Apolipoprotein D (Apo D) is a key molecule in the lipid transport during homeostasis and repair processes in normal and pathological conditions of the nervous system with a putative neuroprotective effect. In the last decades, huge experimental efforts have been made to know the exact mechanism of action of Apo D, even though, it remains an open question. In this regard, studies in mammals and flies have suggested that Apo D seems to act through a variety of cellular mechanisms related with its ability to selectively bind different lipid ligands. For instance, this apolipoprotein is required to myelin compaction, it participates in axon regeneration/remyelination, and it can control the magnitude and timing of the inflammatory response after injury, promoting myelin clearance, and regulating the number of immune cells recruited to the damaged area. These, among others, are some of the reasons to study Apo D in multiple sclerosis (MS) pathology, where it could be particularly important since the autoimmune reaction against oligodendrocytes (OLGs) and myelin is generally assumed as the most plausible cause of this pathology. The aim of this work was to investigate the Apo D expression pattern in MS lesions, including active and inactive demyelinating plaques, and also remyelinating ones. Human brain tissues with inflammatory demyelination consistent with MS were used to quantify Apo D immunosignal in different lesions. Our results show a clear decrease of Apo D expression in all sclerosis plaques, being lower in the inactive than in active areas but recovers in the remyelination ones. Apo D is mainly produced by the matured OLGs of white matter and is located in cell processes surrounding the myelin sheath. All these data seem to indicate an important role of Apo D in myelination/remyelination processes as a molecule with a neuroprotective potential, and may serve as a good starting point for its study in MS. Multiple sclerosis (MS) is a chronic, neurodegenerative, and demyelinating disease of the central nervous system (CNS) that affects to more than 2.1 million people worldwide and for which there is still no cure . The maiIn MS, autoreactivity to different myelin proteins involves cellular and humoral immunity. It has been described that a defective and permeable blood-brain barrier (BBB) can lead to some T lymphocytes to infiltrate the brain parenchyma, secrete proinflammatory cytokines, and stimulate monocytes/macrophages that promote damage of myelin sheaths and the loss of OLGs . For itsMS focal demyelinating lesions, known as plaques, appear as scars in the white matter (WM) throughout the brain and spinal cord . Often, Apolipoprotein D (Apo D) belongs to the lipocalin family whose members share the ability to bind and transport small hydrophobic ligands, that is, arachidonic acid, cholesterol, or steroids, due to their conserved tertiary structure with a ligand-binding pocket . This 29In non-pathological conditions of the CNS, Apo D expression is always greater in the WM than in the gray one and is widely expressed in many nervous cells such as periventricular cells, neurons, OLGs, and astrocytes . NoteworData from proteomic studies have currently suggested that various apolipoproteins, Apo D and Apo E among them, are involved in MS; elevated levels of these proteins were found in the CSF of MS patients . UnfortuThe present study was conducted according to the Declaration of Helsinki, and it has been approved by the local Research Ethics Committee of Principado de Asturias.n = 3), Barcelona University-Clinical Hospital (n = 6), Central Bank Madrid (CIEN Foundation) (n = 1), and Navarra Hospital (n = 4). Eleven subjects between 27 and 68 years old with histologically proven inflammatory demyelination consistent with MS, properly confirmed by a neuropathologist, were used in this study (Table 1). The ethics committees of each participating biobank have reviewed and approved the study protocol. Whereas most biobanks waived the need for informed consent due to the anonymous and non-interventional fashion of this study, a formal written consent obtained from patients or surrogates was an essential requirement for other ones.Human brain and spinal cord tissues were provided by several Spanish brain banks: Biobank of the University Central Hospital of Asturias  slides, and dried at 36°C for 24 h.To visualize the morphological features and the different cell types in the studied regions, sections were desparaffined in xylene, and partially hydrated by successive alcohols. Then, and in order to locate demyelination plaques and determine lesion activity, sections were stained using hematoxylin-eosin, luxol fast blue (LFB) myelin stain, periodic acid–Schiff (PAS), and ferric hematoxylin, a technique developed in our laboratory , which s2O2 , washed in distilled water, and treated with PBS (2 min). Non-specific binding was blocked by incubation with 1% BSA (30 min). Incubation with a specific rabbit antibody against human Apo D , was can method , dehydraTable 1) were photographed using a 