Sex differences in lung function of adolescents or young adults born prematurely or of very low birth weight: a systematic review

Introduction

Individuals who are born very prematurely or with very low birth weight do not reach the full lung growth potential of their term or normal birthweight counterparts [1]. Lung function is further impaired in infants who had bronchopulmonary dysplasia (BPD) [2]. In those adults with reduced lung growth, the natural decline in lung function seen in all adults, therefore, leads to a higher likelihood of them developing obstructive lung disease in adulthood such as chronic obstructive pulmonary disease (COPD) [3].

There are known structural differences in the lungs between males and females at the time of birth, which is hypothesised to be partially due to androgen receptors in the fetal lung [4]. One animal model demonstrated that exposure of androgen receptors to dihydrotestosterone affects early lung morphogenesis leading to a higher rate of branching morphogenesis and cell proliferation. This leads to a higher number of terminal lung buds but delays the growth arrest required for terminal epithelial differentiation and therefore delays lung maturation [5]. As a result male infants reach surfactant maturity on average 1.4 weeks later than female infants [6]. They have a higher incidence of respiratory distress syndrome [6] and worse respiratory outcomes in infancy [7], 8], including an increased severity of BPD [9] and a higher mortality [10]. In childhood they have an increased incidence of inhaler use and asthma and have more readmissions for respiratory infections [8], 11], 12]. The differences following puberty and adolescence are less clear, with some studies reporting worse respiratory outcomes for males [13], 14], but others highlighting a higher prevalence of respiratory symptoms in women [15]. During puberty there is greater thoracic growth in males which may reduce obstructive airway disease. We, therefore, hypothesised that adult lung function would differ between the sexes in those born prematurely or with very low birth weight. A systematic review was undertaken with the primary outcome being sex differences in lung function following preterm birth.

Methodology of the systematic review

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations, a systematic literature search was undertaken with two databases: PubMed and Embase. The databases were searched from their beginning (1996 and 1947 respectively) until 1st May 2024. The search terms included (respiratory function or lung function or spirometry) and (preterm or low birthweight) and (adult or adolescence). Additionally, manual review of the bibliography of key articles which fulfilled the eligibility criteria and review articles was carried out.

Studies were included if they involved preterm individuals (that is those born at less than 37 weeks of gestational age) or had a birthweight less than 1,500 g. The individuals must have had lung function testing after the age of 16 years and the studies included details or description of lung function by sex. The following types of articles were excluded: duplicates, letters, reviews, editorials, meeting abstracts and commentaries. The study protocol (Long-Term Respiratory Morbidity in Very Low Birth Weight Infants born in the Surfactant Era – A Systematic Review) was registered on PROSPERO (ID: CRD42024510179).

Two authors independently screened all studies, looking at titles, abstracts and full text reviews. They applied the inclusion criteria and assessed methodological quality. If there were discrepancies a third reviewer was called upon. Data extraction was carried out by one person and checked by a second for each study. This included citation information, location of the research, language of the publication, time period of the study, study objective, design of the study, gestational age, birth weight, age at lung function testing, lung function parameters, inclusion and exclusion criteria and the study results.

None of the studies were randomised and all were cohort studies, hence the Newcastle-Ottawa Quality Assessment Scale (NOS) [16] was used to assess methodological quality. The NOS scores three areas of a study: selection of the sample (0–4), comparability between the groups (0–2) and outcomes (0–3). This gave a total of nine points. Studies scoring a minimum of six points [1], [2], [3] were classified as good quality, studies scoring a minimum of five points [1], 2] were of fair quality and those with a score less than that were classified as of poor quality.

Quality of the studies

Of the 1969 potentially relevant studies, only seven met the inclusion criteria: [17], [18], [19], [20], [21], [22], [23]. The PRISMA flow diagram of the search process is shown in Figure 1.

Figure 1:

PRISMA flow diagram.

