The effect of experimental diabetes and membrane occlusiveness on guided bone regeneration: A proof of principle study.

OBJECTIVES: To evaluate the effect of membrane occlusiveness and experimental diabetes on early and late healing following guided bone regeneration. MATERIAL AND METHODS: A total of 30 Wistar rats were randomly allocated to three groups: healthy (H), uncontrolled diabetic (UD) and controlled diabetic (CD). A critical size calvarial defect (CSD) was created at the mid-portion of one parietal bone, and it was treated with a double layer of e-PTFE membrane presenting 0.5 mm perforations. The animals were killed at 7 and 30 days of healing, and qualitative and quantitative histological evaluations were performed. Data were compared with the ones previously obtained from other 30 animals (10H, 10UD, 10 CD), where two CSDs were randomly treated with a double-layer e-PTFE occlusive membrane or left empty. RESULTS: Following application of cell occlusive or cell permeable membranes, significant regeneration can be observed. However, at 30 days in the H group occlusive compared to cell permeable membranes promoted enhanced bone regeneration (83.9 ± 7.3% vs. 52.5 ± 8.6%), while no significant differences were observed within the CD and UD groups. UD led to reduced regeneration compared to H when an occlusive barrier was applied, whereas comparable outcomes to H and CD were observed when placing perforated membranes. CONCLUSION: The application of cell permeable membranes may have masked the potentially adverse effect of experimental UD on bone regeneration. CLINICAL RELEVANCE: Membrane porosity might contribute to modulate the bone regenerative response in UD conditions. Future studies are needed to establish the degree of porosity associated with the best regenerative outcomes as well as the underlying molecular mechanisms.

Expression of growth mediators in the gingival crevicular fluid of patients with aggressive periodontitis undergoing periodontal surgery.

OBJECTIVES: To describe changes in growth factor mediators in the gingival crevicular fluid (GCF) of patients with aggressive periodontitis (AgP) undergoing regenerative (GTR) and access flap (AF) surgery. MATERIALS AND METHODS: This was a 12-month, single-blind, split-mouth RCT involving 18 AgP patients with a bilateral intrabony defect which was treated with GTR or AF. GCF was collected prior to surgery and at subsequent follow-up visits from 3 days to 12 months post-operatively, and the levels of angiopoietin-1 (Ang-1), vascular-endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), bone morphogenetic protein-2 (BMP-2), osteoprotegerin (OPG), tissue inhibitor of metalloproteinase 1 (TIMP-1), keratinocyte growth factor (KGF) and platelet-derived growth factor-AB (PDGF-AB) were measured. At baseline, 6 and 12 months post-surgery, periodontal clinical parameters were evaluated. ANOVA was applied to test for differences in the amount of mediators (p < 0.05). RESULTS: Higher amounts of BMP-2 and OPG and a higher area under the curve (AUC) of KGF at the GTR versus AF sites were observed. The maximum change in the amount of KGF correlated significantly with periodontal clinical parameters at the GTR sites at 6 and 12 months. The AUC over 30 days of the amount of Ang-1, VEGF and KGF significantly correlated with periodontal clinical parameters at the AF sites at 6 months. CONCLUSIONS: AF and GTR differentially affected the profile of the growth mediators in GCF, and significant correlations between certain GCF mediators and periodontal clinical outcomes were identified. CLINICAL RELEVANCE: GCF components represent attractive prognostic markers for periodontal tissues undergoing repair or regeneration. However, the available evidence is not robust enough to suggest the use of a specific marker, and future adequately powered studies are warranted to identify the most relevant mediators that could be applied in clinical practice.

Enamel matrix derivative for the treatment of partially contained intrabony defects: 12-month results.

BACKGROUND: The aim of the study was to evaluate the use of enamel matrix derivative (EMD) alone or in association with deproteinized bovine bone mineral (DBBM) for the treatment of partially contained intrabony defects. METHODS: A total of 20 two-walled intrabony defects belonging to nine patients were included. Ten defects were treated with EMD alone (test group 1) and the other 10 were treated with EMD and DBBM (test group 2), applying either modified papilla preservation technique or simplified papilla preservation technique. RESULTS: Twelve months after surgery, in the test group 1, PD was 2.8 ± 0.8 mm, REC was 2.3 ± 2.4 mm and CAL was 5.0 ± 2.8 mm, significantly reduced from baseline values (P < 0.05). Likewise, in test group 2, PD, REC and CAL reduced to 3.0 ± 0.7 mm, 3.9 ± 1.5 mm and 6.9 ± 1.1 mm respectively, from baseline values at 12 months (P < 0.05). No significant differences between groups were found. CONCLUSIONS: The results showed that the use of EMD alone and the use of a combination of EMD and DBBM for the treatment of partially contained defects showed comparable clinical and radiographic outcomes after 12 months.

