Towards lifelong healthy LUNGS: a multidisciplinary follow-up framework for preterm infants.

Approximately 8% of all births occur between 30-36 weeks of gestation
(moderate-late prematurity). Respiratory tract infections (RTI) and wheezing
illnesses disproportionally affect preterms, resulting in a 1.5-2 fold higher
hospitalisation rate during the first years of life compared to term born
children. Besides prematurity, several other modifiable influencing factors are
associated with increased risk of respiratory morbidity and impaired pulmonary
development. These factors include rapid weight gain and obesity at early age,
tobacco smoke exposure, air pollution, microbiome composition and recurrent RTI.

To promote optimal lung health and development in moderate-late preterm
infants, increased respiratory health surveillance and protection against RTI
in early life might be crucial. Previous research has shown that the
introduction of a multidisciplinary follow up framework in children with
bronchopulmonary dysplasia resulted in a significant reduction of hospital
readmissions.

Despite the burden of respiratory disease, moderate to late preterms do not
currently receive standardised respiratory follow-up care. With LONG LOVE we
introduce a novel follow-up framework tailored for preterms and designed to
improve respiratory health. As the risk of the onset of pulmonary disease is
further increased by postnatal factors such as tobacco smoke exposure, air
pollution and RTI, our main focus is the detection and treatment of these
modifiable influencing factors. LONG LOVE incorporates eHealth and new
technology in order to measure pulmonary function and air quality. Intervention
strategies include counselling on nutrition, lifestyle, medication and
improving indoor air quality.

The project*s overarching aim is to diminish respiratory disease burden in
moderate-late preterm born infants in their first 18 months of life.

We have formulated the following specific objectives:
1. Determine whether the introduction of our follow-up framework will reduce
the number and/or severity of RTI and wheezing episodes in the first 18 months
of life
2. Analyse the predictive value of nocturnal impedance pneumatography on lower
respiratory symptoms in premature born infants < 1 year of age. Further,
correlate this novel tool to other forms of pulmonary function analyses such as
the Lung Clearance Index and Hypoxic Challenge Test.
3. Conduct a cost-benefit analysis after the implementation of our framework.

We intend a quasi-experimental design based on a non-randomized cluster trial,
in which moderate-late preterm born infants will be allocated to the
intervention or control group based on location of birth. This design was
chosen based on the limited amount of participating clusters and feasibility.
As a quasi-experimental design can result in confounding by cluster and to
increase internal validity, subjects of the control and intervention groups
will be demographically matched at baseline[54,55]

Cluster 1
Consists of participants born in Franciscus Gasthuis (FG) and/or Vlietland (FV)
and will be allocated to the intervention group, receiving additional (in
addition to current standard of care) follow-up in accordance with our newly
developed framework to identify modifiable influencing factors compromising
pulmonary health using validated questionnaires, weekly monitoring of
respiratory symptoms as reported by parents using an app, in- and outdoor air
quality measurements and non-invasive pulmonary function measurements based on
impedance pneumatography.
In case of any modifiable influencing factors, appropriate lifestyle and/or
medical interventions will be undertaken.

Cluster 2 (control)
Consist of participants born in Maasstad Ziekenhuis (MSZ) and Albert Schweitzer
Ziekenhuis (ASZ) and will receive standard of care follow-up.
Parents are requested to provide informed consent for the registration of
outcome measurements and requested to complete validated questionnaires. Data
on utilization of medical services will be inquired to avoid recall bias.

Follow-up regimen after premature birth using the LONG LOVE framework:

Identification of modifiable influencing factors
Five study visits are scheduled to monitor health status on 1-1.5*, 3, 6, 12
and 18 months of age. These visits are planned in conjunction with regular
follow-up examinations. Well-being and other potential risks will be determined
by: growth, nutritional problems, feeding mode, pets, maternal stress
(Edinburgh Postnatal Depression Scale questionnaire), sleep (Infant Sleep
Questionnaire (ISQ)), tobacco smoke exposure, day-care attendance, existence of
siblings.

Air quality measurements
Outdoor air analysis will be obtained using national and regional air
measurement networks (RIVM Luchtmeetnet; DCMR Milieudienst Rijnmond). This
network consists of a large number of air quality measurement sites, measuring
harmful substances: nitric oxides (NOx, NO2), particulate matter (PM2.5, PM10)
and ozone. Measurements will be taken from a station located nearest to the
home address of the participant. Measurements are provided as publicly
accessible data by the Dutch government.

Indoor air quality will be analysed using a commercially available environment
monitor. This device offers real-time monitoring of air quality factors such as
temperature, humidity, particulate matter (PM1, PM2,5, PM10), carbon
dioxide(CO2), and volatile organic compounds (TVOCs). Readings are exported
using the AirThings web platform. Air quality measurements will be taken from
the living room for a total duration of 12 months. All recorded data is
encrypted using 128-AES end-to-end encryption.

Pulmonary function analysis
Pulmonary function analysis using impedance pneumatography will be measured at
3, 6 and 12 months age during two consecutive nights using the Ventica
recorder.

eHealth
All parents are requested to install a newly developed application on their
phones when enrolled in the study. The app is used for a weekly evaluation of
respiratory symptoms. The following clinical parameters/variables will be
monitored throughout the study: Respiratory health will be determined as
follows: physician-diagnosed lower RTI- and wheezing episodes, hospitalizations
for respiratory problems, clinical variables such as other respiratory
episodes, common colds, medication use (bronchodilators, corticosteroids,
antibiotics).

Interventions
Aside from identification of potential health risks, our framework is designed
to offer interventions if required. At baseline, all participants receive
verbal and written information (App) defining potential hazardous factors
regarding pulmonary development and overall health. In the event of pulmonary
symptoms, parents are requested to consult a doctor.
In case of modifiable influencing factors, the following lifestyle and medical
interventions will be performed:

In the case of 1.5 SDS weight gain or loss (based on birth weight), nutritional
advice is provided by a paediatrician and follow-up by primary infant health
care services.
In case of EPDS-scores >=12 (stress-depression mother) consultation by lifestyle
coach or community worker (Kleine Heldenhuis). If required, referral to general
practitioner or psychologist/psychiatrist.
If sleep quality is affected (ISQ): medical advice and sleep training is
provided by a paediatrician and/or primary infant health care services
In the case of pulmonary symptoms: clinical assessment by general practitioner
or paediatrician. Administration of antibiotics according to Dutch board of
Paediatricians guideline, optionally C-reactive protein measurement to prevent
unnecessary antibiotics use
If one or both caretakers are smoking: consultation by general practitioner and
primary infant health care services to provide stop smoking services
In case of inferior indoor air quality: visit by PhD-student or pulmonary care
nurse to instruct how to improve air quality
Optimal identification and treatment of comorbidity: gastro-oesophageal reflux
disease, vitamin D deficiency, iron deficiency anaemia by paediatrician
Active consultancy and treatment of nasal congestion using saline and-or
xylometazoline by paediatrician
Bronchodilator/broncholytic (salbutamol) trial by pediatrician in event of
recurrent clinical bronchial obstruction and/or abnormal expiratory variability
index using impedance pneumatography. If bronchodilator therapy is regularly
required (a minimum of 2 episodes 2-3 days of week for a minimal duration of
two weeks), inhaled corticosteroids can be prescribed.

These interventions are performed by both primary and secondary healthcare
professionals (including the PhD-student who has an active role in patient
management). Primary infant healthcare services operating in the Rijnmond
region will fulfill an important role and are directly involved with the
implementation of this framework.

Safety is important in paediatric studies. All subjects will receive standard
of care follow-up after preterm birth as specified by the directive *Te vroeg
en/of small for gestational age (SGA) geboren kinderen'' of the Dutch Primary
Infant Health Care Services (Jeugd Gezondheidszorg). However, subjects enrolled
in cluster 1 and using our novel framework will experience better surveillance
of pulmonary condition with an expected reduction of healthcare consumption
(e.g. hospitalization and medication usage). Lung function analysis based on
expiratory variation index is a non-invasive form of measurement and requires
placement of four individual skin-friendly chest electrodes (as used for EKG
and respiratory monitoring) near the armpits. A special bodysuit or shirt made
from certified toxic-free Ökotex100 material is used to house the recorder.
Measurements are taken at night and do not require cooperation. All other lung
function analyses are non-invasive. Additonal (voluntary) lung test in Sophia
Children's hospital are non-invasive and offer high success rates. There are no
serious AEs anticipated in relation to pulmonary function testing.

The burden of participation in this study is expected to be minor. A total of 5
study visits are planned in conjunction with routine follow-up visits. s.
Optional additional pulmonary function analysis requires an extra visit. Using
the app to file a weekly report will take no more than 5 minutes.

Based on the assessment of benefits and risks, it is considered justified to
perform this study. Any alleged risk to the subject is outweighed by potential
near- and long-term benefits associated with better pulmonary surveillance and
health.