Mode of delivery and weight shape the intestinal microbiome composition progression in preterm infants: results of a prospective study

Abstract Background: In preterm infants the intestinal microbiome differs markedly from term infants. However, it is unclear whether the microbiome follows infant specific maturation patterns or whether it is mainly characterized by varying states of dysbiosis. We investigated the development of the intestinal microbiome in extremely preterm infants over time by 16S rRNA amplicon sequencing. We analysed the first meconium and faecal samples from the 2 nd , 3 rd and 4 th weeks, and (clinical) metadata to identify the main factors influencing the microbiota composition development. Results: The study included 41 extremely preterm infants (gestational age 25-30 weeks; birth weight (BW) 430-990g). Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium and in weeks 2 and 3 an increased combined abundance of Escherichia and Bacteroides (maternal aerotolerant fecal bacteria) was associated with vaginal delivery (p=0.039, p=0.0002, p=0.034, respectively) while Staphylococcus epidermidis (skin bacterium) was associated with CS (p=0.001, p=0.0003 p=0.048, respectively). Secondly, a switch was observed from a microbiome dominated by S. epidermidis (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria, mainly represented by Klebsiella and Escherichia ), in which the stage of progression appeared to be dependent upon the current weight of the infant, irrespective of the week of sampling or the mode of birth. Conclusions: Our data shows that the mode of delivery does affect the meconium microbiome composition. It also suggests that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than gestational/postnatal age. We hypothesize that impaired growth, for example due the effects of diminished placental function during pregnancy, is a key factor in the maturation of the intestinal microbiome in extreme premature infants.

Download Full-text

Weight Shapes the Intestinal Microbiome in Preterm Infants: Results of a Prospective Observational Study

10.21203/rs.3.rs-264310/v1 ◽

2021 ◽

Author(s):

Fardou H. Heida ◽

Elisabeth M. W. Kooi ◽

Josef Wagner ◽

Thi-Yen Nguyen ◽

Jan B. F. Hulscher ◽

...

Keyword(s):

Preterm Infants ◽

Mode Of Delivery ◽

Intestinal Microbiome ◽

Skin Microbiome ◽

Term Infants ◽

Microbiome Composition ◽

Mode Of Birth ◽

Postconceptional Age ◽

Specific Factors ◽

Microbiome Development

Abstract Background: The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors. Methods: We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and feacal samples til the 4th week via 16S rRNA amplican sequencing. Results: We included 41 infants (gestational age 25-30 weeks; birth weight 430-990g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium and in weeks 2 and 3 an increased combined abundance of Escherichia and Bacteroides (maternal fecal representatives) was associated with vaginal delivery (p=0.021, p=0.0002, p=0.028, respectively) while Staphylococcus (skin microbiome representative) was associated with CS (p=0.0008, p=0.0003 p=0.046, respectively). Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria). Conclusions: Mode of delivery affects the meconium microbiome composition. It also suggests that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age.

Download Full-text

Weight shapes the intestinal microbiome in preterm infants: results of a prospective observational study

BMC Microbiology ◽

10.1186/s12866-021-02279-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fardou H. Heida ◽

Elisabeth M. W. Kooi ◽

Josef Wagner ◽

Thi-Yen Nguyen ◽

Jan B. F. Hulscher ◽

...

Keyword(s):

Preterm Infants ◽

Mode Of Delivery ◽

Intestinal Microbiome ◽

Skin Microbiome ◽

Term Infants ◽

Microbiome Composition ◽

Faecal Samples ◽

Mode Of Birth ◽

Postconceptional Age ◽

Specific Factors

Abstract Background The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors. Methods We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and faecal samples til the 4th week via 16 S rRNA amplican sequencing. Results We included 41 infants (gestational age 25–30 weeks; birth weight 430-990 g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium samples and in samples from weeks 2 and 3 the abundance of Escherichia and Bacteroides (maternal faecal representatives) were associated with vaginal delivery while Staphylococcus (skin microbiome representative) was associated with CS. Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria). Conclusions Our data show that the mode of delivery affects the meconium microbiome composition. They also suggest that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age as it less confounded by various infant-specific factors.

Download Full-text

The diversity of rearranged immunoglobulin heavy chain variable region genes in peripheral blood B cells of preterm infants is restricted by short third complementarity-determining regions but not by limited gene segment usage

Blood ◽

10.1182/blood.v97.5.1511 ◽

2001 ◽

Vol 97 (5) ◽

pp. 1511-1513 ◽

Cited By ~ 36

Author(s):

Michael Zemlin ◽

Karl Bauer ◽

Michael Hummel ◽

Sabine Pfeiffer ◽

Simone Devers ◽

...