Osseointegration in osteoporotic-like condition: A systematic review of preclinical studies.

Osteoporosis is one of the most common skeletal disorders affecting a significant percentage of people worldwide. Research data suggested that systemic diseases such as osteoporosis could act as risk factors for osseointegration, jeopardizing the healing process and thus the predictability of dental implant success on compromised patients. It is well accepted that preclinical studies in animal models reproducing the osteoporotic condition are one of the most important stages in the research of new biomaterials and therapeutic modalities. The aim of this systematic review was to investigate whether osteoporosis compromises dental implant osseointegration in experimental osteoporotic-like conditions. A 3-stage systematic literature research was conducted in MEDLINE via OVID and EMBASE up to and including March 2017. Experimental studies reporting on dental implant osseointegration on different osteoporotic animal models were assessed. The studies had to report on the percentage of bone-to-implant contact (%BIC) as the primary outcome. ARRIVE guidelines for reporting on animal research were applied to evaluate the methodological quality and risk of bias of the studies. Fifty-seven studies met the inclusion criteria and were assessed qualitatively. The most adopted animal model was the rat. A variability of %BIC values was observed, ranging from 30% to 99% and from 26% to 94% for the healthy and osteoporotic group, respectively. The great majority (47) of the included studies concluded that estrogen deficiency significantly affects BIC values, 9 studies stated that it was not possible to observe statistical differences in BIC between ovariectomized and healthy groups and 1 study did not provide a comparison between the healthy and osteoporotic group. Owing to the great heterogeneity in implant surface, study design, observation time-points, site of implant placement and reported outcomes, a meta-analysis could not be performed. An overall high risk of bias was observed, owing to the limited information on animal housing and husbandry, baseline characteristics and health status, ethical statement and allocation to the experimental groups provided. Although the available studies seem to suggest a lower osseointegration in osteoporotic-like conditions, no robust conclusions can be drawn due to the great heterogeneity and overall low quality of the available studies. Future studies with emphasis on minimizing the possible sources of bias and evaluating osseointegration of dental implants placed into jawbones instead of long bones are warranted.

Pro-osteogenic properties of hydrophilic and hydrophobic titanium surfaces: Crosstalk between signalling pathways in in vivo models.

BACKGROUND: It is now generally accepted that the response to a particular signal, such as the surgical trauma following implant placement, is not the result of a single linear signalling pathway, but rather reflects pathway integration, which can occur at multiple levels. Although it is well documented that both SLA and SLActive surfaces are able to promote bone formation and osseointegration, it is still unclear which are the key signalling pathways involved and how surface hydrophilicity/hydrophobicity might affect pathway integration. OBJECTIVE: To combine gene and protein data from in vivo studies applying titanium hydrophobic (Sandblasting, Large-grit, Acid-etching, SLA) and hydrophilic (SLActive) surfaces to understand the molecular mechanisms responsible for the pro-osteogenic properties of these surfaces. METHODS: The Kyoto Encyclopedia of Genes and Genomes (KEGG® ) pathway database and the Ingenuity® Pathway Analysis (IPA® ) software were applied to the genomic and proteomic data of previous in vivo studies applying SLA and SLActive surfaces, with the specific aim to focus on bone formation-related signalling pathways. While gene data were derived from a human study on osseointegration, protein data originated from a preclinical study in rabbits. Data were available for the 4, 7 and 14 days of healing periods. RESULTS: Both genomic and proteomic data showed that the osteogenesis process takes place mainly at 7 and 14 days of healing on both SLA and SLActive surfaces. Surface hydrophilicity enhances bone formation at multiple levels, by directly promoting an earlier expression of pathways involved in cell proliferation and osteoblast precursor differentiation (eg, mitogen-activated protein kinase, phosphoinositide-3 kinase-AKT, Wnt, Notch, transforming growth factor-ß), but also by positively regulating angiogenesis, bone mineralization and bone remodelling. CONCLUSION: This study combined, for the first time, different 'omics' outputs to get new insights on the molecular mechanisms behind the influence of surface hydrophilicity on osseointegration/bone formation. Specific signalling pathways, such as Wnt, vascular endothelial growth factor and mitogen-activated protein kinase, were identified as differentially modulated by titanium surface hydrophilicity both at a genomic and proteomic level. These findings may be used in the future to monitor/predict the bone formation/osseointegration process, or as a screening tool towards the manufacture of new pro-osteogenic implant surfaces. In order to take into account the full complexity and interplay of cell signalling during bone formation, powerful bioinformatics tools integrating different 'omics' data and predicting signalling pathways trends should be applied by future studies.

