Endotypes leading to very and extremely preterm birth are clustered into two groups: infection/inflammation and dysfunctional placentation. We conducted a systematic review of observational studies exploring the association between these two endotypes and the pharmacological closure of patent ductus arteriosus (PDA) induced by cyclooxygenase (COX) inhibitors. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for gestational age (SGA) or intrauterine growth restriction. PubMed/Medline and Embase databases were searched. The random-effects odds ratio (OR) and 95% confidence interval (CI) were calculated for each association. We included 30 studies (12639 infants). Meta-analysis showed a significant association between exposure to HDP and increased rate of pharmacological closure of PDA (17 studies, OR 1.41, 95% CI 1.10-1.81, p=0.006). In contrast, neither chorioamnionitis (13 studies, OR 0.75, 95% CI 0.47-1.18, p=0.211) nor SGA (17 studies, OR 1.20, 95% CI 0.96-1.50, p=0.115) were significantly associated with the response to therapy. Subgroup analyses showed that the higher response to COX inhibitors in the HDP group was significant for indomethacin (OR 1.568, 95% CI 1.147-2.141, p=0.005) but not for ibuprofen (OR 1.107, 95% CI 0.248-4.392, p=0.894) or for the studies using both drugs (OR 1.280, 95% CI 0.935-1.751, p=0.124). However, meta-regression showed that this difference between the drugs was not statistically significant (p=404). In conclusion, our data suggest that the pathologic condition that triggers prematurity may alter the response to pharmacological treatment of PDA. The DA of infants exposed to HDP appears to be more responsive to COX inhibitors.

The authors have declared no competing interest.

This study was partially funded by FUNDACION CANARIA COLEGIO DE MEDICOS DE LAS PALMAS, Grant No. 26/2021.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study is a meta-analysis based on published data

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors