Midwifery 30 (2014) 1149–1151
Contents lists available at ScienceDirect
Midwifery journal homepage: www.elsevier.com/midw
Commentary
Is society being reshaped on a microbiological and epigenetic level by the way women give birth? Hannah Grace Dahlen, RN, RM, BN (Hons), Grad Cert Mid (Pharm) MCommN, PhD, FACM (Professor of Midwifery)a,n, Soo Downe, BA(Hons), MSc, PhD, RM, OBE (Professor of Midwifery Studies)b, Holly Powell Kennedy, CNM, PhD, FACNM, FAAN (Helen Varney Professor of Midwifery)c, Maralyn Foureur, RN RM BA GraDip Clin EpidemBiostats PhD FACM (Professor of Midwifery)d a
School of Nursing and Midwifery, University of Western Sydney, Locked Bag 1797, Penrith 2751, NSW, Australia University of Central Lancashire, Preston PR3 2LE, Lancashire, UK c School of Nursing, Yale University, 100 Church Street South, PO Box 9740, New Haven, CT 06536, USA d Centre for Midwifery, Child and Family Health, Faculty of Health, University of Technology Sydney, PO Box 123, Broadway, Ultimo, Sydney, NSW 2700, Australia b
Intervening in childbirth is like throwing a pebble into a pond. The ripples keep on going and you don't know where they will end up – but you can bet that on some distant shore there will be an effect. It is only relatively recently that we have been looking beyond the throw of the stone to the distant shore. What we see is very, very scary. (Dahlen, 2007) Since early in the 20th century, well meaning practitioners have implemented obstetric interventions, only to find, years later, that some of these caused harm to women and/or infants; for example, the use of thalidomide for morning sickness (Kim and Scialli, 2011), or diethylstilbestrol for recurrent miscarriage (Hoover et al., 2011). Many of these interventions were instituted without well-designed research to support their safety or benefits (Chalmers, 1989). Even when research is undertaken, it tends to be based on the assumption that women's pregnant and labouring bodies need fixing, rather than supporting. Many of the outcomes used measure increases or decreases in pathological outcomes (such as morbidity). The inclusion of physiological (or salutogenic) outcomes, which measure optimum and/or positive maternal and neonatal health and well-being, is much less common (Smith et al., 2014). As in other scientific disciplines, this kind of simplistic linear thinking is often limited in its capacity to solve some of the so-called ‘wicked’ (as in complex and resistant to change) problems society is now encountering (Ferlie et al., 2013). New scientific approaches, including a move towards understanding complex emergent phenomena in self-organising systems like the human body, have n
Corresponding author. E-mail addresses: [email protected] (H.G. Dahlen), [email protected] (S. Downe), [email protected] (H.P. Kennedy), [email protected] (M. Foureur). http://dx.doi.org/10.1016/j.midw.2014.07.007 0266-6138/& 2014 Elsevier Ltd. All rights reserved.
catalysed the link between two ‘wicked problems’ in health: the exponential growth in common interventions during birth (e.g. caesarean section, induction and augmentation of labour, use of antibiotics) and the rise in chronic auto-immune disease as highlighted in our recent papers (Downe and McCourt, 2008; Dahlen et al., 2013). Two leading hypotheses are in the spotlight and are generating further research and debate by researchers and activists who are keen to either confirm or refute them. In 1915, when caesarean section was rare, Kendall observed that microbes, which colonise the infant's gastrointestinal tract following vaginal birth, ‘may be protective’ (Kendall, 1915). He said, ‘Very shortly after birth bacteria make their appearance in the mouth of the newborn, and organisms appear in the meconium from four to twenty hours post partum’ (Kendall, 1915, p. 209). Contemporaries of Kendall had undertaken experiments sterilising the environments (including undertaking caesareans) and foods of newly born/ hatched animals, observing that development became affected under these conditions. This led Kendall to suggest that these bacteria may be protective under ‘ordinary conditions’. Over 70 years later Strachan (1989) published the hygiene hypothesis, proposing that declining family size, improved household amenities, and higher standards of personal cleanliness reduced opportunities for cross infection in families, leading to a reduction in the prevalence of ‘positive’ bacteria and, therefore, growing levels of atopic and autoimmune responses (Strachan, 1989). However, others noted that this rise in autoimmune disorders occurred years after changes in hygiene practices (Weiss, 2008). One subsequent amendment, termed the ‘Old Friends’ hypothesis, (Rook, 2010) holds that, as a result of physiological processes beginning in pregnancy and the perinatal period, the neonatal gut acquires flora that has been inherited across generations from Neolithic times, and that a co-dependency has
1150
H.G. Dahlen et al. / Midwifery 30 (2014) 1149–1151
built up between these organisms and the human immune system. Loss of the usual labour and breast feeding route of colonisation leaves an infant vulnerable to later atopic and auto-immune disease (Penders et al., 2006). Remarkably, 100 years after Kendall published his observations, vaginal swabs are now being taken from some women giving birth by caesarean section and smeared on their nipples or onto the infant's face and lips to help seed the infant with important bacteria (Donegan, 2014). An alternative explanation is focused on the stress response and the role of epigenetics in gene expression. This field is currently generating a great deal of interest in a number of research fields. While we are all born with a unique DNA/gene profile, we now know that how our DNA is expressed depends on several environmentally triggered processes, such as DNA methylation. Methylation relates to the silencing or switching off of whole, or parts of, individual genes so that they cannot function thus gene expression is altered (Phillips, 2008). For example, in a comparative study, Almgre et al. (in press) found that certain cord blood cells of infants born by caesarean section had more global DNA methylation than those from infants born vaginally. This could mean that changes to the gene have occurred due to exposures at birth and could have long-term implications that are currently unknown. Almgre and colleagues go on to suggest that the potential for adverse effects (disease) can lie dormant, unless or until a specific trigger acts on genes through these epigenetic processes (Almgre et al., in press). This might explain why labour and birth events are associated with chronic (especially auto-immune) disease states in the future although the relevant research available at the moment cannot definitely demonstrate that one event ‘causes’ another (Hyde et al., 2012). Almgre et al.'s study is only the latest of a growing body of similar studies that is contributing to the development of a new set of research questions in this area and new research groups are joining this field, including some who are working in maternity care. In 2011, we founded the international EPIIC (EPIgenetic Impact of Childbirth) research group. On the basis of an examination of a range of studies in this area, we developed our EPIIC hypothesis, (Dahlen et al., 2013). We proposed that nonphysiological interventions during the intrapartum period, and specifically the use of synthetic oxytocin, epidural analgesia, and caesarean section, may interrupt the physiological eustress of being born. We hypothesise that eustress (normal levels of stress) is needed to prime the immune system via complex neurohormonally mediated processes involving hormones such as cortisol and others. Dys-stress (stress that is too high, or too low) may affect the physiological remodelling processes through DNA methylation, with unknown impacts on the subsequent health of the mother and child. Our hypothesis is supported by studies in other fields that link life stressors with the experience of illness and/or recovery (Dhabhar, 2014) and by an early study that showed changes in salivary cortisol levels associated with mode of birth at two months postnatal, when the infant was exposed to a new stressor (immunisation) (Miller et al., 2005). Again, these studies are too early in the research process to be able to say that one event (interventions in birth) causes another (chronic autoimmune disease). However, given that epigenetic changes are heritable (they are manifest across generations), any risk that they might occur as a result of childbirth practices requires urgent exploration. Both the Hygiene/Old Friends theory and our EPIIC hypothesis lead us back to the same pressing question: Is society being reshaped on a microbiological and epigenetic level by the way women give birth? This is a profoundly disturbing question that warrants urgent research in an era of unparalleled intervention in childbirth in many countries. This question also provides an urgent provocation to midwives to refocus attention and re-energise their knowledge, skills and