Degradation pattern of a porcine collagen membrane in an in vivo model of guided bone regeneration.

BACKGROUND AND OBJECTIVE: Although collagen membranes have been clinically applied for guided tissue/bone regeneration for more than 30 years, their in vivo degradation pattern has never been fully clarified. A better understanding of the different stages of in vivo degradation of collagen membranes is extremely important, considering that the biology of bone regeneration requires the presence of a stable and cell/tissue-occlusive barrier during the healing stages in order to ensure a predictable result. Therefore, the aim of this study was to investigate the degradation pattern of a porcine non-cross-linked collagen membrane in an in vivo model of guided bone regeneration (GBR). MATERIAL AND METHODS: Decalcified and paraffin-embedded specimens from calvarial defects of 18, 10-month-old Wistar rats were used. The defects were treated with a double layer of collagen membrane and a deproteinized bovine bone mineral particulate graft. At 7, 14 and 30 days of healing, qualitative evaluation with scanning electron microscopy and atomic force microscopy, and histomorphometric measurements were performed. Markers of collagenase activity and bone formation were investigated using an immunofluorescence technique. RESULTS: A significant reduction of membrane thickness was observed from 7 to 30 days of healing, which was associated with progressive loss of collagen alignment, increased collagen remodeling and progressive invasion of woven bone inside the membranes. A limited inflammatory infiltrate was observed at all time points of healing. CONCLUSION: The collagen membrane investigated was biocompatible and able to promote bone regeneration. However, pronounced signs of degradation were observed starting from day 30. Since successful regeneration is obtained only when cell occlusion and space maintenance exist for the healing time needed by the bone progenitor cells to repopulate the defect, the suitability of collagen membranes in cases where long-lasting barriers are needed needs to be further reviewed.

The use of omics profiling to improve outcomes of bone regeneration and osseointegration. How far are we from personalized medicine in dentistry?

Increased life expectancy and broader restorative dental treatment alternatives for missing teeth have resulted in an increasing request of bone regeneration/augmentation procedures not only in healthy patients, but also in elderly and medically compromised ones. This is also combined with a growing demand for short implant loading protocols and for optimal aesthetic results. In order to meet these new dental needs, personalized treatment strategies tailored on each individual's characteristics and healing profile are warranted. Omics technologies are emerging as powerful tools to uncover molecules and signalling pathways involved in bone formation and osseointegration and to investigate differences in the molecular mechanisms between health and systemic diseases that could be targeted by future therapies. This review critically appraises the available knowledge on the application of omics technologies in the field of bone regeneration and osseointegration and explores their potential use for personalized medicine in the dento-maxillo-facial field. SIGNIFICANCE: The use of omics in personalising dental maxillo-facial treatments emerges as a desirable diagnostic and treatment strategy. Omics represent, in fact, powerful tools not only to shade light on the cascade of events taking place during bone formation/osseointegration, but also to identify specific signalling pathways and molecules that can be targeted by future therapies with the aim to enhance clinical outcomes in patients with compromised healing conditions.

Protein expression during early stages of bone regeneration under hydrophobic and hydrophilic titanium domes. A pilot study.

BACKGROUND AND OBJECTIVES: There is significant evidence that, during the early stages of osseointegration, moderately rough hydrophilic (SLActive) surfaces can accelerate osteogenesis and increase bone-to-implant contact in comparison to hydrophobic (SLA) surfaces. However, very little is known regarding the molecular mechanisms behind the influence that surface chemistry modifications to increase hydrophilicity determine on bone healing. The aim of this study was to describe for the first time the proteins and related signalling pathways expressed during early osseous healing stages under SLA and SLActive titanium domes for guided bone regeneration. MATERIAL AND METHODS: One SLA and 1 SLActive dome with an internal diameter of 5.0 mm and a height of 3.0 mm were secured to the parietal bones of nine 6-month-old male New Zealand rabbits. Three animals were randomly euthanized at 4, 7 and 14 days and the newly formed tissues retrieved under the domes were analysed with liquid chromatography-mass spectrometry/mass spectrometry. STRING and KEGG databases were applied for Gene Ontology and pathway analyses. RESULTS: A different modulation of several pathways was detected between the 2 groups at all healing times. The main differences in the osseous healing response associated to the 2 surfaces were related to pathways involved in regulating the inflammatory response, differentiation of osteoblast precursors and skeletogenesis. At day 7, the highest number of proteins and the highest cellular activity were observed in both groups, although a more complex and articulated proteome in terms of cellular metabolism and signal transduction was observed in SLActive samples. CONCLUSION: This is the first study describing the proteome expressed during early healing stages of guided bone regeneration and osseointegration. A combination of enhanced early osteogenic response and reduced inflammatory response were suggested for the hydrophilic group. Future studies are needed to corroborate these findings and explore the molecular effects of different titanium surfaces on the cascade of events taking place during bone formation.

The effect of experimental diabetes and glycaemic control on guided bone regeneration: histology and gene expression analyses.

OBJECTIVES: To investigate the effect of experimental diabetes and metabolic control on intramembranous bone healing following guided bone regeneration (GBR). MATERIAL AND METHODS: Ninety-three Wistar rats were allocated to three experimental groups, healthy (H), uncontrolled diabetes (D) and controlled diabetes (CD). Twenty one days following diabetes induction, a standardised 5-mm defect was created at the mid-portion of each parietal bone. In 75 animals (25H, 25D, 25CD), one defect was treated with an intracranial and extracranial membrane according to the GBR principle, and one defect was left empty (control); five animals per group were then randomly sacrificed at 3, 7, 15, 30 and 60 days and processed for decalcified histology. In 18 animals (6H, 6D, 6CD), both defects were treated according to the GBR principle; three animals from each group were then randomly sacrificed at 7 and 15 days of healing and employed for gene expression analysis. RESULTS: Application of the GBR therapeutic principle led to significant bone regeneration even in the D group. However, at 15 and 30 days, the osteogenesis process was impaired by uncontrolled diabetes, as shown by the significant reduction in terms of defect closure (38-42%) and newly formed bone (54-61%) compared to the healthy group. The comparison of the D vs. H group at 15 days of healing yielded the largest number of genes with significantly differential expression, among which various genes associated with the ossification process (bmp4, ltbp4, thra and cd276) were identified. CONCLUSIONS: Uncontrolled diabetes seems to affect early phases of the bone regeneration following GBR. A misregulation of genes and pathways related to cell division, energy production, inflammation and osteogenesis may account for the impaired regeneration process in D rats. Further studies are warranted to optimise the GBR process in this medically compromised patient population.

Maxillary Sinus Floor Augmentation Using an Equine-Derived Graft Material: Preliminary Results in 17 Patients.

OBJECTIVE: Sinus floor elevation with lateral approach is probably the most frequently performed reconstructive procedure to rehabilitate posterior maxilla when a bone deficiency is present. Different graft materials have been proposed and tested, often with high clinical performances and predictable results. Histological analysis is required when evaluating new materials. We investigated human biopsies retrieved after sinus floor elevation procedure by histomorphometric evaluation to test the performance of an equine-derived bone grafting material. STUDY DESIGN: Seventeen consecutive patients were enrolled and sinus lift surgeries were performed using an equine bone graft. Six months after surgery, at implant placement, bone samples were collected. Histomorphometry analysis was carried out on decalcified samples. RESULTS: All surgeries were uneventful and no additional grafting was required prior to implant insertion. Forty percent of new bone formation was detected, which represented the most abundant tissue retrieved, followed by the residual graft material (33%) and fibrous tissue (27%). A significant reduction in particles size demonstrates a remodeling activity of the graft material. CONCLUSION: Within the limitations of this study, this equine-derived bone graft proved to be an effective material to induce new bone formation in the sinus floor elevation procedure.

Study of GSK3b inhibitors SB415286 and SB216763 to improve osteoblastic differentiation on microstructured titanium.

