The EPIIC hypothesis: Intrapartum effects on the neonatal epigenome and consequent health outcomes

Abstract

There are many published studies about the epigenetic effects of the prenatal and infant periods on health outcomes. However, there is very little knowledge regarding the effects of the intrapartum period (labor and birth) on health and epigenetic remodeling. Although the intrapartum period is relatively short compared to the complete perinatal period, there is emerging evidence that this time frame may be a critical formative phase for the human genome. Given the debates from the National Institutes of Health and World Health Organization regarding routine childbirth procedures, it is essential to establish the state of the science concerning normal intrapartum epigenetic physiology. EPIIC (Epigenetic Impact of Childbirth) is an international, interdisciplinary research collaboration with expertise in the fields of genetics, physiology, developmental biology, epidemiology, medicine, midwifery, and nursing. We hypothesize that events during the intrapartum period – specifically the use of synthetic oxytocin, antibiotics, and cesarean section – affect the epigenetic remodeling processes and subsequent health of the mother and offspring. The rationale for this hypothesis is based on recent evidence and current best practice.

Introduction

Epigenetics, an expanding field of biomedicine, is the study of heritable changes in gene expression independent of underlying DNA sequence [1], [2]. Environmental factors surrounding the antenatal and early postpartum period are thought to influence the fetal and neonatal epigenome [1], [2]. Current research suggests the fetal epigenome may be the hidden link between early life exposure and later life event(s) or health outcomes [1]. It is plausible that in order to prepare for extra-uterine life, the fetal genome undergoes epigenetic remodeling during the intrapartum period; however, the degree of remodeling has not been elucidated. Additionally, the pathological implications for infant and maternal health also have not been investigated. We propose that not only the antenatal period, but the intrapartum period of childbearing and birth are important timespans to consider when examining epigenetic changes in the neonate and mother.

The antenatal period (the entire pregnancy up until labor onset) has been a focus of attention for research as it is a prolonged period of time in which the growing fetus may be particularly vulnerable to maternal environmental factors. Epigenetic features in the infant during this time period, such as gene silencing, may be influenced by maternal nutrition status, stress, and toxins (such as smoking) at specific gestational phases, with potential long-term adverse effects [2], [3], [4]. Perinatal stress, including poor maternal engagement and separation from the baby immediately after birth have been shown to permanently increase stress sensitivity and alter behavior in offspring [5] and adults later in life [6]. Early and stable epigenetic modifications have been demonstrated as the mechanism for changes within the phenotype, including DNA methylation and covalent histone modifications [5], [6], [7].

Historically, the intrapartum period (onset of labor until delivery of baby and placenta) has been considered too short a time period to exert an epigenetic influence. However, research addressing the impact of clinical intrapartum factors on outcomes has raised the question that the process of childbirth might be catalytic to affect a range of postnatal and longer-term health consequences in the neonate [8]. Studies have linked mode of birth (particularly cesarean section) to increasing rates of asthma, eczema, Type-1 diabetes, infant bronchiolitis, multiple sclerosis and obesity [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Other studies also suggest a relationship between specifically early delivery and the aforementioned adverse health outcomes [17], [19]. The potential contribution of routine childbirth interventions, such as induction of labor (use of artificial oxytocin or prostaglandins) or the routine use of antibiotics during cesarean section was not evaluated in the studies mentioned above.

The ‘hygiene hypothesis’ (lack of exposure in early childhood to infectious agents and microorganisms) has been provided as one explanation for the rise in atopic disease seen in many developed nations [20]. Due to declining family size, improved household amenities, higher standards of personal cleanliness, and reduced opportunities for cross infection in young families, this hypothesis suggests these factors have led to increased widespread expression of atopic disease [20]. Applying this hypothesis to cesarean section delivery, there is a lack of exposure to vaginal flora that could lead to changes in key physiological immune responses. However, this hypothesis has not sufficiently explained the array of health outcomes emerging in epidemiological studies associated with childbirth interventions. The hygiene hypothesis has been challenged as possessing inconsistencies and previous studies utilizing this theory have been difficult to replicate [21]. The EPIIC group proposes a novel logical pathway that utilizes epigenomic remodeling at the core, and relating these changes during the intrapartum period.