passion in supporting women to give birth without unnecessary intervention, thus removing the possible cause. Intervention in childbirth could be regarded as a potential environmental trigger with epigenetic consequences that may alter the human epigenome. Very recently, it has been argued that, on the day of birth, a person is at a higher risk of death than for any other day until they are over 90 years old (Walker et al., 2014). Those who might argue for increased intervention during labour and birth in the name of safety might also pause to consider that the preservation of physiological birth as far as possible might be the passport for the lifelong health and well-being of not only an infant, but also for its future offspring. The day of birth may turn out to be one of life's most defining events. The time is now right – indeed, a major documentary Microbirth will be launched in September 2014, exploring the evidence for, and implications of, both of the hypotheses presented in this editorial (Harman, 2014). Exploration of the interconnectivity between birth and later chronic disease will inevitably generate critique, as it challenges the current norms in evidence based medicine. However as Drucker so wisely says, ‘the greatest danger in times of turbulence is not the turbulence; it is to act with yesterday's logic’ (Drucker, 1989). We welcome such debate and critique and challenge midwives around the world to engage in this important discussion, and to work with multidisciplinary teams to conduct the best research to answer the important questions raised in this editorial.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References Almgre, M., Schlinzig, T., Gomez-Cabrero, D., et al., 2014. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? Am. J. Obstet. Gynecol. 211, http://dx.doi.org/10.1016/ j.ajog.2014.05.014, in press. Chalmers, I., 1989. Evaluating the effects of care during pregnancy and childbirth. In: Chalmers, I., Enkin, M., Keirse, M.J.N.C. (Eds.), Effective Care In Pregnancy and Childbirth, vol. 1. Oxford University Press, Oxford, pp. 3–29. Dahlen, H., 2007. The Effect of a Rising Caesarean Section Rate on Maternal and Perinatal Health. Paper Presented at the NSW Health Department Caesarean Section Forum. Dahlen, H.G., Kennedy, H.P., Anderson, C.M., et al., 2013. The EPIIC hypothesis: intrapartum effects on the neonatal epigenome and consequent health outcomes. Med. Hypothesis 8, 656–662. Dhabhar, F.S., 2014. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol. Res. 58, 193–210. Donegan, T., 2014. How Friendly Bacteria in Birth Can Protect Your Baby's Health Eumom. 〈http://www.eumom.ie/pregnancy/how-friendly-bacteria-in-birthcan-protect-your-babys-health/〉. Downe, S., McCourt, C., 2008. From being to becoming: reconstructing childbirth knowledges. In: Downe, S. (Ed.), Normal Birth, Evidence and Debate, 2nd edn. Elsevier, Oxford. Drucker, P.F., 1989. The New Realities. Heinemann, Oxford. Ferlie, E., Fitzgerald, L., McGivern, G., Dopson, S., Bennett, C., 2013. Making Wicked Problems Governable?: The Case of Managed Networks in Health Care. Oxford University Press, Oxford. Harman, T., 2014. Microbirth: Why ‘Seeding Baby's Microbiome’ Needs to Be on Every Birth Plan. Huffingtonpost. 〈http://www.huffingtonpost.co.uk/toni-har man/microbirth-babys-mircobiome_b_4947959.html〉. Hoover, R.N., Hyer, M., Pfeiffer, R.M., et al., 2011. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N. Engl. J. Med. 365, 1304–1314. http://dx.doi.org/10.1056/NEJMoa1013961. Hyde, M.J., Mostyn, A., Modi, N., Kemp, P.R., 2012. The health implications of birth by caesarean section. Biol. Rev. 87, 229–243. Kim, J.H., Scialli, A.R., 2011. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol. Sci. 122, 1–6. Kendall, A.I., 1915. The bacteria of the intestinal tract of man. Science XLll 1076, 209–212.
H.G. Dahlen et al. / Midwifery 30 (2014) 1149–1151
Miller, N.M., Fisk, N.M., Modi, N., Glover, V., 2005. Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy. BJOG 2, 921–926. Penders, J., Thijs, C., Vink, C., et al., 2006. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–521. Phillips, T., 2008. The role of methylation in gene expression. Nat. Educ. 1, 116–119. Rook, G.A.W., 2010. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the ‘hygiene' or ‘old friends' hypothesis. Clin. Exp. Immunol. 160, 70–79.
1151
Smith, V., Daly, D., Lundgren, I., Eri, T., Benstoem, C., Devane, D., 2014. Salutogenically focused outcomes in systematic reviews of intrapartum interventions: a systematic review of systematic reviews. Midwifery 30, e151–e156. Strachan, D.P., 1989. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260. Walker, K.F., Cohen, A.L., Walker, S.H., Allen, K.M., Baines, D.L., Thornton, J.G., 2014. The dangers of the day of birth. BJOG 121, 714–718. Weiss, S.T., 2008. Asthma in early life: is the hygiene hypothesis correct? J. Pediatr. 84, 475–476.