Rough titanium surfaces enhance cell response to activation of Wnt canonical signalling, a pathway required for osteoblast differentiation. The present study investigated the effects of GSK3ß-inhibitors SB216763 and SB415286 on osteoblastic differentiation on titanium surfaces with different topography and wettability. Osteoblastic MC3T3 cells were plated on smooth (Pickled), sand-blasted/acid-etched (SLA) or hyper hydrophilic SLA (modSLA) titanium discs and transfected with a reporter vector sys-tem for Wnt canonical signalling. Cells were also seeded in the presence or in the absence of GSK3b-inhibitors SB216763 or SB415286 and their viability, morphology and the expression of Wnt target and osteoblast specific genes was assessed by Real Time PCR. Inhibitors altered cell morphology and mostly reduced cell viability at high concentration. SB415286 markedly increased the expression of ALP in MC3T3 cells on rough surfaces at the concentration of 100 nM before decreasing its expression at higher concentrations. OCN expression was unaffected. Increasing concentrations of SB216763 increased the expression of ALP in MC3T3 cells on rough surfaces but OCN expression was not changed at any con-centration. SB216763 and SB415286 inhibitors should be further investigated as potential tools to improve cell differentiation on titanium surfaces for endosseous implants.

Microarray gene expression during early healing of GBR-treated calvarial critical size defects.

OBJECTIVES: To investigate the gene expression and molecular pathways implicated in the regulation of the osseous healing process following guided bone regeneration (GBR). MATERIAL AND METHODS: Six 6-month-old Wistar male rats were used. Standardized 5-mm critical size defects were created in the parietal bones of each animal and treated with an extracranial and intracranial ePTFE membrane, according to the GBR principle. Three animals were randomly sacrificed after 7 and 15 days of healing. Total RNA was extracted from each sample and prepared for gene expression analysis. RNA quality and quantity were assessed, followed by hybridization of the cRNA to Affymetrix GeneChip Rat Genome 230 2.0 Arrays. The Affymetrix data were processed, and first-order analysis, quality control and statistical analysis were performed. Biological interpretation was performed via pathway and Gene Ontology (GO) analysis. RESULTS: Between the 7- and 15-day samples, 538 genes were differently regulated. At day 7, inflammatory and immune responses were clearly upregulated. In addition, GO terms related to angiogenesis and cell cycle regulation were overexpressed. At day 15, a more complex cellular activity and cell metabolism were evident. The bone formation processes were significantly overexpressed, with several genes encoding growth factors, enzyme activity, and extracellular matrix formation found as upregulated. Remarkably, a negative regulation of Wnt signalling pathway was observed at 15 days. DISCUSSION: The gene expression profile of the cells participating in osseous formation varied depending on the healing stage. A number of candidate genes that seem differentially expressed during early stages of intramembranous bone regeneration was suggested.

The effect of experimental osteoporosis on bone regeneration: part 2, proteomics results.

OBJECTIVES: To identify and describe protein expression in a Wistar rat calvarial critical size defect (CSD) model following treatment with guided bone regeneration in healthy and osteoporotic conditions. MATERIAL AND METHODS: Thirty-six 10-month-old female Wistar rats were used. Half of them were ovariectomized (OVX) and fed with a low-calcium diet to induce an osteoporotic-like status. In each animal of both groups, two 5-mm calvarial CSDs were treated with deproteinized bovine bone mineral graft particles and a bilayer collagen membrane. Six OVX and six control rats were randomly euthanized at 7, 14, and 30 days. One defect/animal was randomly chosen for proteomic analysis. Differently expressed proteins between the two groups were identified with matrix-assisted laser desorption time-of-flight mass spectrometry and liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: At 7 days, 29 and 27 proteins were, respectively, identified in the healthy and OVX animals. At 14 days, 103 proteins were detected in the healthy controls and 20 proteins in the OVX rats, while at 30 days, 31 and 75 proteins were identified, respectively. Only limited proteins known to play a role in the later stages of bone formation and maturation were identified within the animals 'proteomes. DISCUSSION: The osseous formation process was quite immature even at 30 days of healing. An overexpression of inflammatory and stress response pathways was detected in the OVX animals, as well as a tendency toward a delayed maturation of the osseous wound and a reduced/delayed differentiation of osteoblast cell precursors.

Tardive Dyskinesia, Oral Parafunction, and Implant-Supported Rehabilitation.

