Intestinal Microbiota Composition After Antibiotic Treatment in Early Life (INCA)

"Intestinal Microbiota Composition After Antibiotic Treatment in Early Life. The INCA Study"

In this prospective observational cohort study the potential clinical consequences of antibiotic use in early life and perturbations in the gastrointestinal microbiota composition due to that antibiotic use are studied. It is hypothesized that altered microbiota may be an important underlying mechanism for impediments in the developing immune system.

Differentiation will be made between a group of neonates who received antibiotics in the first week of life, and control infants who were not exposed to antibiotics in the neonatal period.

Study Overview

• Status: Unknown
• Conditions: Eczema; Microbiota; Atopy

Detailed Description

Healthy newborns born in the hospital, observed for low probability of neonatal infection will be compared to newborns exposed to antibiotic therapy in early life (first 1-2 weeks).

Infants are recruited from the maternity wards and neonatal wards of four teaching hospitals in the Netherlands. In total 150 infants, treated with antibiotics because of (a high suspicion of) a perinatal infection during the first week of life, will be recruited. The control group comprises 300 healthy newborns, born in the hospital and needing clinical observation for 24-48 hours for several reasons like maternal comorbidity, low probability of neonatal infection, blood sugar monitoring, meconium containing amniotic fluid, or delivery by caesarean section.

Differences in clinical outcomes between antibiotic treated infants and controls are investigated. Incidence of atopic dermatitis (eczema), food allergy, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GITI) and excessive crying are evaluated, prospectively assessed by parental reports and retrospectively assessed by doctor's diagnoses. The clinical endpoints will be linked to the developing intestinal microbiota during the first year of life.

Potential differences in intestinal fecal microbiota composition and diversity can be determined at eight time points during the first year of life, as sampling moments include: day one (T1), day two (T2), one week (T3), two weeks (T4), one month (T5), three months (T6), six months (T7), one year (T8).

• Study Type: Observational
• Enrollment (Anticipated): 450

Contacts and Locations

• Study Contact: Name: Nicole B Rutten, MD; Phone Number: +31 88 320 6325; Email: n.rutten@antoniusziekenhuis.nl
• Study Contact Backup: Name: Arine M Vlieger, MD, PhD; Phone Number: +31 88 320 6325; Email: a.vlieger@antoniusziekenhuis.nl

Study Locations

• Netherlands
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands, 7334 DZ
      • Recruiting
      • Gelre Hospitals
      • Contact: Johanna H Oudshoorn, MD, PhD; Phone Number: +31 55 581 8181; Email: a.oudshoorn@gelre.nl
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3813 TZ
      • Recruiting
      • Meander Medical Centre
      • Contact: Clemens B Meijssen, MD; Phone Number: +31 33 850 5050; Email: CB.Meijssen@meandermc.nl
    • Blaricum, Utrecht, Netherlands, 1261 AN
      • Recruiting
      • Tergooi Hospital
      • Contact: Clarissa E Crijns, MD; Phone Number: 088 753 1753; Email: ce.crijns@yahoo.com
    • Nieuwegein, Utrecht, Netherlands, 3430 EM
      • Recruiting
      • St Antonius hospital
      • Contact: Arine M Vlieger, MD, PhD; Phone Number: +31 88 320 6325; Email: a.vlieger@antoniusziekenhuis.nl
      • Contact: Carin Bunkers; Phone Number: +31 88 320 6325; Email: k.bunkers@antoniusziekenhuis.nl
      • Principal Investigator: Nicole B Rutten, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 1 week (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Healthy newborns born in the hospital, observed for low probability of neonatal infection will be compared to newborns exposed to antibiotic therapy in early life (first 1-2 weeks) by investigating potential differences in intestinal fecal microbiota composition

Description

Inclusion Criteria:

1. Term-born babies (≥ 36 weeks gestational age)
2. (Short) stay on maternal ward or admission to neonatal ward because of antibiotic treatment
3. Signed informed consent by the parents

Exclusion Criteria:

1. Congenital illness or malformations
2. Severe perinatal infections for which transfer to the neonatal intensive care unit is needed
3. Maternal probiotic use ≤ six weeks before delivery
4. Insufficient knowledge of the Dutch language.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Antibiotics; 150 infants, (because of hospital protocol) treated with antibiotics because of a perinatal infection during the first week of life
Controls; The control group comprises 300 healthy newborns, born in the hospital and needing clinical observation for 24-48 hours for several reasons like maternal comorbidity, low probability of neonatal infection, blood sugar monitoring, meconium containing amniotic fluid, or delivery by caesarean section

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical endpoints	Differences in clinical outcomes between antibiotic treated infants and controls are investigated. Incidence of atopic dermatitis (eczema), food allergy, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GITI) and excessive crying are evaluated. Data are prospectively assessed by parental reports (calendar lists).	Participants will be followed during their first year of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiota composition	Fecal bacterial composition and diversity is determined at eight time points during the first year of life, from birth on. Sampling points include: day one (T1), day two (T2), one week (T3), two weeks (T4), one month (T5), three months (T6), six months (T7), one year (T8). Potential differences in microbiota composition and diversity will be determined by use of 16S-23S ribosomal ribonucleic acid (rRNA) gene analysis (IS-pro).	Samples will be taken at eight time points during the participant's first year of life
Vaccine response	Immunoglobulin G antibodies against Tetanus toxoid, Diphtheria toxoid, Haemophilus influenza type B, and the capsular polysaccharides of the pneumococcal 10-valent conjugate vaccine will be determined. Antibody concentrations will be determined from blood samples. Measured in international units per milliliter or microgram per milliliter.	around 1 year of age
Doctor's diagnosis	Diagnoses are defined by selected International Classification system of Primary Care (ICPC) codes, diagnosticated during the first year of life. These include: dyspnea (R02), wheezing (R03), cough (R05), acute upper tract infection (R74), acute bronchi(oli)tis (R78), pneumonia (R81), asthma like symptoms (R96), breath problems [R04], sneeze [R07], other symptoms of the nose [R08], symptoms of the throat [R21], abnormal sputum [R25], concern about respiratory illness [R27], acute laryngitis [R77], influenza [R88], other infections of the airways [R83], and other respiratory diseases [R99], infectious diarrhea (D70), vomiting (D10), susceptible gastro-intestinal infection (D73), other symptoms/complaints of the skin (S21), dry skin/ flaking (S21.01), infantile colic (A14).	Participants will be followed during their first year of life