Contents lists available at ScienceDirect
Midwifery journal homepage: www.elsevier.com/midw
Commentary
Is society being reshaped on a microbiological and epigenetic level by the way women give birth? Hannah Grace Dahlen, RN, RM, BN (Hons), Grad Cert Mid (Pharm) MCommN, PhD, FACM (Professor of Midwifery)a,n, Soo Downe, BA(Hons), MSc, PhD, RM, OBE (Professor of Midwifery Studies)b, Holly Powell Kennedy, CNM, PhD, FACNM, FAAN (Helen Varney Professor of Midwifery)c, Maralyn Foureur, RN RM BA GraDip Clin EpidemBiostats PhD FACM (Professor of Midwifery)d a
School of Nursing and Midwifery, University of Western Sydney, Locked Bag 1797, Penrith 2751, NSW, Australia University of Central Lancashire, Preston PR3 2LE, Lancashire, UK c School of Nursing, Yale University, 100 Church Street South, PO Box 9740, New Haven, CT 06536, USA d Centre for Midwifery, Child and Family Health, Faculty of Health, University of Technology Sydney, PO Box 123, Broadway, Ultimo, Sydney, NSW 2700, Australia b
Intervening in childbirth is like throwing a pebble into a pond. The ripples keep on going and you don't know where they will end up – but you can bet that on some distant shore there will be an effect. It is only relatively recently that we have been looking beyond the throw of the stone to the distant shore. What we see is very, very scary. (Dahlen, 2007) Since early in the 20th century, well meaning practitioners have implemented obstetric interventions, only to find, years later, that some of these caused harm to women and/or infants; for example, the use of thalidomide for morning sickness (Kim and Scialli, 2011), or diethylstilbestrol for recurrent miscarriage (Hoover et al., 2011). Many of these interventions were instituted without well-designed research to support their safety or benefits (Chalmers, 1989). Even when research is undertaken, it tends to be based on the assumption that women's pregnant and labouring bodies need fixing, rather than supporting. Many of the outcomes used measure increases or decreases in pathological outcomes (such as morbidity). The inclusion of physiological (or salutogenic) outcomes, which measure optimum and/or positive maternal and neonatal health and well-being, is much less common (Smith et al., 2014). As in other scientific disciplines, this kind of simplistic linear thinking is often limited in its capacity to solve some of the so-called ‘wicked’ (as in complex and resistant to change) problems society is now encountering (Ferlie et al., 2013). New scientific approaches, including a move towards understanding complex emergent phenomena in self-organising systems like the human body, have n
Corresponding author. E-mail addresses: [email protected] (H.G. Dahlen), [email protected] (S. Downe), [email protected] (H.P. Kennedy), [email protected] (M. Foureur). http://dx.doi.org/10.1016/j.midw.2014.07.007 0266-6138/& 2014 Elsevier Ltd. All rights reserved.
catalysed the link between two ‘wicked problems’ in health: the exponential growth in common interventions during birth (e.g. caesarean section, induction and augmentation of labour, use of antibiotics) and the rise in chronic auto-immune disease as highlighted in our recent papers (Downe and McCourt, 2008; Dahlen et al., 2013). Two leading hypotheses are in the spotlight and are generating further research and debate by researchers and activists who are keen to either confirm or refute them. In 1915, when caesarean section was rare, Kendall observed that microbes, which colonise the infant's gastrointestinal tract following vaginal birth, ‘may be protective’ (Kendall, 1915). He said, ‘Very shortly after birth bacteria make their appearance in the mouth of the newborn, and organisms appear in the meconium from four to twenty hours post partum’ (Kendall, 1915, p. 209). Contemporaries of Kendall had undertaken experiments sterilising the environments (including undertaking caesareans) and foods of newly born/ hatched animals, observing that development became affected under these conditions. This led Kendall to suggest that these bacteria may be protective under ‘ordinary conditions’. Over 70 years later Strachan (1989) published the hygiene hypothesis, proposing that declining family size, improved household amenities, and higher standards of personal cleanliness reduced opportunities for cross infection in families, leading to a reduction in the prevalence of ‘positive’ bacteria and, therefore, growing levels of atopic and autoimmune responses (Strachan, 1989). However, others noted that this rise in autoimmune disorders occurred years after changes in hygiene practices (Weiss, 2008). One subsequent amendment, termed the ‘Old Friends’ hypothesis, (Rook, 2010) holds that, as a result of physiological processes beginning in pregnancy and the perinatal period, the neonatal gut acquires flora that has been inherited across generations from Neolithic times, and that a co-dependency has
