Introduction

Overview of neonatal skin conditions

According to the World Health Organisation (WHO), neonates are infants who are less than 28 days old. Neonates have a higher mortality rate, largely occurring due to low birth weight, infections, immune reactions and trauma. This is usually because of their immature immune system and developing body systems.¹ Neonatal Skin Conditions result from temporary lesions to severe pathological injuries on the surface of the skin.²
Neonates may be either mature or premature at birth, and this influences the physiology and structure of their skins. Generally, Neonatal Skin is less moist with a higher pH and higher sebum production as compared to adult skin and therefore requires care and attention. At childbirth, neonatal skin undergoes a dynamic maturation. This results in a decreased epidermal and stratum corneum thickness with an unorganised microvasculature. Also, there is a low 

production of melanin, which may result in melanomas in unfavourable high UV exposures.
These characteristics differentiate adult skin from neonatal skin and are there because of the rapid switch from the embryonic or foetal environment to the outside environment, which is dry, different and full of microorganisms.³ 

Transient neonatal pustular melanosis (TNPM)

• Clinical features, incidence, and natural course

TNPM refers to a short-lived, unusual benign neonatal skin condition characterised by skin blisters and pustules with fluid-filled vesicular eruptions, which heal with hyperpigmented macules.⁴ The rate of development of TNPM varies amongst different ethnicities, races and continents. There is an increased prevalence of TNPM in Africans and a lower prevalence in Europeans, Asians and Caucasians. Generally, TNPM has an incidence of about 0.2 to 4% in all newborns and about 15% in black children⁵. There are 3 stages of TNPM, which are differentiated by their different characteristics. Namely, Pustular phase, Colarrette phase and Macular phase. The pustular stage is characterised by fragile superficial pustules with no redness. The colarrette stage is, however, characterised by white scale and colarrette. The macular stage, on the other hand, is characterised by hyperpigmented macules.⁶

• Histopathology and diagnostic criteria

Histopathologic techniques reveal polymorphonuclear(neutrophil) infiltration with lesser or no eosinophils and lymphocytes. It also reveals fused inflammatory infiltration effused into connective tissue cells, containing serous fluid with debris. Case studies also uncover the presence of subcorneal pustules in the epidermis, which reveals neutrophils and increased melanin in macrophages with the use of Wright's stain. Fontana-Masson stains also reveal hyperpigmentation in focal basal areas.⁶
It is clinically presented with pustules shortly after birth on the neck, trunk and face. To diagnose this, other infections and skin conditions are first ruled out along with any other systemic conditions in order to diagnose.⁷

Differential diagnosis

Differential diagnosis of TNPM entails the collection of information concerning a patient's symptoms and other information to identify underlying and immediate causes of the patient’s symptoms. Differential diagnoses are made by considering conditions and symptoms such as Erythema Toxicum Neonatorum (ETN), neonatal acne, miliaria, eczema, psoriasis and more.⁸

• Erythema Toxicum Neonatorum (ETN) is a cutaneous eruption that presents as a whitish or pale-yellow blotchy rash pustule, and papule with a reddish surrounding²⁰
• Neonatal Acne presents as pimples with white and black tips²³
• Miliaria is caused by blockage of endocrine ducts and glands and presents as rash²¹
• Psoriasis is caused by chronic inflammation that causes a buildup of skin cells. It presents as whitish scales and erythema of the surrounding tissues²²

Neonatal skin microbiota

Development of neonatal skin microbiota

Skin microbiota, also known as microbiome, is simply the microorganisms that live on or in the skin as its natural flora or habitat. The skin is the outermost and largest organ, which has protective, secretory and sensory functions. Scientists have discovered a lot of microorganisms, specifically bacteria on the skin that enable it to perform its function and also derive benefits from it.¹⁸ One of the very important things is its influence on the differentiation of keratinocytes, which in turn produces keratin for the provision of strength and rigidity. These microorganisms include: bacteria such as Streptococcus, Staphylococcus, Propionibacteria, Acinetobacter, fungi such as Malassezia spp, Aspergillus spp and many more.⁹ 