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
infant height	Individual height is monitored during the first year of life. Parents report the most recently measured height of the child on the calendar lists. (height is measured in centimeters)	Participant's height is monitored during the first year of life
infant weight	Individual weight is monitored during the first year of life. Parents report the most recently measured weight of the child on the calendar lists. (weight is measured in kilograms)	Participant's weight is monitored during the first year of life
coughing	Parental reported symptom on calendar list (yes/no). Description: The child coughs several times a day and/or has coughing. Regularly there are signs of cold. Cough because of choking does not have to be recorded.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
wheezing	Parental reported symptom on calendar list (yes/no). Description: During expiration the parents notice a whistling, wheezy sound coming from the lower airways of the child. During expiration the child is trying to squeeze the air outwards. Wheezing coming from or through the nose does not have to be recorded.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
fever >38 degrees Celsius	Parental reported symptom on calendar list (yes/no). Description: Clear from itself, whereby it is important that parents use a rectal thermometer, measure twice and the temperature is >38 degrees Celsius on both occasions.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
runny nose	Parental reported symptom on calendar list (yes/no). Description: Signs of cold with white/yellow/green mucus running from the nose.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
glue ear	Parental reported symptom on calendar list (yes/no). Description: The child seems to have earache and/or grasps its ear (the ear frequently is high-colored or bends) and/or glue egresses from the ear.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
rash	Parental reported symptom on calendar list (yes/no). Description: More than one day existing skin-redness (spots, rash, pimples) on the face, arms or legs, trunk. Disease-symptoms are not necessarily present. The rash can be eczema; eczema mostly is red, scaly and may itch. Infants cheeks are affected mostly. When children grow up, elbow and knees are preferred sites.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
diarrhea	Parental reported symptom on calendar list (yes/no). Description: Watery or mucous defecation, more than three times a day, that continues more than one day.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
>3 crying hours a day	Parental reported symptom on calendar list (yes/no). Description: Clear from itself, whereby the total crying episodes add up to more than three hours a day (24 hours) in total.	the symptom is daily reported as present or not present (by the parents, on the calendar list), during the infant's first year of life
prescribed antibiotics	Any prescribed (systemic) antibiotic treatments during the first year of life are investigated. Measured as number of antibiotic courses during the first year of life, [1] parental reported (on the calendar list) and [2] checked via pharmacist's medication records.	Participants will be followed during their first year of life and prescription of antibiotic courses will be monitored
allergic sensitization	(serum) allergen antibodies to food and inhalant allergens are determined. Measured in kilo unit.	around 1 year of age

Collaborators and Investigators

• Sponsor: Agentschap NL
• Collaborators: Amsterdam UMC, location VUmc; Danone Research
• Investigators: Principal Investigator: Arine M Vlieger, MD, PhD, St Antonius Hospital Nieuwegein, the Netherlands

Publications and helpful links

General Publications

• Kamphorst K, Vlieger AM, Oosterloo BC, Garssen J, van Elburg RM. Neonatal Antibiotics and Food Allergy Are Associated With FGIDs at 4-6 Years of Age. J Pediatr Gastroenterol Nutr. 2022 Jun 1;74(6):770-775. doi: 10.1097/MPG.0000000000003428. Epub 2022 Feb 24.
• Oosterloo BC, Van't Land B, de Jager W, Rutten NB, Klopping M, Garssen J, Vlieger AM, van Elburg RM. Neonatal Antibiotic Treatment Is Associated With an Altered Circulating Immune Marker Profile at 1 Year of Age. Front Immunol. 2020 Jan 10;10:2939. doi: 10.3389/fimmu.2019.02939. eCollection 2019.
• Kamphorst K, Oosterloo BC, Vlieger AM, Rutten NB, Bunkers CM, Wit EC, van Elburg RM. Antibiotic Treatment in the First Week of Life Impacts the Growth Trajectory in the First Year of Life in Term Infants. J Pediatr Gastroenterol Nutr. 2019 Jul;69(1):131-136. doi: 10.1097/MPG.0000000000002360.
• Rutten NB, Rijkers GT, Meijssen CB, Crijns CE, Oudshoorn JH, van der Ent CK, Vlieger AM. Intestinal microbiota composition after antibiotic treatment in early life: the INCA study. BMC Pediatr. 2015 Dec 9;15:204. doi: 10.1186/s12887-015-0519-0.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ANTICIPATED): April 1, 2016
• Study Completion (ANTICIPATED): October 1, 2016

Study Registration Dates

• First Submitted: August 21, 2015
• First Submitted That Met QC Criteria: August 28, 2015
• First Posted (ESTIMATE): September 1, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): September 1, 2015
• Last Update Submitted That Met QC Criteria: August 28, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: infant; antibiotics; allergy; intestinal microbiota
• Additional Relevant MeSH Terms: Skin Diseases; Dermatitis; Skin Diseases, Eczematous; Eczema
• Other Study ID Numbers: NL.37233.100.11, R-11.26AM