Keyword(s):

B Cells ◽

Preterm Infants ◽

Heavy Chain ◽

Peripheral Blood ◽

Gene Segment ◽

Immunoglobulin Heavy Chain ◽

Term Infants ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Complementarity Determining Regions

The immunoglobulin diversity is restricted in fetal liver B cells. This study examined whether peripheral blood B cells of extremely preterm infants show similar restrictions (overrepresentation of some gene segments, short third complementarity-determining regions [CDR3]). DNA of rearranged immunoglobulin heavy chain genes was amplified by polymerase chain reaction, cloned, and sequenced. A total of 417 sequences were analyzed from 6 preterm infants (25-28 weeks of gestation), 6 term infants, and 6 adults. Gene segments from the entire VHand DH gene locus were rearranged in preterm infants, even though the DH7-27 segment was overrepresented (17% of rearrangements) compared to term infants (7%) and adults (2%). CDR3 was shorter in preterm infants (40 ± 10 nucleotides) than in term infants (44 ± 12) and adults (48 ± 14) (P < .001) due to shorter N regions. Somatic mutations were exclusively found in term neonates and adults (mutational frequency 0.8% and 1.8%). We conclude that preterm infants have no limitations in gene segment usage, whereas the diversity of CDR3 is restricted throughout gestation.

Download Full-text

The gut microbiome of extremely preterm infants randomized to the early progression of enteral feeding

Pediatric Research ◽

10.1038/s41390-021-01831-w ◽

2021 ◽

Author(s):

Ariel A. Salas ◽

Kent A. Willis ◽

Waldemar A. Carlo ◽

Nengjun Yi ◽

Li Zhang ◽

...

Keyword(s):

Human Milk ◽

Microbial Diversity ◽

Preterm Infants ◽

Enteral Feeding ◽

Gut Microbiome ◽

Mode Of Delivery ◽

Early Feeding ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Early Progression

Abstract Background Early progression of feeding could influence the development of the gut microbiome. Methods We collected fecal samples from extremely preterm infants randomized to receive either early (feeding day 2) or delayed (feeding day 5) feeding progression. After study completion, we compared samples obtained at three different time points (week 1, week 2, and week 3) to determine longitudinal differences in specific taxa between the study groups using unadjusted and adjusted negative binomial and zero-inflated mixed models. Analyses were adjusted for a mode of delivery, breastmilk intake, and exposure to antibiotics. Results We analyzed 137 fecal samples from 51 infants. In unadjusted and adjusted analyses, we did not observe an early transition to higher microbial diversity within samples (i.e., alpha diversity) or significant differences in microbial diversity between samples (i.e., beta diversity) in the early feeding group. Our longitudinal, single-taxon analysis found consistent differences in the genera Lactococcus, Veillonella, and Bilophila between groups. Conclusions Differences in single-taxon analyses independent of the mode of delivery, exposure to antibiotics, and breastmilk feeding suggest potential benefits of early progression of enteral feeding volumes. However, this dietary intervention does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. Trial Registration ClinicalTrials.gov identifier: NCT02915549. Impact Early progression of enteral feeding volumes with human milk reduces the duration of parenteral nutrition and the need for central venous access among extremely preterm infants. Early progression of enteral feeding leads to single-taxon differences in longitudinal analyses of the gut microbiome, but it does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. Randomization in enteral feeding trials creates appealing opportunities to evaluate the effects of human milk diets on the gut microbiome.

Download Full-text

Does early object exploration support gesture and language development in extremely preterm infants and full-term infants?

Journal of Communication Disorders ◽

10.1016/j.jcomdis.2018.09.004 ◽

2018 ◽

Vol 76 ◽

pp. 91-100 ◽

Cited By ~ 5

Author(s):

Mariagrazia Zuccarini ◽

Annalisa Guarini ◽

Jana Marie Iverson ◽

Erika Benassi ◽

Silvia Savini ◽

...

Keyword(s):

Language Development ◽

Preterm Infants ◽

Full Term ◽

Term Infants ◽

Object Exploration ◽

Extremely Preterm ◽

Extremely Preterm Infants

Download Full-text

Radiation Exposure of Premature Infants Beyond the Perinatal Period

Hospital Pediatrics ◽

10.1542/hpeds.2018-0008 ◽

2018 ◽

Vol 8 (11) ◽

pp. 672-678

Author(s):

Alexander H. Hogan ◽

Eran Bellin ◽

Lindsey Douglas ◽

Terry L. Levin ◽

Nora Esteban-Cruciani

Keyword(s):

Radiation Exposure ◽

Preterm Infants ◽

Premature Infants ◽

Low Socioeconomic Status ◽

Urban Hospital ◽

Term Infants ◽

Hospital System ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Birth Hospitalization

