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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Med Hypotheses. Author manuscript; available in PMC May 1, 2013.
Published in final edited form as:
PMCID: PMC3612361
NIHMSID: NIHMS447569
The EPIIC hypothesis: Intrapartum effects on the neonatal epigenome and consequent health outcomes
H.G. Dahlen,a* H.P. Kennedy,b1 C.M. Anderson,c A.F. Bell,d A. Clark,b M. Foureur,e2 J.E. Ohm,f3 A.M. Shearman,g4 J.Y. Taylor,b5 M.L. Wright,c6 and S. Downeh7
aSchool of Nursing and Midwifery, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW 2751, Australia
bSchool of Nursing, Yale University, 100 Church Street South, Room 295, P.O. Box 9740, New Haven, CT 06536, USA
cCollege of Nursing and Professional Disciplines, University of North Dakota, 430 Oxford Street, Stop 9025, Grand Forks, ND 58202-9025, USA
dUniversity of Illinois at Chicago, College of Nursing, Department of Women, Children, and Family Health Science, 845 South Damen Ave, MC 802, Chicago, IL 60612, USA
eCentre for Midwifery, Child and Family Health, Faculty of Health, University of Technology Sydney, PO Box 123, Broadway, Ultimo, Sydney, NSW 2700, Australia
fUniversity of North Dakota, School of Medicine, Department of Biochemistry and Molecular Biology, Stop 9037, 501 N Columbia Road, Grand Forks, ND 58203, USA
gSchool of Health, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK
hUniversity of Central Lancashire, Preston, Lancashire PR3 2LE, UK
H.G. Dahlen: h.dahlen/at/uws.edu.au; H.P. Kennedy: Holly.kennedy/at/yale.edu; C.M. Anderson: cindy.anderson/at/email.und.edu; A.F. Bell: Abell2/at/uic.edu; A. Clark: Ashley.clark/at/yale.edu; M. Foureur: Maralyn.Foureur/at/uts.edu.au; J.E. Ohm: joyce.ohm/at/med.und.edu; A.M. Shearman: amshearman/at/yahoo.com; J.Y. Taylor: Jacquelyn.taylor/at/yale.edu; M.L. Wright: Michelle.wright/at/my.und.edu; S. Downe: sdowne/at/uclan.ac.uk
*Corresponding author. Tel.: +61 2 96859118; fax: +61 2 96859599
1Tel.: +1 203 737 1302.
2Tel.: +61 448 448 735.
3Tel.: +1 701 777 2760.
4Tel.: +44 28 90484212.
5Tel.: +1 203 737 2364.
6Tel.: +1 707 777 4096.
7Tel.: +44 (0)1 772 89315.
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.
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 [24]. 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 [57].
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 [818]. 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.
The EPIIC hypothesis indicates that physiological labor and birth have evolved to exert eustress (a healthy positive form of stress) on the fetus, and that this process has an epigenomic effect on particular genes, particularly those that program immune responses, genes responsible for weight regulation, and specific tumor-suppressor genes. Reduced or elevated levels of cortisol, adrenalin, and oxytocin produced during labor may lead to fetal epigenomic remodeling anomalies which exert influence on abnormal gene expression. This reprogramming could manifest in a range of non-communicative diseases and biobehavioral problems in the neonate and adulthood. This suggests that physiology of labor and birth may be crucial to epigenetic remodeling, specifically between fetal and extrauterine life. Due to a dearth of research in this domain, epigenetic transformations which may occur due to medical interventions and environment interactions remain unknown, as well as the health implications for mother and child.
Epigenetic rationale for the hypothesis
Epigenetics has been increasingly recognized as a key component in the onset and progression of devastating human diseases [2227]. Gene expression changes occurring during development are largely epigenetic. Assuming that the genetic code is faithfully replicated and remains uniform from cell to cell within an individual, this process orchestrates the activation and inactivation of genes required for successful development of trillions of cells from one single fertilized egg. Epigenetic remodeling is extensive in utero and is expected to continue to varying degrees throughout the lifespan [107].
Epigenetic changes during normal development
Basic understanding of epigenetics will provide a platform to examine and understand genetic and genomic development within the fetus. Extensive chromatin remodeling occurs throughout development. As embryonic stem (ES) cells differentiate, they lose pluripotency (the potential of a cell to develop into more than one type of mature cell, depending on environment). ES cells have a remarkably open, active, transcriptionally-permissive chromatin structure, much of which is lost with lineage commitment [28]. There is an increase in regions of condensed heterochromatin and an increase in the global levels of the accompanying repressive histone modifications associated with differentiation [28,29]. Structural chromatin proteins also become more stably associated with chromatin in differentiated cells [28]. The extent that adult tissue-specific stem/progenitor cells retain this global permissive chromatin status is likely tied to the extent with which they retain pluripotency. Enrichment of individual histone modifications also varies on a global level during the post-blastocyst phase as developmental and tissue specific genes are activated [29].