Skin microbiota arises from several factors. In utero child skin is sterile and therefore, microbiota has been proposed to arise from the maternal vagina or skin environment, depending on the method of birth (Vagina or cesarean section). The microbiota arises immediately after birth in full-term births, 2 to 3 weeks after birth in preterm and gradually disperses to all parts of the child's skin. Other factors that may influence this microbiota are the hospital or birthplace environment, feeding type and the child’s bath. As the child ages, the microbiota gradually changes from one similar to the birth mum to a unique microbiota.^10,11

Function and importance

• Barrier formation, immune modulation, and pathogen defence

Neonatal skin microbiota is important for the prevention of pathogenic invasion of foreign microorganisms, immune and inflammation modulation, maintaining the integrity of the skin, and maintaining homeostasis of the skin. Immediately after birth, the skin microbiome is undeveloped and develops and disperses over time. It is essential that there is a balance between interspecies and intraspecies relationships in order to maintain healthy skin.¹²

Linking TNPM with microbial colonisation

Hypothesis: Microbial triggers or modulators of TNPM

• Possible role of specific microbes in neutrophilic response

Early colonisation of microorganisms is a factor that could possibly affect neonatal skin. Microbial activities not only stimulate keratinocyte production but also stimulate MAIT(Mucosal Associated Invariant T) cells, which are required for the recognition of pathogens and IL-17, which are involved in T-cell production.¹⁷ Imbalances or certain microbial pathways can trigger an immune response and inflammation, which can result in symptoms seen in TNPM. Although modern research relates TPNM to hormonal triggers by the mother against neonatal skin and neonatal skin maturation, the actual cause of this disorder is unknown.^13,14 Neutrophils are the first leukocytes observed at acute inflammatory sites. The presence of neutrophils at pustules serves as an indication for the stimulation of inflammation. Staphylococcus has been associated with dermatitis. C. acne has also been associated with the production of proinflammatory factors that produce acne.¹⁹ This evidence provides a basis for suspicion of microbial activity in TNPM conditions.

Pathophysiological mechanisms

• Microbial stimulation of innate immunity (e.g., TLR activation)

One unique factor to consider is the exposure of the neonate to the maternal microbial environment. This exposure takes place based on the mode of delivery (vagina or cesarean section) of the baby. The neonate may be exposed to the external parts of the female reproductive system which is made up of its own microbial environment. This microbial environment may be influenced by the mother’s hygiene, the mother’s cosmetics or even previous infections of the mother. Another factor is the exposure of the child to maternal immunity in the uterus due to exchange of substances and antibodies even before delivery. This builds and determines the neonate's initial immunity and protection and may be associated with fetal reaction to the external environment outside the womb in the first few days after birth.

The pathophysiology is not yet fully understood. Although the presence of neutrophils in pustules and macrophages may suggest the involvement of the innate immune system and inflammation. Toll-like receptors recognise antigens on the surface of the skin and serve as a signal system for immune modulation. Microbial stimulation may also stimulate innate immunity, and therefore, more research into this area may reveal any link.¹⁶

Conclusion

TNPM is a benign condition in newborns and lasts for a short time. It is usually self-cured and doesn't pose any systemic damage to neonates. This field requires extensive research to uncover the association between TNPM and microbiota. Although this condition cannot be prevented, management methods such as good neonatal baths and care can help relieve the symptoms in shorter periods of time should be used. Parental guidance should also be given to manage the condition and also to prevent anxiety due to the condition.

Summary

Neonates are children who fall below the age of 28 days. TNPM affects neonates and is characterized by skin blisters and pustules with fluid-filled vesicular eruptions, which heal with hyperpigmented macules. It is a benign transient condition¹⁵. Its causes are not fully known, although it may be related to immune-triggering factors. The microbiota refers to microorganisms found on the skin of a neonate after birth. The microorganisms are undifferentiated at first, but gradually mature and balance over time. Microbiota can be associated with TNPM due to their immune-triggering actions, but there is still no evidence available for that claim and more research is required in order to investigate the cause of TNPM.