The Newcastle-Ottawa Quality Assessment Scale scores ranged from six to nine for the seven studies (Appendix Table A1). Points were lost for the non-representativeness of exposed cohorts, failure to select a non-exposed cohort and inadequacy of follow up. Please see Appendix A for full results.

The included studies evaluated 766 individuals born prematurely or with very low birth weight who had lung function testing as adults. All of the studies were prospective cohort studies (Table 1).

Discussion

We have demonstrated that there is insufficient evidence to draw firm conclusions about the effect of sex on adult lung function in prematurely born individuals. Whilst four studies demonstrated no difference in lung function in adulthood between the sexes, two large studies by Harris et al. [19] and Lundberg et al. [18] found significant differences between the sexes. Both Harris and Lundberg reported lung function results consistent with obstructive airway disease and found significant reductions in the FEV₁/FVC, but no significant difference in FVC. Additionally, Harris et al. [19] reported a lower FEF₇₅ in the males suggesting sex might also affect small airway function. An explanation for the differences in lung function could be that, although there is increased thoracic growth in males through puberty compared to females, there might be an element of acquired dysanapsis. Incongruity between the airway diameter and lung size with smaller airways than would be expected for the size of lung parenchyma would lead to higher resistance [24], 25]. As a result, there would be a lower FEV₁ and FEV₁/FVC ratio but no reduction in FVC. This discordance between lung parenchyma and airway size is thought to be affected by sex in the non-preterm born population [26]. If there is existing airflow obstruction, there could be subsequent parenchymal hyperinflation and further dysanapsis described as an ‘acute on chronic’ effect [25].

Harris et al. [19] described no significant difference in reported respiratory symptoms between preterm born adolescent males and females, despite a higher proportion of males having obstructive lung results. Additionally, Harris et al. found that males had better exercise capacity. This is perhaps due to physical fitness being determined by a variety of factors including muscle mass [27] and cardiovascular fitness [28], in addition to lung function.

Brostrom et al. [29] assessed infants born at less than 35 weeks of gestation or with a birth weight of less than 2,000 g for females and 2,100 g for males compared to control infants born between 1925 and 1949. They found in preterm born or low birth weight born females as birth weight and gestational age decreased, there was an increasing risk of obstructive airway disease (asthma and COPD) in adulthood. This association was not found in males. This might suggest that the sex effect on respiratory outcomes continues to change throughout adult life.

The differences in sex-related differences in lung fuction between studies could be explained by surfactant administration. The two studies which reported differences by sex in adult lung function included patients born in the era during which surfactant was routinely used. Harris et al. [19] reported 97 % of their study participants had received surfactant. Lundberg did not specify the percentage of participants who received surfactant, but refers to the study period as the ‘post-surfactant era’. The remaining studies [17], 20], 21], 23], aside from Kaczmarczyk et al. [22] where it is not clearly stated, included individuals born prior to routine surfactant administration. Given the small number of studies available for inclusion in this review, it cannot be determined whether surfactant administration plays a role in the sex differences in lung function.

There are strengths and some limitations to this review. This is the first systematic review, to our knowledge, that has looked at sex differences in preterm or low birth weight born adolescents and adults. The search criteria for this review were wide, so we are confident that all relevant papers were screened. The limitations include the inability to conduct a metanalysis due to lack of lung function data presented in a consistent form. This emphasises the importance of consistent reporting in scientific literature. We would recommend the use of z-scores (age-adjusted scoring) for all lung function tests reported in the future. We were unsuccessful in obtaining raw data from the authors, meaning that statistical comparisons could not be made between studies. Additionally, there were only two studies reporting cohorts in the post-surfactant era. Surfactant is known to affect lung function but whether it has an additional sex specific effect could not be assessed.

Conclusions

Male born preterm individuals were reported to have worse lung function at adulthood, but only in two of seven studies. Further research is needed to provide robust data regarding the effect of sex on adulthood lung function.