An important component of the genome-wide characterization of chromatin in terms of embryonic development involves the concept of “bivalent” chromatin, consisting of the simultaneous presence at certain gene promoters of both “active” and “repressive” histone modifications. This pattern has recently been described in normal murine ES cells for a subset of developmental genes that are maintained in a low expression state [3032]. This bivalent state is resolved to a primarily active or repressive chromatin conformation with differentiation depending on which direction the transcription of the involved genes changes with differentiation cues [30].
Just as normal stem/progenitor cells are remodeling chromatin during differentiation, it is also important to note that these cells use DNA methylation to collaborate with chromatin configuration to stabilize key gene expression patterns which emerge during normal development and adult tissue cell turnover. Due to this, DNA methylation may be a key component for all types of cells with repressive chromatin. This methylation functions to provide long-term silencing of transposons, (stabilization of silenced genes in the processes of imprinting and x-inactivation) as well as a mechanism to permanently silence important pluripotency-associated genes [33].
Permanent, heritable gene silencing via DNA methylation plays a significant role in normal differentiation, at least for a limited number of stem cell regulatory genes (specifically PcG proteins may play a key role in this process) [3541]. Generally, the methylation seen for these pluripotency associated genes has been limited to a small number of CpG dinucleotides within promoter regions, in contrast to dense CpG island methylation seen on the inactive X chromosome [35,36]. This multifaceted collaboration of histone modifications, nucleosome remodeling, and DNA methylation provides an elegant control system producing heritable patterns of gene expression to assure the complex functions of mammalian organisms.
Epidemiological studies have suggested a critical link between toxic environmental exposures and the development of human disease later in life [4244]. Early-age environmental stimuli have also been shown to affect epigenomic patterning [45,46], positioning epigenetics as a potential mediator of this developmental exposure model (Fig. 1). Chemical and environmental toxins have been shown to disrupt epigenetic regulation of gene expression in cells by altering DNA methylation patterns [4751] and chromatin structure [48,5254]. These epigenetic changes can affect not only heritable changes in gene expression, but also disrupt overall genomic stability. Effects of environmental stress on epigenetic changes may have direct implications for a variety of human diseases including cancer, infertility, and neurodegenerative disorders [5559].
Fig. 1
Fig. 1
Epigenetics as a potential mediator of developmental exposure model.
Labor as a critical-life event
It is plausible that different birth events can trigger differential responses in neonatal epigenetic remodeling and that such changes may affect gene expression [60]. Maladaptive perinatal stress associated with labor interventions, such as cesarean section, is proposed as a cause of DNA methylation [60]. The effect of stress in early fetal and neonatal life on an individual’s genetic architecture has been demonstrated by studies examining DNA methylation and this gave rise to the EPIIC hypothesis [5,61,62].
The stress of being born is said to exceed that of any other critical life-event [60]. During labor there is a massive sympathoadrenal activation [63] that helps to mobilize the fetal journey through the birth canal and to trigger lung reabsorption [64], which is preparatory for adaptation to extrauterine life. Labor triggers inflammatory defense systems and maturation of the central nervous system [65]. Infants delivered by elective cesarean section before the onset of labor lack the catecholamine response seen with those born vaginally [63,104].
Routine labor management in most institutional settings across the developed world involve the use of pharmacological pain relief, oxytocic agents for induction and augmentation of labor, prophylactic antibiotics, active management of the third stage (period from birth of baby until delivery of placenta and membranes) of labor, and separation of the infant from mother immediately following birth. To illustrate the logic of our hypothesis on childbirth and epigenetic consequences, a summary of epidemiological evidence for iatrogenesis as a consequence of four intrapartum procedures commonly used worldwide will follow: synthetic oxytocin, epidural analgesia; prophylactic antibiotics; and cesarean section.
Exposure to synthetic oxytocin
Positive maternal mood and sensitive mothering (modulated by endogenous oxytocin) are critical to normal child development [67,68]. Given the evidence that intrapartum factors can predict postpartum mood disturbances [69,70] and that perinatal manipulation of the oxytocin system can predict dysfunctional maternal care in animals [71,72], the oxytocin receptor gene (OXTR) is a potential candidate for epigenetic modulation. Although the intrapartum synOT (synthetic oxytocin) has been thought to cross the placenta [73] there has been limited investigation of long-term effects after fetal synOT exposure.
