Background Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage.

Bronchopulmonary dysplasia (BPD) is the most common complication after preterm birth. Pasteurized donor human milk (DHM) has increasingly become the standard of care for very preterm infants over the use of preterm formula (PF) if the mother’s own milk (MOM) is unavailable. Studies have reported beneficial effects of DHM on BPD. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies on the effects of DHM on BPD and other respiratory outcomes. Eighteen studies met the inclusion criteria. Meta-analysis of RCTs could not demonstrate that supplementation of MOM with DHM reduced BPD when compared to PF (three studies, risk ratio (RR) 0.89, 95% confidence interval (CI) 0.60–1.32). However, meta-analysis of observational studies showed that DHM supplementation reduced BPD (8 studies, RR 0.78, 95% CI 0.67–0.90). An exclusive human milk diet reduced the risk of BPD, compared to a diet with PF and/or bovine milk-based fortifier (three studies, RR 0.80, 95% CI 0.68–0.95). Feeding raw MOM, compared to feeding pasteurized MOM, protected against BPD (two studies, RR 0.77, 95% CI 0.62–0.96). In conclusion, our data suggest that DHM protects against BPD in very preterm infants.

Background Antenatal pathological conditions are key in the pathogenesis of bronchopulmonary dysplasia (BPD). Pathophysiological pathways or endotypes leading to prematurity and perinatal lung injury can be clustered into two groups: infection and dysfunctional placentation, which include hypertensive disorders of pregnancy (HDP) and intrauterine growth restriction (IUGR). We conducted a systematic review of observational studies exploring the association between the dysfunctional placentation endotype and BPD. Methods MEDLINE, Embase and Web of Science databases were searched up to February 2020 for studies reporting data on the diagnosis of HDP, IUGR or small for gestational age (SGA) and BPD risk. BPD was classified as BPD28 (supplemental oxygen on day 28), BPD36 (oxygen at 36 weeks postmenstrual age), severe BPD (≥ 30% oxygen or mechanical ventilation), BPD36/death and BPD-associated pulmonary hypertension. Results Of 6319 studies screened, 211 (347 963 infants) were included. Meta-analysis showed an association between SGA/IUGR and BPD36 (OR 1.56, 95% CI 1.37 to 1.79), severe BPD (OR 1.82, 95% CI 1.36 to 2.29) and BPD/death (OR 1.91, 95% CI 1.55 to 2.37). Exposure to HDP was not associated with BPD but was associated with decreased odds of BPD/death (OR 0.77, 95% CI 0.64 to 0.94). Both HDP (OR 1.41, 95% CI 1.10 to 1.80) and SGA/IUGR (OR 2.37, 95% CI 1.86 to 3.02) were associated with BPD-associated pulmonary hypertension. Conclusion When placental vascular dysfunction is accompanied by fetal growth restriction or being born SGA, it is associated with an increased risk of developing BPD and pulmonary hypertension. The placental dysfunction endotype of prematurity is strongly associated with the vascular phenotype of BPD. Prospero registration number Review protocol was registered in PROSPERO database (ID=CRD42018086877).

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of very preterm birth and can lead to lifelong health consequences. Optimal nutrition is a cornerstone in the prevention and treatment of BPD. In very preterm infants, mother's own milk (MOM) feeding is associated with lower risks of necrotizing enterocolitis, retinopathy of prematurity, and sepsis. Although several studies have shown that MOM may protect against BPD, a systematic analysis of the evidence has not been performed to date. Methods: A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE, from their inception to 1 December 2017. Longitudinal studies comparing the incidence of BPD in preterm infants fed with exclusive MOM, MOM supplemented with preterm formula (PF), and/or exclusively fed with PF were selected. A random-effects model was used to calculate the Mantel Haenszel risk ratio (RR) and 95% confidence interval (CI). Results: Fifteen studies met the inclusion criteria (4,984 infants, 1,416 BPD cases). Use of exclusive MOM feedings was associated with a significant reduction in the risk of BPD (RR 0.74, 95% CI 0.57–0.96, 5 studies). In contrast, meta-analysis could not demonstrate a significant effect on BPD risk when infants fed with more than 50% MOM were compared with infants fed with <50% MOM (RR 0.98, 95% CI 0.77–1.23, 10 studies) or when infants fed with MOM supplemented with PF were compared with infants fed with exclusive PF (RR 1.00, 95% CI 0.78–1.27, 6 studies). Meta-regression showed that differences in gestational age were a significant confounder of the effect of MOM. Conclusion: To our knowledge, this is the first systematic review and meta-analysis that specifically evaluates the role of MOM on BPD. Our data indicate that MOM may reduce the incidence of BPD when used as an exclusive diet, but this result needs to be interpreted with caution. We did not find the same difference in analyses with other dosages of MOM. Further studies adequately powered to detect changes in BPD rates and that adjust for confounders are needed to confirm the beneficial effects of MOM on BPD.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches.