Skin thickness dimensions in histological section measurement during late‐fetal and neonatal developmental period: A systematic review

Abstract Background The development and maturation of the skin is a process that occurs during the gestation and neonatal period. Histological skin biopsy studies are relevant to improve knowledge on the skin protective barrier during the perinatal period. The thin skin of preterm newborns is unable to maintain homeostasis, thermal regulation through the skin, and is susceptible to infections. This study systematically reviewed the evidence regarding histological thickness dimensions of the skin and its layers during the late‐fetal and neonatal period. Methods PubMed, Scopus, BVS, and e SciELO library databases, with no limits in the period of analysis or idiom. Eligibility criteria were as follows: studies describing the thickness of the entire skin or its layers during late‐fetal life or the neonatal period; human being; skin biopsy analysis; and any scientific report. Two independent reviewers screened the search and extracted the following standard data: fetal or neonatal age of assessment, biopsy site, technique used for preparation and staining of histological slides, measurement techniques, and values of skin thickness. Results Fifty‐nine studies were screened, and eleven were identified from other sources. We recognized six studies that met the criteria for inclusion for proper extraction. Expressive differences between sites for sampling, methods of slide preparation, and number of layers measured made the thicknesses values summarization difficult. There were no reliable dimensions reported on this tissue. Conclusion Despite the importance of studying the human skin barrier, these findings confirmed limited evidence on skin thickness dimensions obtained by histology.


| INTRODUC TI ON
The skin is considered the largest organ of the human body, having several vital functions 1 and acting as a defensive physical barrier between the organism and the environment. 2 The skin collaborates with other organs, providing consonant functioning of the organism, as well as control of body temperature and metabolic synthesis. Such relevance explains why the structural development of the human skin has been intensely studied and documented at the electron microscopy level. 3 This tissue consists of dermis and epidermis, acting harmonically and cooperatively. The epidermal layer has a barrier function where the stratum corneum is positioned as having the outermost exposure to the environment. 1 There are critical clinical relations between the skin barrier competence and the neonatal survival due to hypothermia and neonatal infections, besides risk factors for newborn deaths. 4 The functional and structural development of the skin is a dynamic process, which begins during embryogenesis and ends in the first year of life. 1,5 Even the barrier maturation has particular importance during the late gestation and early neonatal period, histological studies are limited due to its invasive acquisition of materials from the human being, for ethical issues. 3 Microscopy analysis of the tissue suggests that the skin structure is complete at 34 weeks of pregnancy.
Thus, term newborns already have a competent barrier, comparable to adults. 6 In contrast, preterm neonates are poorly prepared to face the extrauterine environment, as they lack development in the epidermal skin layer. 6 Such weakness on the immature stratum corneum increases susceptibility to infections and percutaneous uptake of harmful toxins, and also leading to inability to maintain homeostasis, poor thermoregulation, and more risk of death. 7,8 The measurement of skin thickness is an important parameter that indirectly reflects the state of neonatal maturity and how prepared the newborn will be in the period of adaptation to the external environment. 9 The depth of this tissue and the structure of epidermal and dermal layers differ according to the body site analyzed. 10 Over the palm, sole and along joints, the epidermal layer is thicker than other parts, whereas between scapulae, the dermal layer is thicker than others sites. 10 In other sites of the fetal body, especially the eyelids and near the genitals, the skin is typically thin, since there is no lucidum sub-layer in the epidermis and the stratum corneum is reduced. 10,11 A considerable part of the knowledge on skin morphophysiology relies on the mouse model for skin maturation analysis, experimental culture models, and recently noninvasive approaches, due to restrictions on access to human fetal tissue. 3 However, invasive biopsies of skin are still indispensable in situations where histology is the gold standard as a reference for the validation of imaging exams, as well as the potential to diagnose cutaneous pathologies. 12 This study seeks to systematically review the published evidence in order to establish the magnitude of the dimension of human skin thickness and its layers during late-fetal development and the neonatal period, assessed by biopsies and histological analysis.

| ME THODS
This systematic review was conducted in accordance with the PRISMA Statement. 13 The authors previously prepared the review protocol using the application software StArt (Systematic Review System). 14 The research question that guided the study was: What is the thickness of the human skin at birth, directly measured by histology? The main outcome was the value of skin thickness.

| Search strategy and selection criteria
The search strategy was performed using the following keyword combination for the composition of PICO query:

| Study selection
Two reviewers independently screened the search output to identify potentially relevant studies, analyzing only titles and abstracts using the following predetermined eligibility criteria:

| Data analysis
The selected publications were fully and independently read for extraction. A standard data extraction supported by software 14 gathered the following variables: authors, year of publication, fetal or neonatal age, body site of biopsy, skin layer, technique used for preparation and staining of histological slides, methods of measurement, and mean, median, or range values of total skin thickness or the layers: stratum corneum, epidermis, and dermis. When data were missing or unclear, the original authors were contacted by electronic mail to clarify critical points before the aggregation of skin thickness dimensions.
The summary of the primary outcome with values of skin thickness was organized by body site where biopsies occurred, whether it was measured during late-fetal or neonatal period, and the skin layers measured in the primary studies. For standardization, in the case of multiple sites, the following data were extracted: sole, palm, abdomen, back, and capillitium. The original descriptive values in terms of mean, maximum, minimum, and standard deviation, when present, were recovered from the primary source. To facilitate the comparability of the measured values, the unit of measure was micrometer (μm). We performed transformation when necessary. When skin thickness was indirectly described, as using a linear regression equation along timing, the birth value was obtained by assuming age zero days in the prediction equation. For studies that evaluated the thickness of the fetal skin at different moments of fetal life, only the measurements assessed near the gestational term were extracted.    The back was the body site whose skin thickness was most frequently measured, and five of six studies assessed the skin during the neonatal phase (Table 2).

| D ISCUSS I ON
The results of this review revealed lack of reliable evidence on his- in specialized text-book reports regarding newborns' skin. 28 To date, a reliable histological thickness of newborns' skin is unknown and there are only a few studies addressing this topic.
This comprehensive review summarized evidence on skin thickness during birth obtained by invasive biopsy sampling of fetuses and newborns. Taking into consideration the importance of the skin barrier maturation in preterm neonates, for further investigations, analysis with better methodological quality will still be relevant to better sizing skin at birth, as well as correlating them to clinical challenges, such as maintaining temperature, infections, and other prognosis indicators.

CO N FLI C T S O F I NTE R E S T
Author ZSNR declares a patent deposit BR1020170235688 (CTIT-PN862) approach to analyze newborn skin reflection and assess ges-