Studies in humans suggest a dose-response relationship between exposure to intrapartum synOT and behavioral processes believed to be influenced by endogenous oxytocin, including autism spectrum disorder (ASD), attention deficit disorder (ADHD), and infant feeding behavior. For example, higher synOT dosage was associated with less successful breastfeeding, as well as with the detection of ASD at six years of age (n = 400) [74]. Similarly, higher synOT dosage has been associated with less likelihood of exclusive breastfeeding at three months, as well as less optimal sucking behaviors (n = 20) [75]. Prefeeding behavioral cues one hour after birth have been examined in relation to synOT exposure (n = 47). SynOT exposed infants showed fewer prefeeding cues, and a significantly decreased level of prefeeding organization compared to nonexposure [76]. A dose-response relationship was also evident in a study examining potential predictors of ADHD, including birth complications, gender and familial ADHD incidence (n = 172) [77]. The authors reported a statistically significant predictive relationship between synOT exposure and subsequent childhood ADHD onset (67.1% of synOT cases vs. 35.6% in nonexposure cases, p < 0.001). There is less of a relationship found with gestational age, fetal exposure time to synOT, and duration of labor. While there have been no epigenetic studies targeting intrapartum synOT, hypermethylation of a region in the OXTR promoter (measured in both peripheral blood and cortex tissue) was reported to significantly relate to humans with ASD [78].
The effects of synOT may also differ if combined with epidural anesthesia. One of the most common intrapartum procedures associated with synOT is epidural anesthesia. Since opioids have an inhibitory effect on secretion of oxytocin (via mu and kappa receptors) [79] synOT is often required after the administration of an epidural. While the half life of synOT is only 10–12 min or less [80] and intrapartum endogenous oxytocin levels correlate with synOT dosage rate [81], recent evidence suggests the interactions between epidural and synOT may modulate the oxytocin system beyond labor [82]. Compared to women who did not have an epidural, higher maternal plasma levels of oxytocin were evident the day after birth, if synOT had been administered in labor; yet lower plasma levels were evident if synOT had been administered with epidural anesthesia [82].
Developmental studies in rodents suggest that manipulations in early life using either synOT or an oxytocin antagonist can have long-term behavioral and endocrine consequences [7,8385]. For example, in prairie voles, exposure to synOT within 24 h after birth had enduring dose-dependent effects on the capacity to form pair bonds in later life [84]. In this model, exposure to a low dose of synOT facilitated pair bonding, while exposure to a high dose inhibited pair bond formation. Exposure to an oxytocin antagonist in the same time period inhibited subsequent pro-social behaviors, including the willingness to care for unrelated infants (alloparenting), possibly mediated by increases in anxiety [83]. Exposure to synOT or an oxytocin antagonist administered on day one or by repeated injections throughout the first week affected the stress behavior of pups [85]. Ongoing studies in prairie voles also suggest that endogenous oxytocin can be affected by early handling with subsequent effects on the oxytocin receptor [7]. In summary, the complex neuroendocrine regulation of developing behavior underscores caution in exposing the fetus to synOT and suggests that the conditions of birth are important, such as the dosage, timing, and duration of synOT. In addition, these effects may be modulated by the presence or absence of labor pain medication.
Prophylactic antibiotics
Intrapartum antibiotics and mode of birth can affect the type of commensal organisms present in the mother [86] and baby [87] and the prevalence of atopic disease [8890]. Use of intrapartum antibiotics is commonly indicated for prophylaxis in cases of cesarean section, prolonged ruptured membranes, and Group B Strep [91] involving single or multiple drug regimens [92]. Antibiotic prophylaxis, including commonly used penicillins and cephalosporins administered to pregnant women during the intrapartum period reach the fetal circulation and amniotic fluid with significant blood levels persisting into the newborn period [93,94]. Emerging evidence for the association between antibiotic administration and subsequent adverse health outcomes, including obesity [108110] and in particular the prevalence of atopic disease [8890], suggests the induction of undefined mechanistic insults during critical periods of susceptibility. However limited attention has been given to the intrapartum use of antibiotics and subsequent health outcomes [13]. Antibiotics have been shown to trigger altered gene expression and intestinal microbiota in rats, influencing immune system development and function [95,96]. The influence of fetal/neonatal exposure to antibiotics on development of immune dysfunction may initiate a cascade of events associated with future health conditions unexplained by the acute response of altered intestinal flora induced by maternal antibiotic exposure during a susceptible period [97]. Csoka and Szyf (2009) hypothesize pharmaceuticals create a gene-environment interaction which prompts cells to adapt by remodeling chromatin architecture and DNA methylation and that such epigenetic changes may persist after the drug has ceased [98]. Although the mechanisms responsible for drug-associated epigenetic changes remain unknown, the potential implications for drug-induced remodeling of chromatin architecture or DNA methylation that lead to persistent epigenetic changes are profound, providing a putative explanation for mechanistic underpinnings of the future development of disease.