20× lens.Before quantification, we took advantage of the fluorescent qualities that myelin displays in formalin fixation to choose different areas in demyelination plaques: active, inactive, and remyelinization areas. For the quantification of Apo D presence, the chromogenic signal was selected with Adobe Photoshop CS 8.0.1  and quantified with ImageJ 1.37c  software according to a procedure developed by our group . Six ran2O2 , washed in distilled water again, and treated with PBS for 2 min. Non-specific binding was blocked by incubation with 1% BSA (30 min). Incubation with a specific rabbit antibody against Apo D (1:2000 dilution) was carried out overnight at 4°C. The immunoreactivity was detected with an Extravidin–biotin–alkaline phosphatase staining kit . Enzymatic activity was shown by incubation with Vector blue substrate . Slides were rinsed in PBS, placed in a plastic Coplin jar filled with 0.01 M sodium citrate buffer (pH 6), and incubated in a household microwave oven. Microwave treatment involves completely blocking contaminating staining in the double-labeling technique using primary antibodies from the same species and the same secondary antibody [see 2O2 (33%). Finally, sections were mounted in aqueous mounting medium. For controls, representative sections were processed in the same way with 1% BSA in place of the primary antibody. In addition, control sections were also incubated with Apo D antibody preabsorbed with Apo D immunizing peptide (80 μg/ml). Under these conditions, no specific immunostaining was observed.A double immunostaining for Apo D protein and neurofilament (NF-200) was carried out according to the following protocol. The sections were treated sequentially with Triton X-100 , washed in distilled water, treated with Hbody see . Then, i2O2 , washed in distilled water again, and treated with PBS for 2 min. Slides were rinsed in PBS, placed in a plastic Coplin jar filled with 0.01 M sodium citrate buffer (pH 6), and incubated in a household microwave oven. Then sections were washed in PBS for 2 min and non-specific binding was blocked by incubation with 1% BSA (30 min). Incubation with a specific monoclonal antibody against alpha B crystallin  (1:200 dilution) was carried out overnight at 4°C. Sections were incubated with a biotinylated horse universal antibody  . Afterward, sections were incubated with extravidin , and peroxidase activity was visualized by incubation with Sigma Fast DAB  at room temperature for 30 min. After that, slides were rinsed in PBS, placed into a plastic coplin jar filled with 0.01 M sodium citrate buffer (pH 6), and heated twice for 5 min at 700 W in a household microwave. Microwave treatment involves completely blocking contaminating staining in the double-labeling technique using primary antibodies from the same species and the same secondary antibody [see The double immunostaining for crystallin and Apo D protein was carried out according to the following protocol. The sections were treated sequentially with Triton X-100 , washed in distilled water, treated with Hbody see . ImmunosFinal images were obtained by the digital superposition of the corresponding DAB  and fluorescence  images of the same sections. The positive signal of each image was selected according to the method of Finally, a double immunohistochemical technique for crystallin and the specific astrocytic marker, GFAP, was performed in order to study the possible crystallin expression in other CNS cells. The immunohistochemistry was carried out according to the method described above; a specific monoclonal antibody against alpha B crystallin visualized by Sigma Fast DAB and a specific polyclonal antibody against GFAP  visualized by streptavidin labeled with Fluorolink Cy2  were used. Final images were obtained by the digital superposition of the corresponding DAB  and fluorescence  images of the same sections. Crystallin DAB signal was converted to red and GFAP signal to green channel of a new RGB picture. This new image shows the GFAP fluorescence signal in green and the crystallin fluorescence signal in red.Sections were observed using an Epi-Fl Nikon Eclipse E400 microscope equipped with Plan-Fluor objectives, and images were recorded by a digital camera (NikonDN-100).t-test. Significant differences were considered when p < 0.05.The data in the graphs are presented as the mean ± SEM. All statistical calculations were conducted using SPSS 21.0 for Windows. The test of Kolmogorov–Smirnov with the correction of Lilliefors was used to evaluate the fit of the data to a normal distribution and the test of Levene to evaluate the homogeneity of variance. Significance was analyzed by one-way ANOVA test followed by a Tukey’s test for multiple comparisons, or a Student’s Figures 1a,b). Chronic-active plaques were more frequently detected than acute active ones probably due to the high number of patients with progressive MS. Chronic-active plaques consist in big plaques with an inactive center and one or more expansive edges with macrophages inside . In some cases, chronic-active