1150
H.G. Dahlen et al. / Midwifery 30 (2014) 1149–1151
built up between these organisms and the human immune system. Loss of the usual labour and breast feeding route of colonisation leaves an infant vulnerable to later atopic and auto-immune disease (Penders et al., 2006). Remarkably, 100 years after Kendall published his observations, vaginal swabs are now being taken from some women giving birth by caesarean section and smeared on their nipples or onto the infant's face and lips to help seed the infant with important bacteria (Donegan, 2014). An alternative explanation is focused on the stress response and the role of epigenetics in gene expression. This field is currently generating a great deal of interest in a number of research fields. While we are all born with a unique DNA/gene profile, we now know that how our DNA is expressed depends on several environmentally triggered processes, such as DNA methylation. Methylation relates to the silencing or switching off of whole, or parts of, individual genes so that they cannot function thus gene expression is altered (Phillips, 2008). For example, in a comparative study, Almgre et al. (in press) found that certain cord blood cells of infants born by caesarean section had more global DNA methylation than those from infants born vaginally. This could mean that changes to the gene have occurred due to exposures at birth and could have long-term implications that are currently unknown. Almgre and colleagues go on to suggest that the potential for adverse effects (disease) can lie dormant, unless or until a specific trigger acts on genes through these epigenetic processes (Almgre et al., in press). This might explain why labour and birth events are associated with chronic (especially auto-immune) disease states in the future although the relevant research available at the moment cannot definitely demonstrate that one event ‘causes’ another (Hyde et al., 2012). Almgre et al.'s study is only the latest of a growing body of similar studies that is contributing to the development of a new set of research questions in this area and new research groups are joining this field, including some who are working in maternity care. In 2011, we founded the international EPIIC (EPIgenetic Impact of Childbirth) research group. On the basis of an examination of a range of studies in this area, we developed our EPIIC hypothesis, (Dahlen et al., 2013). We proposed that nonphysiological interventions during the intrapartum period, and specifically the use of synthetic oxytocin, epidural analgesia, and caesarean section, may interrupt the physiological eustress of being born. We hypothesise that eustress (normal levels of stress) is needed to prime the immune system via complex neurohormonally mediated processes involving hormones such as cortisol and others. Dys-stress (stress that is too high, or too low) may affect the physiological remodelling processes through DNA methylation, with unknown impacts on the subsequent health of the mother and child. Our hypothesis is supported by studies in other fields that link life stressors with the experience of illness and/or recovery (Dhabhar, 2014) and by an early study that showed changes in salivary cortisol levels associated with mode of birth at two months postnatal, when the infant was exposed to a new stressor (immunisation) (Miller et al., 2005). Again, these studies are too early in the research process to be able to say that one event (interventions in birth) causes another (chronic autoimmune disease). However, given that epigenetic changes are heritable (they are manifest across generations), any risk that they might occur as a result of childbirth practices requires urgent exploration. Both the Hygiene/Old Friends theory and our EPIIC hypothesis lead us back to the same pressing question: Is society being reshaped on a microbiological and epigenetic level by the way women give birth? This is a profoundly disturbing question that warrants urgent research in an era of unparalleled intervention in childbirth in many countries. This question also provides an urgent provocation to midwives to refocus attention and re-energise their knowledge, skills and