Cesarean section
There have been two studies published on epigenetic modulation related to cesarean section [60,105]. In the first study published in 2009 the authors examined the immune system as a candidate area that could plausibly be sensitive to epigenetic changes at birth. Thirty-seven healthy term newborns were studied who either were born by spontaneous vaginal birth (n = 21) or cesarean birth (n = 16) without labor. DNA was extracted from cord blood at birth and as part of the newborn screening a heel prick was performed at 3–5 days post birth. A global measure of DNA methylation in white blood cells demonstrated that newborns born by cesarean without labor had significantly higher methylation at birth than those born vaginally with labor (p < 0.001). At 3–5 days post-birth, methylation patterns did not alter within the vaginal birth group but were significantly decreased in the cesarean group. The decreased methylation did not reach similar levels of epigenetic activity in the vaginal group. The immune system epigenetic modulation related to elective cesarean may have transcriptional sequela triggered by environmental factors later in life thereby increasing risk for immune disorders increasingly associated with mode of birth [60].
In the second paper published in 2012 the authors found that delivery type was not associated with global methylation at birth when they examined DNA isolated from umbilical venous cord blood of babies born by cesarean section and vaginal birth. This study included a larger sample size and adjusted for maternal age, smoking and infant gender. Potential methylation and birth method differences due to ethnicity, parity, maternal body weight, infant birth weight/gestational age and intrapartum labor interventions were not included in analyses in this large study conducted in an urban setting.
By looking only at global methylation and at methylation of repetitive elements, neither of these two papers identified gene specific methylation in/near promoter regions, which may have more significance in terms of gene expression and functional outcomes. There is a need for further genome-wide, gene-specific measures of DNA methylation that can be correlated with biological outcomes.
There are key differences between cesarean undertaken during labor (emergency) and those undertaken prior to onset of labor (elective). Critically, babies born by cesarean following some labor have the benefits of stress hormones released during labor, such as catecholamines and cortisol that help prepare the infant for extra-uterine life, promoting lung maturity, increase blood flow, activate the central nervous system and priming the newborns immune system.
Other differences that need to be taken into account in future studies are the different gestational ages of babies born by elective and emergency cesareans and vaginal births. A recent study showed special education needs of children steadily declined with increasing gestational age up to 40–41 weeks and then increased amongst those delivered postdates (>42 weeks) [106]. Because of their frequency, early term deliveries (37–39 weeks) contributed to more cases of special education needs in children compared to preterm births [106], making one question current policies identifying 39 weeks gestation as the ideal time at which to undertake an elective cesarean section.
There is substantial epidemiological and biological evidence of an increase in immediate impairments in lung function, reduced thermogenic response, altered metabolism, altered feeding, altered immune phenotype, and altered blood pressure [8] in babies born by cesarean section. Longer term effects of cesarean may include: asthma and allergies [8,12,15,16,99101], gastroenteritis, Type 1 diabetes [9], childhood leukemia [102,103], testicular cancer [10], obesity [11], multiple sclerosis [14], and potential brain development [19]. An underlying mechanism has not been clarified but epigenetic modulation is one possible explanation [1,60].
Consequences of the hypothesis and discussion
The EPIIC hypothesis raises a question as to whether childbirth is a formative or summative event. Formative events are those supporting development, whereas summative activity implies an end product. The prenatal period is considered a formative period for the fetus, with the birth of a child serving as a summative product, measured in discrete perinatal outcomes. Emerging data summarized in this paper suggests that events around childbirth are also formative, with the potential for lifelong and even transgenerational health consequences.
The EPIIC hypothesis allows for an examination of the potential for physiological childbirth to remodel the fetal epigenetic profile. This process may actually prime the fetus to optimize a range of postnatal behaviors, such as breastfeeding and maternal attachment, and may also provide protection against immune-system mediated non-infectious disease (such as Type-1 diabetes). The theoretical construct in this case posits that physiological birth is a eustressor, acting to prime the fetal genome to trigger optimal responses to extrauterine life. Given current debates regarding the nature and treatment of intractable disorders (from behavioral problems to non-communicable diseases) a program of research specifically addressing this hypothesis could be a valuable addition to science in labor and birth.
Future research
Many questions remain unanswered concerning epigenetic remodeling during the intrapartum period. The scientific community does not know which individuals may be epigenetically vulnerable to adverse effects of birth conditions/interventions or the implications of genetic variation with epigenetic underpinnings. This research will be essential in order to reduce vulnerability to adverse effects of birth conditions and interventions.
A program of research to test the EPIIC hypothesis is suggested with an examination of general patterns of epigenomic remodeling in neonates born after home births in the most familiar environment to the woman and without medical interventions compared to those born after elective cesarean section for breech presentation where there are no underlying medical complications preceding the cesareans. Subsequent research will include prospective longitudinal cohorts of mothers and infants undergoing various modalities of labor, using diverse environments, and a range of interventions. These studies will include various ethnic groups, gestational ages, maternal ages and socioeconomic backgrounds. Participants will be followed into late adulthood, thereby establishing potential effects of labor activities on the epigenome of mothers and babies across the lifespan. This program of research offers the potential to optimize childbirth for mothers and babies, consequently maximizing the potential for greater health.
A fundamental tenet of clinical practice is to “do no harm”. The EPIIC group hypothesizes the routine application of interventions during a healthy childbirth event can alter physiological epigenetic remodeling, with the potential for negative health effects. This suggests that physiological labor and birth is finely tuned to generate optimal epigenetic effects for later wellbeing. It is paramount to the wellbeing and protection of mothers and babies to adequately explore this area of research and investigate patterns of methylation related to mode of delivery and birth. The implications as explored may carry significant implications and it is our obligation as scientists to provide the best quality care to patients while driving the state of the science to further heights.
Footnotes
Conflict of interest statement
None.
1. Moshe E. Early life, the epigenome, and human health. Acta Paediatr. 2009;98:1082–4. [PubMed]
2. Odom LN, Taylor HS. Environmental induction of the fetal epigenome. Expert Rev Obstet Gynecol. 2010;5:657–64. [PMC free article] [PubMed]
3. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3:97–106. [PubMed]
4. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;180:462–7. [PMC free article] [PubMed]
5. Fish EW, Shahrokh D, Bagot R, et al. Epigenetic programming of stress responses through variations in maternal care. Ann N Y Acad Sci. 2004;1036:167–80. [PubMed]
6. Welberg LA, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol. 2001;13:113–28. [PubMed]
7. Bales KL, Boone E, Epperson P, Hoffman G, Carter CS. Are behavioral effects of early experience mediated by oxytocin? Front Psychiatry. 2011;2:24. [PMC free article] [PubMed]
8. Hyde MJ, Mostyn A, Modi N, Kemp PR. The health implications of birth by cesarean section. Biol Rev Camb Philos Soc. 2012;87:229–43. [PubMed]
9. Cardwell CR, Stene LC, Joner G, et al. Cesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia. 2008;51:726–35. [PubMed]
10. Cook MB, Graubard BI, Rubertone MV, Erickson RL, McGlynn KA. Perinatal factors and the risk of testicular germ cell tumors. Int J Cancer. 2008;122:2600–6. [PubMed]
11. Goldani HA, Bettiol H, Barbieri MA, et al. Cesarean delivery is associated with an increased risk of obesity in adulthood in a Brazilian birth cohort study. Am J Clin Nutr. 2011;93:1344–7. [PubMed]
12. Hakansson S, Kallen K. Cesarean section increases the risk of hospital care in childhood for asthma and gastroenteritis. Clin Exp Allergy. 2003;33:757–64. [PubMed]
13. Joffe TH, Simpson NA. Cesarean section and risk of asthma. The role of intrapartum antibiotics: a missing piece? J Pediatr. 2009;154:154. [PubMed]
14. Maghzi AH, Etemadifar M, Heshmat-Ghahdarijani K, Nonahal S, Minagar A, Moradi V. Cesarean delivery may increase the risk of multiple sclerosis. Mult Scler. 2012;18:468–71. [PubMed]
15. Pistiner M, Gold DR, Abdulkerim H, Hoffman E, Celedon JC. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J Allergy Clin Immunol. 2008;122:274–9. [PubMed]
16. Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between cesarean section and childhood asthma. Clin Exp Allergy. 2008;38:629–33. [PubMed]
17. McKay JA, Groom A, Potter C, et al. Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One. 2012;7:e33290. [PMC free article] [PubMed]
18. Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by cesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child. 2012;97:610–6. [PubMed]
19. MacKay DF, Smith GC, Dobbie R, Pell JP. Gestational age at delivery and special educational need: retrospective cohort study of 407,503 school children. PLoS Med. 2010;7:e1000289. [PMC free article] [PubMed]
20. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60. [PMC free article] [PubMed]
21. Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis” Thorax. 2000;55(Suppl 1):S2–10. [PMC free article] [PubMed]
22. Reddy MA, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011;90:421–9. [PMC free article] [PubMed]
23. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–68. [PubMed]
24. Heim C, Binder EB. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol. 2012;233:102–11. [PubMed]
25. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92. [PubMed]
26. Arngrimsson R. Epigenetics of hypertension in pregnancy. Nat Genet. 2005;37:460–1. [PubMed]
27. Rodriguez-Cortez VC, Hernando H, de la Rica L, Vento R, Ballestar E. Epigenomic deregulation in the immune system. Epigenomics. 2011;3:697–713. [PubMed]
28. Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol. 2006;7:540–6. [PubMed]
29. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32. [PubMed]
30. Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26. [PubMed]
31. Azuara V, Perry P, Sauer S, et al. Chromatin signatures of pluripotent cell lines. Nat Cell Biol. 2006;8:532–8. [PubMed]
32. Mikkelsen TS, Ku M, Jaffe DB, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448:553–60. [PMC free article] [PubMed]
33. Kiefer JC. Epigenetics in development. Dev Dyn. 2007;236:1144–56. [PubMed]
35. Lopatina NG, Poole JC, Saldanha SN, et al. Control mechanisms in the regulation of telomerase reverse transcriptase expression in differentiating human teratocarcinoma cells. Biochem Biophys Res Commun. 2003;306:650–9. [PubMed]
36. Hattori N, Imao Y, Nishino K, et al. Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells. Genes Cells. 2007;12:387–96. [PubMed]
37. Deb-Rinker P, Ly D, Jezierski A, Sikorska M, Walker PR. Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. J Biol Chem. 2005;280:6257–60. [PubMed]
38. Feldman N, Gerson A, Fang J, et al. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol. 2006;8:188–94. [PubMed]
39. Hattori N, Nishino K, Ko YG, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J Biol Chem. 2004;279:17063–9. [PubMed]
40. Yeo S, Jeong S, Kim J, Han JS, Han YM, Kang YK. Characterization of DNA methylation change in stem cell marker genes during differentiation of human embryonic stem cells. Biochem Biophys Res Commun. 2007;359:536–42. [PubMed]
41. Aoto T, Saitoh N, Ichimura T, Niwa H, Nakao M. Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol. 2006;298:354–67. [PubMed]
42. Edwards TM, Myers JP. Environmental exposures and gene regulation in disease etiology. Environ Health Perspect. 2007;115:1264–70. [PMC free article] [PubMed]
43. Bollati V, Baccarelli A. Environmental epigenetics. Heredity. 2010;105:105–12. [PMC free article] [PubMed]
44. Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology. 2006;67:494–6. [PubMed]
45. Weaver IC, Diorio J, Seckl JR, Szyf M, Meaney MJ. Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci. 2004;1024:182–212. [PubMed]
46. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005;135:1382–6. [PubMed]
47. Watson RE, McKim JM, Cockerell GL, Goodman JI. The value of DNA methylation analysis in basic, initial toxicity assessments. Toxicol Sci. 2004;79:178–88. [PubMed]
48. Arita A, Costa M. Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. Metallomics. 2009;1:222–8. [PMC free article] [PubMed]
49. Poirier LA, Vlasova TI. The prospective role of abnormal methyl metabolism in cadmium toxicity. Environ Health Perspect. 2002;110(Suppl 5):793–5. [PMC free article] [PubMed]
50. Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Curr Opin Pediatr. 2009;21:243–51. [PMC free article] [PubMed]
51. Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res. 2003;286:355–65. [PubMed]
52. Ballestar E, Esteller M. The epigenetic breakdown of cancer cells: from DNA methylation to histone modifications. Prog Mol Subcell Biol. 2005;38:169–81. [PubMed]
53. Foster WG, McMahon A, Rice DC. Sperm chromatin structure is altered in cynomolgus monkeys with environmentally relevant blood lead levels. Toxicol Ind Health. 1996;12:723–35. [PubMed]
54. Song C, Kanthasamy A, Anantharam V, Sun F, Kanthasamy AG. Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Mol Pharmacol. 2010;77:621–32. [PubMed]
55. Lahiri DK, Maloney B, Zawia NH. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry. 2009;14:992–1003. [PubMed]
56. Ren X, McHale CM, Skibola CF, Smith AH, Smith MT, Zhang L. An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis. Environ Health Perspect. 2011;119:11–9. [PMC free article] [PubMed]
57. Tunc O, Tremellen K. Oxidative DNA damage impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet. 2009;26:537–44. [PMC free article] [PubMed]
58. Donkena KV, Young CY, Tindall DJ. Oxidative stress and DNA methylation in prostate cancer. Obstet Gynecol Int. 2010;2010:302051. [PMC free article] [PubMed]
59. Zawia NH, Lahiri DK, Cardozo-Pelaez F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radical Biol Med. 2009;46:1241–9. [PMC free article] [PubMed]
60. Schlinzig T, Johansson S, Gunnar A, Ekstrom TJ, Norman M. Epigenetic modulation at birth altered DNA-methylation in white blood cells after cesarean section. Acta Paediatr. 2009;98:1096–9. [PubMed]
61. Feng J, Fouse S, Fan G. Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res. 2007;61:58R–63R. [PubMed]
62. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54. [PubMed]
63. Lagercrantz H, Slotkin TA. The “stress” of being born. Sci Am. 1986;254:100–7. [PubMed]
64. Olver RE, Walters DV, Wilson M. Developmental regulation of lung liquid transport. Annu Rev Physiol. 2004;66:77–101. [PubMed]
65. Yektaei-Karin E, Moshfegh A, Lundahl J, Berggren V, Hansson LO, Marchini G. The stress of birth enhances in vitro spontaneous and IL-8-induced neutrophil chemotaxis in the human newborn. Pediatr Allergy Immunol. 2007;18:643–51. [PubMed]
67. Tronick E, Reck C. Infants of depressed mothers. Harv Rev Psychiatry. 2009;17:147–56. [PubMed]
68. Carter CS, Grippo AJ, Pournajafi-Nazarloo H, Ruscio MG, Porges SW. Oxytocin, vasopressin, and sociality. Prog Brain Res. 2008;170:331–6. [PubMed]
69. Blom EA, Jansen PW, Verhulst FC, et al. Perinatal complications increase the risk of postpartum depression, the generation R study. BJOG. 2010;117:1390–8. [PubMed]
70. Murray L, Cartwright W. The role of obstetric factors in postpartum depression. J Reprod Infant Psychol. 1993;11:215–9.
71. Poindron P. Mechanisms of activation of maternal behaviour in mammals. Reprod Nutr Dev. 2005;45:341–51. [PubMed]
72. Leng G, Meddle SL, Douglas AJ. Oxytocin and the maternal brain. Curr Opin Pharmacol. 2008;8:731–4. [PubMed]
73. Malek A, Blann E, Mattison DR. Human placental transport of oxytocin. J Matern Fetal Med. 1996;5:245–55. [PubMed]
74. Gonzales ME. Hard data about the side effects of synthetic oxytocin. Mid-pacific conference on birth and primal health research; Honolulu, HI. 2012.
75. Olza Fernandez I, Marin Gabriel M, Malalana Martinez A, Fernandez-Canadas Morillo A, Lopez Sanchez F, Costarelli V. Newborn feeding behaviour depressed by intrapartum oxytocin: a pilot study. Acta Paediatr. 2012;101:749–54. [PubMed]
76. Bell AF, White-Traut R, Rankin K. Fetal exposure to synthetic oxytocin and prefeeding cues within one-hour postbirth. Early Hum Dev. 2012 http://dx.doi.org/10.1016/j.earlhumdev.2012.09.017. [PubMed]
77. Kurth L, Haussmann R. Perinatal Pitocin as an early ADHD biomarker: neurodevelopmental risk? J Atten Disord. 2011;15:423–31. [PubMed]
78. Gregory SG, Connelly JJ, Towers AJ, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009;7:62. [PMC free article] [PubMed]
79. Morris MS, Domino EF, Domino SE. Opioid modulation of oxytocin release. J Clin Pharmacol. 2010;50:1112–7. [PubMed]
80. Arias F. Pharmacology of oxytocin and prostaglandins. Clin Obstet Gynecol. 2000;43:455–68. [PubMed]
81. Mazzuca M, Minlebaev M, Shakirzyanova A, et al. Newborn analgesia mediated by oxytocin during delivery. Front Cell Neurosci. 2011;5:3. [PMC free article] [PubMed]
82. Jonas K, Johansson LM, Nissen E, Ejdeback M, Ransjo-Arvidson AB, Uvnas-Moberg K. Effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin, in response to suckling during the second day postpartum. Breastfeed Med. 2009;4:71–82. [PubMed]
83. Bales KL, Pfeifer LA, Carter CS. Sex differences and developmental effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles. Dev Psychobiol. 2004;44:123–31. [PubMed]
84. Bales KL, van Westerhuyzen JA, Lewis-Reese AD, Grotte ND, Lanter JA, Carter CS. Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles. Horm Behav. 2007;52:274–9. [PMC free article] [PubMed]
85. Kramer KM, Cushing BS, Carter CS. Developmental effects of oxytocin on stress response: single versus repeated exposure. Physiol Behav. 2003;79:775–82. [PubMed]
86. Benn CS, Thorsen P, Jensen JS, et al. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol. 2002;110:72–7. [PubMed]
87. Connelly JJ, Kenkel W, Erickson E, Carter CS. Are birth and oxytocin epigenetic events?. 41st Annual Conference of the Society for Neuroscience; Washington, DC. 2011.
