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Traditionally, tissue expanders (TEs) for breast reconstruction have been placed beneath the pectoralis major muscle with or without acellular dermal matrix. More recently, full acellular dermal matrix coverage has been described for prepectoral TE placement. Our study aims to explore differences in clinical and quality-of-life (QOL) outcomes for prepectoral versus subpectoral TE breast reconstruction.We identified patients who underwent postmastectomy breast reconstruction with prepectoral or subpectoral TE placement between 2011 and 2015 and completed QOL surveys. Primary outcomes were postoperative pain and QOL scores. Secondary outcomes were clinical outcomes. We used Wilcoxon rank-sum test, chi-square test, and linear regression to compare outcomes. Postoperative follow-up for each patient was at least 60 days, except that of pain scores, which were at least 30 days. Mean age was 49 ± 10 years.Twenty-six prepectoral TE patients and 109 subpectoral TE patients met inclusion criteria. Pain scores were significantly lower at 12 hours, 1 day, 7 days, and 30 days postoperatively for the prepectoral group, compared with the subpectoral group, even after adjusting for confounding variables [PO12H: Sub-Pectoral (SP) median (interquartile range), 7 (5–8), Pre-Pectoral (PP), 5 (2.5–7.5), P value = 0.004; PO1D: SP, 5 (4–6), PP 3 (2–4), P value = < 0.001; PO7D: SP, 2 (0–4), PP, 0 (0–2), P value = 0.004; PO30D: SP, 0 (0–2), PP, 0 (0–0), P value = 0.039)]. Breast-Q scores were not significantly different between study groups. RAND-36 Physical Health scores were lower among prepectoral TE patients.Prepectoral TE breast reconstruction presents an opportunity to improve upon current reconstructive methods and does result in significantly lower pain scores. The associated risks have yet to be fully described and are important considerations, as these prepectoral patients had lower physical health outcome scores.