OBJECTIVES: To determine the odds of premature compared with term infants exceeding the recommended radiation exposure threshold in the first year after discharge from birth hospitalization. METHODS: In this observational retrospective cohort study, we compared the radiation exposure of premature and term infants between 2008 and 2015 in an urban hospital system. The primary outcome was crossing the radiation exposure threshold of 1 millisievert. We assessed prematurity’s effect on this outcome with multivariable logistic regression. RESULTS: In our study, 20 049 term and 2047 preterm infants met inclusion criteria. The population was approximately one-half female, predominantly multiracial or people of color (40% African American and 44% multiracial), and of low socioeconomic status. Premature infants had 2.25 times greater odds of crossing the threshold compared with term infants after adjustment for demographics (95% confidence interval [CI]: 1.66–3.05). Adjustment for complex chronic conditions, which are validated metrics of pediatric chronic illness, attenuated this association; however, premature infants still had 1.58 times greater odds of crossing the threshold (95% CI: 1.16–2.15). When the final model was analyzed by degree of prematurity, very preterm and extremely preterm infants were significantly more likely to cross the threshold (1.85 [95% CI: 1.03–3.32] and 2.53 [95% CI: 1.53–4.21], respectively), whereas late preterm infants were not (1.14 [95% CI: 0.73–1.78]). CONCLUSIONS: Premature infants crossed the recommended radiation threshold more often than term infants in the year after discharge from birth hospitalization.

Download Full-text

Peak Inspiratory Pressure During Delivery Room Resuscitation for Infants Born at Less Than 500 Grams.

10.46940/sjnp.02.1011 ◽

2020 ◽

pp. 1-4

Keyword(s):

Preterm Infants ◽

Neonatal Resuscitation ◽

Peak Inspiratory Pressure ◽

Delivery Room ◽

Inspiratory Pressure ◽

Temperature Management ◽

Pulmonary Mechanics ◽

Term Infants ◽

Extremely Preterm ◽

Extremely Preterm Infants

Introduction: With the advent of technological advancement and better scientific understanding it is possible now to successfully resuscitate and save babies born at less than 500 grams. Stabilization of these infants in the delivery room (DR) is one of the goals of the golden hour management. While some factors, including temperature management and airway care have standards, there is paucity of data on the optimal peak inspiratory pressure (PIP). The Neonatal Resuscitation Program (NRP) recommends using the same inflation pressure of 20 cm to 25 cm H2O for preterm infants as used for term infants. Preterm lungs are not the same as term infants. Due to the smaller lung volume, capacities and dynamic pulmonary mechanics, these preterm infants are prone to pulmonary complications including pneumothorax. Therefore, there is need to use PIP judiciously in the DR. Methods and Results: In this brief report we present two cases of newborn infants that were born at less than 500 grams and were successfully resuscitated with a lower PIP. The success criteria in the DR were heart rate greater than 100 per minute and adequate oxygen saturations minute by minute per NRP guidelines with minimal use of supplemental oxygen. Conclusion: While we need good prospectively designed studies to document the ideal PIP for these extreme preterm infants, we suggest a PIP lower than the currently recommended may be sufficient for some extremely preterm infants.

Download Full-text

Abstract 12713: Epidemiology and Mortality of Very and Extremely Preterm Infants With Congenital Heart Defects

Circulation ◽

10.1161/circ.132.suppl_3.12713 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Patricia Y Chu ◽

Jennifer S Li ◽

Andrzej S Kosinski ◽

Christoph P Hornik ◽

Kevin D Hill

Keyword(s):

Preterm Infants ◽

Gestational Age ◽

Congenital Heart ◽

Heart Defects ◽

Multivariate Logistic Regression Analysis ◽

Administrative Database ◽

Term Infants ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Nationally Representative

