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The placenta supports the metabolic and respiratory requirements of the fetus. Placental disorders, caused by various pathophysiological mechanisms, may result in adverse pregnancy and neonatal outcomes. Knowledge gaps remain in the understanding, reporting and interpretation of placental pathology relating to clinical conditions. This project aimed to collaboratively identify the most important unanswered research questions related to placental pathology. An international Priority Setting Partnership (PSP) was conducted, involving (perinatal) pathologists, obstetricians, paediatrician-neonatologists, midwives, and scientists with expertise in placental pathology. In the first survey, participants identified their three most important unanswered research questions. Afterwards literature was reviewed for evidence on the proposed questions. In a second survey, participants ranked the most important questions from an initial long-list. The top-ranked questions were then discussed and finalized in a 1-h online consensus workshop. Ninety participants completed the first survey. The majority of stakeholders were perinatal pathologists (n = 39 (43.3 %) and most were based in Europe (n = 43 (47.8 %). 270 questions were submitted; after review, these were subdivided into 32 overarching questions. The second ranking survey was completed by 53 participants. Twenty-five participants attended the online workshop, which reached consensus on the top 10. The questions focus, among others, on causes, recurrence risk, consistency of reporting, diagnosing tools and potential use of artificial intelligence. Following this international PSP, the top 10 prioritized research questions on placental pathology have been identified. This will inform the research agenda for funders and policy-makers, and is intended to improve care for patients suffering from placental insufficiency. • In this international Priority Setting Partnership, consensus was reached on the top 10 prioritized research questions on placental pathology. •Topics include causes of placental lesions, recurrence risk, consistency in reporting, diagnostic tools and the potential role of artificial intelligence. •The prioritized research questions will inform the research agenda, funders and policymakers, accelerating research on placental pathology. [ABSTRACT FROM AUTHOR]

Placental pathology lesions are common in early-onset fetal growth restriction (eoFGR). Therapeutic interventions to improve eoFGR outcomes are needed. In the international STRIDER trials (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) sildenafil didn't improve perinatal outcomes of eoFGR. We aimed to study the underlying placental pathology in the Dutch STRIDER trial and the effects of sildenafil on placental histopathology by describing the associations with sildenafil treatment, placental-dysfunction serum biomarkers and markers of oxidative stress. The Dutch STRIDER trial was a randomized controlled trial of sildenafil versus placebo in 216 singleton pregnancies complicated by eoFGR, included between 20+0- and 29+6-weeks' gestation. In 158 cases, placental histology was available. Lesions were classified independently by three perinatal pathologists blinded for clinical data, according to the international criteria of the Amsterdam Placental Workshop Group Consensus Statement. Blood samples taken at inclusion were analyzed for free thiols (FT), placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1, n = 85). The 'big four' placental lesions (maternal and fetal vascular malperfusion, and chronic or acute inflammatory lesions) were equally distributed in both groups. However, massive perivillous fibrin deposition (MPFD) and chronic histiocytic intervillositis (CHIV) were less common in the sildenafil-treated group compared to the placebo-treated group (p = 0.026 and p = 0.043). FT, PlGF and sFlt-1 at inclusion were not discriminative for placental lesions. Sildenafil had no effect on common placental lesions. The lower incidence of MPFD and CHIV after sildenafil exposure merits more research on the interaction between sildenafil and the immune system. • Sildenafil had no effect on the 'big four' placental lesions (maternal and fetal vascular malperfusion, and chronic or acute inflammatory lesions). • A lower occurrence of the rare placental lesions MPFD and CHIV were seen in cases with sildenafil compared to placebo. • Lower levels of FT at inclusion were not indicative of more severe placental pathology. • In this cohort, MVM is associated with a lower PLGF level and higher sFLT-1 level, which would be expected with placental insufficiency. [ABSTRACT FROM AUTHOR]