Towards Life-Long 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 preterm infants 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 postnatal modifiable influencing factors are associated with increased risk of respiratory morbidity and impaired pulmonary development. These factors include RTI, rapid weight gain, air pollution, tobacco smoke exposition, vitamin D deficiency, maternal stress and antibiotic usage. The investigators hypothesize that a follow-up program aiming at prevention of modifiable influencing factors can reduce respiratory morbidity in moderate and late prematurity. Objectives: To reduce respiratory disease burden in moderate-late preterm infants in the first 18 months of life

Background of the study:

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 hospitalization 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 an 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 in hospital readmissions.

Despite the burden of respiratory disease, moderate to late preterms do not currently receive standardised respiratory follow-up care. With LONG LOVE, the investigators 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 counseling on nutrition, lifestyle, medication, and improving indoor air quality.

Objective of the study:

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

The investigators 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 prematurely 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.

Study design:

The investigators 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 the 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 the 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.

Study population:

Moderate-late preterm infants (GA 30+0-35+6 weeks) without other significant underlying syndromal, cardial, and/or pulmonal morbidities.

Intervention:

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, daycare attendance, the 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 analyzed 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, and volatile organic compounds (VOCs). Air quality measurements will be taken from the living room or participants' sleeping room for a total duration of 1 year.

Pulmonary function analysis Pulmonary function analysis using impedance pneumatography will be measured at 3, 6, and 12 months of 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 \>12): 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 a 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 a 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 re ux 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.

Eligibility Criteria:
Inclusion Criteria:

* Moderate-late preterm infants (GA 30+0 - 35+6 weeks)

Exclusion Criteria:

* bronchopulmonary dysplasia (BPD)
* congenital diaphragmatic hernia (CHD),
* congenital pulmonary disorders
* hemodynamic significant cardiac disease
* immunodeficiency
* severe failure to thrive;
* birth asphyxia with poor neurological outcome
* syndromic or other severe congenital disorders with decreased life expectancy