plaques with remyelination can be observed .In order to analyze the Apo D expression in MS lesions, first of all we localized and characterized demyelination plaques in myelin stained sections according with previous studies . DiffereFigure 1c). Since 27% of our cases showed remyelination features, a new region called remyelinating area .In order to analyze the Apo D implication in demyelination and remyelination processes in MS, we analyzed the Apo D expression pattern in focal demyelinating lesions by immunohistochemistry techniques ; most astrocytes positives for this protein exhibit round-shaped cell bodies, hypertrophy, and numerous fibrillary processes (reactive astrocytes).The active plaque areas show a low overall Apo D signal when we compare with the intact periplaque WM. However, reactive astrocytes and active macrophages of these areas appear intensely labeled for Apo D . This fact may be due to the large amount of Apo D-positive cells present in these surrounding areas as well as the intensity of their labeling .In the case of chronic plaques, Apo D expression was again higher in periplaque WM than in the inactive plaque area . Interestingly, the Apo D immunosignal showed a similar pattern than that of myelin. Thus, the immunoreactivity for Apo D tended to decrease as we approached the plaque border and even more in the demyelinated plaque area . Based in the cell morphology, we observed that OLGs, macrophagic cells, and some isolated astrocytes  were responsible for the expression of Apo D in all these areas . In the remyelinating regions, both myelin and Apo D levels increase in line with the remyelination processes that are taking place .When we analyze myelin of chronic MS lesions with a specific stain for this protein we found that, as it was to be expected, myelin was reduced to low levels in active areas and to very low levels in inactive ones, compared to control WM area and periplaque WM . We found that Apo D appeared preferentially in the cytoplasm and distal cell processes of OLGs in all the plaque types and patients studied. Small granules containing Apo D could also be observed around the myelin sheath of these cells . Noteworthy, in the border of plaques, even with low levels of myelin, some remaining OLGs showed immunolabeling for Apo D . OLGs expressing Apo D reappeared in focal remyelination areas, specifically in those where new myelin envelopes are being formed .Finally, co-localization studies of myelin and Apo D proteins were performed in immunohistochemistry tissue sections counterstained with LFB . The data showed statistically significant differences in the Apo D burden between inactive (36.5 ± 8.2) and active areas (76.6 ± 14.3) in chronic plaques (p < 0.05), and also between inactive and remyelination areas where Apo D recovers , taking periplaque WM as 100% expression . However, we did not find significant differences when we compared active with remyelination areas .The quantification of Apo D protein level in the most frequent and better defined chronic plaques showed clear discrepancies between the different areas under study. Since it was difficult to distinguish plaque areas in immunostaining sections for Apo D, we used the intrinsic fluorescent properties of myelin to unequivocally detect them and improve the quantification process . In fact, only a very few astrocytes were positives for crystallin so these cells have not been taken into account in our studies.Our results clearly demonstrated a decrease in the Apo D content from the active area to the chronic inactive one in parallel with the loss of myelin in all the plaque types and patients studied. However, an important issue still to be determined is the exact relationship between Apo D levels and the number of OLGs present in these areas. For this purpose, first we tested different OLG markers and we found that crystallin  was the Figure 5, in both representative images , and the quantification of OLGs negative for Apo D  and positive for Apo D  . A statistical significant reduction in the number of OLGs expressing Apo D  in the active area (13.04 ± 0.43) compared with the periplaque WM , and a significant number of OLGs do not express Apo D in the periplaque WM  as well as in active areas  was found. In fact, we have found that not all the OLGs are Apo D positives, which becomes more evident in active demyelinating areas in which there also seems to be more colocalization .Double immunostaining for Apo D and crystallin is showed in p < 0.001) . Notably, we have observed that the amount of Apo D and neuronal NF-200 decreased, in a statistical significant way, in parallel from the edge  to the inactive plaque center  . Of note is that many axons conserved immunostaining of NF-200 in active demyelination areas even in absence of Apo D expression . In remyelination areas, both signals were again found  .In the light of the described results and the neuroprotective role suggested for Apo D, we used a double immunostaining for Apo D and NF-200 to study whether the apolipoprotein expression