length, and weight-for-length delta z-scores at each age point.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e. During the 18-month study, 161 infants received a median of 11 (IQR, 5.5-19.5) antibiotic days of therapy which was not associated with weight or length delta z-scores from birth through 12 months’ corrected age.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e. Association of prolonged antibiotic use and neonatal morbidities and mortality may override the potential association with increased weight gain in the NICU and beyond.\u0026nbsp;\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Antibiotic Exposure and Growth Patterns in Preterm, Very Low Birth Weight Infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-11-18 22:02:06","doi":"10.21203/rs.3.rs-106896/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-12-01T00:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-30T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-28T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-11-19T00:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-17T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-17T01:00:00+00:00","index":3,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-11-17T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-17T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-13T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-12T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-12T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-11-09T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"maternal-health-neonatology-and-perinatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mhnp","sideBox":"Learn more about [Maternal Health, Neonatology and Perinatology](http://mhnpjournal.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mhnp/default.aspx","title":"Maternal Health, Neonatology and Perinatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f8117499-8090-4918-8990-8cba6d6d0202","owner":[],"postedDate":"November 18th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1115923,"name":"Maternal \u0026 Fetal Medicine"}],"tags":[],"updatedAt":"2021-01-31T15:02:43+00:00","versionOfRecord":{"articleIdentity":"rs-106896","link":"https://doi.org/10.1186/s40748-021-00126-6","journal":{"identity":"maternal-health-neonatology-and-perinatology","isVorOnly":false,"title":"Maternal Health, Neonatology and Perinatology"},"publishedOn":"2021-01-29 15:02:18","publishedOnDateReadable":"January 29th, 2021"},"versionCreatedAt":"2020-11-18 22:02:06","video":"","vorDoi":"10.1186/s40748-021-00126-6","vorDoiUrl":"https://doi.org/10.1186/s40748-021-00126-6","workflowStages":[]},"version":"v1","identity":"rs-106896","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-106896","identity":"rs-106896","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}