88. McKeever TM, Lewis SA, Smith C, Hubbard R. The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the west midlands general practice database. Am J Respir Crit Care Med. 2002;166:827–32. [PubMed]
89. Rusconi F, Galassi C, Forastiere F, et al. Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med. 2007;175:16–21. [PubMed]
90. Marra F, Lynd L, Coombes M, et al. Does antibiotic exposure during infancy lead to development of asthma? A systematic review and metaanalysis. Chest. 2006;129:610–8. [PubMed]
91. Dinsmoor MJ, Gilbert S, Landon MB, et al. Perioperative antibiotic prophylaxis for nonlaboring cesarean delivery. Obstet Gynecol. 2009;114:752–6. [PMC free article] [PubMed]
92. Hopkins L, Smaill F. Antibiotic prophylaxis regimens and drugs for cesarean section. Cochrane Database Syst Rev. 2012;1:CD001136. [PubMed]
93. Colombo DF, Lew JL, Pedersen CA, Johnson JR, Fan-Havard P. Optimal timing of ampicillin administration to pregnant women for establishing bactericidal levels in the prophylaxis of group B Streptococcus. Am J Obstet Gynecol. 2006;194:466–70. [PubMed]
94. Popovic J, Grujic Z, Sabo A. Influence of pregnancy on ceftriaxone, cefazolin and gentamicin pharmacokinetics in cesarean vs. non-pregnant sectioned women. J Clin Pharm Ther. 2007;32:595–602. [PubMed]
95. Goto K, Yabe K, Suzuki T, Takasuna K, Jindo T, Manabe S. Gene expression profiles in the articular cartilage of juvenile rats receiving the quinolone antibacterial agent ofloxacin. Toxicology. 2008;249:204–13. [PubMed]
96. Lamouse-Smith ES, Tzeng A, Starnbach MN. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PLoS One. 2011;6:e27662. [PMC free article] [PubMed]
97. Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol. 2001;108:516–20. [PubMed]
98. Csoka AB, Szyf M. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses. 2009;73(5):770–80. [PubMed]
99. Metsala J, Kilkkinen A, Kaila M, et al. Perinatal factors and the risk of asthma in childhood a population-based register study in Finland. Am J Epidemiol. 2008;168:170–8. [PubMed]
100. Roduit C, Scholtens S, de Jongste JC, et al. Asthma at 8 years of age in children born by cesarean section. Thorax. 2009;64:107–13. [PubMed]
101. Tollanes MC, Moster D, Daltveit AK, Irgens LM. Cesarean section and risk of severe childhood asthma: a population-based cohort study. J Pediatr. 2008;153:112–6. [PubMed]
102. Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP. Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia. Cancer. 1991;68:1351–5. [PubMed]
103. Cnattingius S, Zack M, Ekbom A, Gunnarskog J, Linet M, Adami HO. Prenatal and neonatal risk factors for childhood myeloid leukemia. Cancer Epidemiol Biomarkers Prev. 1995;4:441–5. [PubMed]
104. Nylund L, Lagercrantz H, Lunell NO. Catecholamines in fetal blood during birth in man. AbeBooks; 1979. [PubMed]
105. Virani S, Dolinoy DC, Halubai S, Jones TR, Domino SE, Rozek LS, et al. Delivery type not associated with global methylation at birth. Clinical Epigenetics. 2012;4(8) http://dx.doi.org/10.1186/868-7083-4- [PMC free article] [PubMed]
106. MacKay DF, Smith GC, Dobbie R, Pell JP. Gestational age at delivery and special educational need: retrospective cohort study of 407,503 schoolchildren. PLoS Med. 2010;7:e1000289. [PMC free article] [PubMed]
107. Hochberg Z, Feil R, Constancia M, Fraga M, Juien C, Carel JC, et al. Child health, developmental plasticity, and epigenetic programming. Endocrine Rev. 2011;32(2):159. [PubMed]
108. Risnes KR, Belanger K, Murk W, Bracken MB. Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children. J Epidemiol. 2011;173(3):310–8. [PMC free article] [PubMed]
109. Wickens K, Pearce N, Crane J, Beasley R. Antibiotic use in early childhood and the development of asthma. Clin Exp Allergy. 1999;29(6):766–71. [PubMed]
110. Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early-life body mass. International Journal of Obesity. 2012 doi: 10.1038/ijo.2012.132. advance online publication 21 August 2012. [PubMed] [Cross Ref]