Association of the dysfunctional placentation endotype of prematurity with bronchopulmonary dysplasia: a systematic review, meta-analysis and meta-regression

Abstract

BackgroundAntenatal 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.MethodsMEDLINE, 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.ResultsOf 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.ConclusionWhen 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 numberReview protocol was registered in PROSPERO database (ID=CRD42018086877).

Endotypes of Prematurity and Phenotypes of Bronchopulmonary Dysplasia: Toward Personalized Neonatology

“…Our studies also confirmed that key factors for the development of BPD are distributed differently in the chorioamnionitis, HDP, and SGA/IUGR groups [ 47 , 48 ]. When compared to their respective control groups, infants exposed to chorioamnionitis showed a significantly lower GA [ 47 ], while those in the HDP and SGA/IUGR groups showed a significantly higher GA [ 48 ].…”

“…Very recently, we conducted two meta-analyses on the association between endotypes of prematurity and BPD [ 47 , 48 ]. In these analyses, the proxy for the infectious/inflammatory endotype was chorioamnionitis [ 47 ], while the placental dysfunction endotype was represented by HDP and fetal growth restriction [ 48 ]. Since most studies defined growth restriction as small for gestational age (SGA), this group was referred to as SGA/IUGR.…”

“…As summarized in Figure 3 , chorioamnionitis was associated with an increased risk of developing BPD as defined by the need for oxygen at 28 days (any BPD) or at 36 weeks PMA (moderate/severe BPD) [ 47 ]. In contrast, meta-analysis could not detect a significant association between HDP and BPD but it did show a significant association between SGA/IUGR and risk of both moderate/severe BPD and severe BPD [ 48 ] ( Figure 3 ). A high degree of heterogeneity was detected in all the analyses [ 47 , 48 ] ( Figure 3 ).…”

“…In contrast, meta-analysis could not detect a significant association between HDP and BPD but it did show a significant association between SGA/IUGR and risk of both moderate/severe BPD and severe BPD [ 48 ] ( Figure 3 ). A high degree of heterogeneity was detected in all the analyses [ 47 , 48 ] ( Figure 3 ).…”

Preempting Bronchopulmonary Dysplasia: Time to Focus on the Placenta?

“…These observations raise interesting questions about BPD endotypes. Inferring those endotypes based on dysfunctional placentation may have important therapeutic implications ( 12 ). Early recognition of risk factors and interventions specifically targeting the pathogenic mechanisms at play may prove effective in preventing BPD.…”