Evidence of Placental Aging in Late SGA, Fetal Growth Restriction and Stillbirth-A Systematic Review

Abstract

During pregnancy, the placenta undergoes a natural aging process, which is considered normal. However, it has been hypothesized that an abnormally accelerated and premature aging of the placenta may contribute to placenta-related health issues. Placental senescence has been linked to several obstetric complications, including abnormal fetal growth, preeclampsia, preterm birth, and stillbirth, with stillbirth being the most challenging. A systematic search was conducted on Pubmed, Embase, and Scopus databases. Twenty-two full-text articles were identified for the final synthesis. Of these, 15 presented original research and 7 presented narrative reviews. There is a paucity of evidence in the literature on the role of placental aging in late small for gestational age (SGA), fetal growth restriction (FGR), and stillbirth. For future research, guidelines for both planning and reporting research must be implemented. The inclusion criteria should include clear differentiation between early and late SGA and FGR. As for stillbirths, only those with no other known cause of stillbirth should be included in the studies. This means excluding stillbirths due to congenital defects, infections, placental abruption, and maternal conditions affecting feto-maternal hemodynamics.

Keywords: cellular senescence; late FGR; late SGA; obstetric complications; placental aging; pregnancy; stillbirth.

Figure 1

PRISMA flow chart.

Figure 2

Molecular mechanisms associated with the placental aging process.Cell stress stimulation triggers the activation of the p53/p21 and p16 pathways, leading to CDK inhibition and the subsequent inhibition of Rb phosphorylation. Rb, which binds to E2F to promote DNA replication, is inactivated, resulting in cell replication arrest at the G1/S phase and triggering cellular senescence. Regulatory factors, such as Sirtuin-1/Sirtuin-3 and Klotho, play a role in controlling this process. p53 also stimulates autophagy by regulating AMPK and mTOR. Moreover, the increased expression of p53 during placental aging leads to apoptosis by inducing mitochondrial dysfunction and upregulating the expression of Bax and Caspase-3. Green arrows indicate proteins downregulated during placental aging, while red indicates upregulated proteins. Created with BioRender (24 May 2023). Klotho—Klotho protein involved in aging; Sirtuin-1/Sirtuin-3—proteins responsible for mitochondrial hemostasis; E2F—a group of transcription factors; CDKs—Cyclin-dependent kinases; AMPK—5′ adenosine monophosphate-activated protein kinase.