Introduction: Congenital heart disease (CHD) is estimated to occur in 6-10 per 1000 births. Although epidemiology and outcomes for term and near term infants with CHD are well described, data are limited for very and extremely preterm (VEP) infants. We used the Healthcare Cost and Utilization Project Kids’ Inpatient Database (KID), a nationally representative administrative database, to evaluate epidemiology and outcomes for VEP infants (25 to 32 weeks gestational age, GA) with CHD. Methods: Two separate cohorts were defined from the KID: an epidemiologic cohort including birth hospitalizations in ‘03, ’06, ’09 and ‘12; and an outcomes cohort including hospitalizations at a children’s hospital or pediatric unit for infants < 1 month of age in ‘06 and ‘09. CHD was defined by ICD-9-CM codes with severe CHD defined as those defects expected to be universally diagnosed during a preterm birth hospitalization. Weighted multivariate logistic regression analysis was used to calculate odds ratios (OR) for mortality, adjusted for race, sex, GA, year, small for gestational age and hospital teaching status. Results: Our epidemiologic and outcomes cohorts included 249,011 and 49,893 VEP infants, respectively. Incidence of CHD (116/1000 VEP births) and severe CHD (7/1000 VEP births) were both higher than previously reported in term infants. Relative risk of severe CHD in VEP vs term infants was 4.80 (95% CI 4.76, 4.84) and decreased with increasing GA (5.7 at 25 weeks GA to 4.3 at 31 weeks, p=0.005). Hospital mortality (Figure) was substantially higher for VEP infants with vs without severe CHD (26% vs 5%; adjusted OR 7.5 [95% CI: 5.9, 9.6]). Overall 16% of VEP infants with severe CHD underwent cardiac surgery during the neonatal hospitalization with mortality after surgery of 16%. Conclusions: CHD incidence is increased in very and extremely preterm infants and outcomes are poor. These data underscore the need for interventions to decrease preterm delivery when severe CHD is diagnosed in utero.

Download Full-text

Cord Blood Cytokine Levels Correlate With Types of Placental Pathology in Extremely Preterm Infants

Frontiers in Pediatrics ◽

10.3389/fped.2021.607684 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hussein Zein ◽

Khorshid Mohammad ◽

Lara M. Leijser ◽

Marie-Anne Brundler ◽

Adam Kirton ◽

...

Keyword(s):

Cord Blood ◽

Preterm Infants ◽

Placental Pathology ◽

Term Infants ◽

Group V ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Cytokine Levels ◽

Post Hoc ◽

Temporal Profiles

Background: Placental abnormalities are associated with inflammation and have been linked to brain injury in preterm infants. We studied the relationship between placental pathology and the temporal profiles of cytokine levels in extremely pre-term infants.Study Design: We prospectively enrolled 55 extremely preterm infants born between June 2017 and July 2018. Levels of 27 cytokines were measured in blood drawn from the umbilical artery at birth and from infants at 1–3 and 21–28 days of life. Placental pathology was grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I).Results: Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin (p = 0.038), G-CSF (p = 0.023), IFN-γ (p = 0.002), IL-1ra (p < 0.001), IL-4 (p = 0.005), IL-8 (p = 0.010), MCP-1 (p = 0.011), and TNFα (p = 0.002). Post-hoc analysis revealed sex differences between and within the placental pathology groups.Conclusion: Specific types of placental pathology may be associated with differential cytokine profiles in extremely pre-term infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.

Download Full-text

Drug utilisation in neonatal units in England and Wales: a national cohort study

European Journal of Clinical Pharmacology ◽

10.1007/s00228-021-03267-x ◽

2022 ◽

Author(s):

Asma Al-Turkait ◽

Lisa Szatkowski ◽

Imti Choonara ◽

Shalini Ojha

Keyword(s):

Cohort Study ◽

Preterm Infants ◽

Drug Utilisation ◽

Late Preterm ◽

Research Database ◽

Term Infants ◽

England And Wales ◽

Very Preterm ◽

Extremely Preterm ◽

Extremely Preterm Infants

Abstract Purpose To describe drug utilisation patterns in neonatal units. Methods Retrospective observational cohort study using data held in the National Neonatal Research Database (NNRD) for neonatal units in England and Wales including infants born at 23 to 44 weeks’ gestational age (GA) from 01 January 2010 to 31 December 2017. Results The cohort included 17,501 (3%) extremely preterm infants; 40,607 (7%) very preterm infants; 193,536 (31%) moderate-to-late preterm infants; and 371,606 (59%) term infants. The number of unique drugs received by an infant (median (IQR)) increased with decreasing GA: 17 (11–24) in extremely preterm, 7 (5–11) in very preterm, 3 (0–4) in moderate-to-late preterm, and 3 (0–3) in term infants. The two most frequently prescribed drugs were benzylpenicillin and gentamicin in all GA groups, and caffeine in extremely preterm. Other frequently used drugs among preterm infants were electrolytes, diuretics and anti-reflux medications. Among infants <32 weeks’ GA, the largest increase in use was for surfactant (given on the neonatal unit), caffeine and probiotics, while domperidone and ranitidine had the largest decline. Conclusion Antibiotics, for all GAs and caffeine, among preterm infants, are the most frequently used drugs in neonatal medicine. Preterm infants are exposed to a high burden of drugs, particularly antibiotics. Changing patterns in use reflect the emergence of evidence in some areas but several non-evidence-based drugs continue to be used widely. Improvements are needed to ensure rational drug use on neonatal units. Registration ClinicalTrials.gov (NCT03773289). Date of registration 21 Dec 2018.

Download Full-text