passion in supporting women to give birth without unnecessary intervention, thus removing the possible cause. Intervention in childbirth could be regarded as a potential environmental trigger with epigenetic consequences that may alter the human epigenome. Very recently, it has been argued that, on the day of birth, a person is at a higher risk of death than for any other day until they are over 90 years old (Walker et al., 2014). Those who might argue for increased intervention during labour and birth in the name of safety might also pause to consider that the preservation of physiological birth as far as possible might be the passport for the lifelong health and well-being of not only an infant, but also for its future offspring. The day of birth may turn out to be one of life's most defining events. The time is now right – indeed, a major documentary Microbirth will be launched in September 2014, exploring the evidence for, and implications of, both of the hypotheses presented in this editorial (Harman, 2014). Exploration of the interconnectivity between birth and later chronic disease will inevitably generate critique, as it challenges the current norms in evidence based medicine. However as Drucker so wisely says, ‘the greatest danger in times of turbulence is not the turbulence; it is to act with yesterday's logic’ (Drucker, 1989). We welcome such debate and critique and challenge midwives around the world to engage in this important discussion, and to work with multidisciplinary teams to conduct the best research to answer the important questions raised in this editorial.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References Almgre, M., Schlinzig, T., Gomez-Cabrero, D., et al., 2014. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? Am. J. Obstet. Gynecol. 211, http://dx.doi.org/10.1016/ j.ajog.2014.05.014, in press. Chalmers, I., 1989. Evaluating the effects of care during pregnancy and childbirth. In: Chalmers, I., Enkin, M., Keirse, M.J.N.C. (Eds.), Effective Care In Pregnancy and Childbirth, vol. 1. Oxford University Press, Oxford, pp. 3–29. Dahlen, H., 2007. The Effect of a Rising Caesarean Section Rate on Maternal and Perinatal Health. Paper Presented at the NSW Health Department Caesarean Section Forum. Dahlen, H.G., Kennedy, H.P., Anderson, C.M., et al., 2013. The EPIIC hypothesis: intrapartum effects on the neonatal epigenome and consequent health outcomes. Med. Hypothesis 8, 656–662. Dhabhar, F.S., 2014. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol. Res. 58, 193–210. Donegan, T., 2014. How Friendly Bacteria in Birth Can Protect Your Baby's Health Eumom. 〈http://www.eumom.ie/pregnancy/how-friendly-bacteria-in-birthcan-protect-your-babys-health/〉. Downe, S., McCourt, C., 2008. From being to becoming: reconstructing childbirth knowledges. In: Downe, S. (Ed.), Normal Birth, Evidence and Debate, 2nd edn. Elsevier, Oxford. Drucker, P.F., 1989. The New Realities. Heinemann, Oxford. Ferlie, E., Fitzgerald, L., McGivern, G., Dopson, S., Bennett, C., 2013. Making Wicked Problems Governable?: The Case of Managed Networks in Health Care. Oxford University Press, Oxford. Harman, T., 2014. Microbirth: Why ‘Seeding Baby's Microbiome’ Needs to Be on Every Birth Plan. Huffingtonpost. 〈http://www.huffingtonpost.co.uk/toni-har man/microbirth-babys-mircobiome_b_4947959.html〉. Hoover, R.N., Hyer, M., Pfeiffer, R.M., et al., 2011. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N. Engl. J. Med. 365, 1304–1314. http://dx.doi.org/10.1056/NEJMoa1013961. Hyde, M.J., Mostyn, A., Modi, N., Kemp, P.R., 2012. The health implications of birth by caesarean section. Biol. Rev. 87, 229–243. Kim, J.H., Scialli, A.R., 2011. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol. Sci. 122, 1–6. Kendall, A.I., 1915. The bacteria of the intestinal tract of man. Science XLll 1076, 209–212.
H.G. Dahlen et al. / Midwifery 30 (2014) 1149–1151
Miller, N.M., Fisk, N.M., Modi, N., Glover, V., 2005. Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy. BJOG 2, 921–926. Penders, J., Thijs, C., Vink, C., et al., 2006. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–521. Phillips, T., 2008. The role of methylation in gene expression. Nat. Educ. 1, 116–119. Rook, G.A.W., 2010. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the ‘hygiene' or ‘old friends' hypothesis. Clin. Exp. Immunol. 160, 70–79.
1151
Smith, V., Daly, D., Lundgren, I., Eri, T., Benstoem, C., Devane, D., 2014. Salutogenically focused outcomes in systematic reviews of intrapartum interventions: a systematic review of systematic reviews. Midwifery 30, e151–e156. Strachan, D.P., 1989. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260. Walker, K.F., Cohen, A.L., Walker, S.H., Allen, K.M., Baines, D.L., Thornton, J.G., 2014. The dangers of the day of birth. BJOG 121, 714–718. Weiss, S.T., 2008. Asthma in early life: is the hygiene hypothesis correct? J. Pediatr. 84, 475–476.