Oral movement disorders may lead to prosthesis and implant failure due to excessive loading. We report on an edentulous patient suffering from drug-induced tardive dyskinesia (TD) and oral parafunction (OP) rehabilitated with implant-supported screw-retained prostheses. The frequency and intensity of the movements were high, and no pharmacological intervention was possible. Moreover, the patient refused night-time splint therapy. A series of implant and prosthetic failures were experienced. Implant failures were all in the maxilla and stopped when a rigid titanium structure was placed to connect implants. Ad hoc designed studies are desirable to elucidate the mutual influence between oral movement disorders and implant-supported rehabilitation.

Panoramic measures for oral bone mass in detecting osteoporosis: a systematic review and meta-analysis.

Different quantitative and qualitative indices calculated on oral panoramic radiographs have been proposed as useful tools to screen for reduced skeletal bone mineral density (BMD). Our aim was to systematically review the literature on linear and qualitative panoramic measures and to assess the accuracy of these indices by performing a meta-analysis of their sensitivity and specificity. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was followed. Fifty studies were included in the qualitative appraisal and 19 were considered for meta-analysis. The methodological quality of the retrieved studies, assessed with the QUADAS-2 tool, was on average low. Three indices were reported by most of the studies: mandibular cortical width, panoramic mandibular index, and the Klemetti index. Mandibular cortical width presented with a better accuracy in excluding osteopenia/osteoporosis (specificity), since patients with a cortical width more than 4 mm had a normal BMD in 90% of the cases. Almost all studies used a cutoff of 0.3 for the panoramic mandibular index, resulting in an estimated sensitivity and specificity in detecting reduced BMD, respectively, of 0.723 (SE 0.160; 95% confidence interval [CI], 0.352-0.926) and 0.733 (SE 0.066; 95% CI, 0.587-0.841). The presence of any kind of mandibular cortical erosion gave an estimated sensitivity and specificity in detecting reduced BMD, respectively, of 0.789 (SE 0.031; 95% CI, 0.721-0.843) and 0.562 (SE 0.047; 95% CI, 0.47-0.651) and a sensitivity and specificity in detecting osteoporosis, respectively, of 0.806 (SE 0.105; 95% CI, 0.528-0.9200) and 0.643 (SE 0.109; 95% CI, 0.417-0.820). The mandibular cortical width, panoramic mandibular index, and Klemetti index are overall useful tools that potentially could be used by dentists to screen for low BMD. Their limitations are mainly related to the experience/agreement between different operators and the different image quality and magnification of the panoramic radiographs.

Dental implants in patients affected by systemic diseases.

Several systemic diseases (and relative medications) have been reported to impair or in some cases complicate dental implant surgery. In broader terms, when dealing with patients suffering from systemic diseases, the monitoring of the medical condition and of the related post-operative complications is of great importance in order to avoid risks which could jeopardise the health of the patient. In this review, the available evidence on implant survival/success, as well as relevant surgical recommendations in patients affected by systemic diseases, are evaluated and when possible, practical suggestions for the clinician are provided.

A etiopatogênese do processo de Restrição de Crescimento Intra-Uterino: um estudo bibliográfico / The etiopathogenesis of the Intra-Uterine Growth Restriction process: a bibliographical study

Revisão bibliográfica, realizada junto aos bancos de dados MEDLINE, SciELO, ScienceDirect e LILACS, com o objetivo de identificar a produção científica na área de saúde sobre os principais fatores envolvidos na etiopatogênese do processo de Restrição de Crescimento Intra-Uterino (RCIU), entre os anos de 1990 e 2008. A RCIU constitui a segunda causa de mortalidade perinatal. O recém-nascido com RCIU possui um aumento de duas a dez vezes nas porcentagens habituais de mortalidade perinatal e apresenta complicações associadas à prematuridade. A morbidade está diretamente relacionada às alterações metabólicas e imunológicas, desacelerações cardíacas, acidose fetal, baixo Índice de Apgar, hipóxia, hipoglicemia, hipotermia, asfixia, coagulação intravascular disseminada, hemorragia intracraniana e aspiração meconial. A identificação das principais alterações maternas, fetais e neonatais envolvidas no processo de RCIU é de fundamental importância para o planejamento de ações de prevenção e melhora da qualidade da assistência de enfermagem prestada às gestantes no pré-natal, pré-parto, parto e puerpério, bem como ao recém-nascido com RCIU durante o período neonatal.