could be related with axonal preservation. As we expected, the expression pattern for both proteins was similar. In fact, the immunolabeling for Apo D and NF-200 statistically significant decreases in the chronic inactive plaque areas  compared to periplaque WM (29.5 ± 0.4 and 17.4 ± 0.23, respectively; While much progress has been achieved on the involvement of Apo D in some neurodegenerative diseases in the past years, little is known about its role in MS. The neuroprotective and antioxidant effects postulated for this apolipoprotein and its proved overexpression in glial cells during demyelinating/remyelinating processes are fundamental reasons to suspect that Apo D could be implicated in MS. The immunohistochemical characterization of Apo D expression pattern in the anatomopathological classical features of MS, sclerosis plaques, is a first step necessary to address this goal.In this work, we have observed that Apo D expression is further reduced in MS lesions respect to the unaffected WM, in all the plaque types and patients studied. In this sense, an interesting finding is that there are labeling differences within the plaque, significantly lower Apo D expression in the inactive area than in the active one which increases again in remyelination areas. Remarkably, the immunohistochemical approaches reveal a possible relationship between OLGs, myelin, and Apo D expression in MS plaques. As it was expected, myelin protein levels decrease in demyelination plaques from the periplaque WM to the border of the lesions an even more to the center. In fact, this loss of myelin sheets wrapping myelinated nerve fibers is closely related with OLGs degeneration that characterize MS pathophysiology . The ApoRegarding the role of Apo D in myelination/remyelination processes, literature indicates that Apo D is a secreted lipocalin that takes place in a neuroprotective mode in various pathophysiological mechanisms of CNS and PNS, almost always in relation with its ability to selectively bind different small lipid molecules . In thisApo D is expressed in the development of the CNS and increases during aging and in some neurodegenerative diseases . Gene prin vivo and in vitro studies (Also of interest is highlighting that Apo D disappears in demyelinated plaques but returns when remyelination occurs. According with our findings, a correlation between Apo D and loss of axonal processes in the sclerosis plaques could be ruled out. Although more studies are needed in this respect, one plausible explanation may place Apo D in the molecular and cellular mechanism that control spontaneous remyelination after damage. As mentioned above, Apo D is expressed mainly by mature OLGs as wells as OPCs in the brain which, in turn, are ultimately responsible for the restoration of new myelin sheaths in demyelinated axons in MS . Indeed, studies . The dat studies . Interes studies . UnfortuApart from OLGs and macrophages, astrocytes also express Apo D in WM. Our group and others have previously reported that in some human neurodegenerative diseases, reactive glial progression seems to be accompanied by an increase in Apo D expression being this increment much higher in astrogliosis areas, probably due to neuron injury or loss . AccordiIn summary, the dual function of Apo D, as a tissue specific lipid carrier and an antioxidant and neuroprotective molecule, makes it a potential versatile player in MS pathology. To our knowledge, this is the first study showing a detailed characterization of Apo D expression pattern not only in the MS lesions but also in different types of cells somehow involved in the disease. Our results seem to indicate an important function of Apo D in MS and may serve as a good starting point for its study in the myelination/remyelination of CNS. However, further investigation is needed to appropriately address the exact implication of Apo D in these processes as well as its neuroprotective potential that, if confirmed, would open new avenues in the search for alternative therapeutically approaches in the fight against demyelinating diseases as MS.AN contributed to writing the manuscript, performed and analyzed the cytoarchitectonic staining and the immunohistochemical techniques. BR performed and analyzed the cytoarchitectonic staining. EdV performed part of the staining procedures. EM-P contributed to writing the manuscript, and assisted in analyzing the results and images processing. AA supervised the project and contributed to the anatomopathological diagnosis. JT contributed by formulating the initial hypothesis, directed the experiments performed, and contributed to scientific discussions and manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This paper explores the changing experience of giving birth in Cambodia over a 53-year period. During this time, Cambodian people experienced armed conflict, extreme privation, foreign invasion, and civil unrest.An historical perspective was used to explore the changing place and nature of birth assistance given to Cambodian women between 1950 and 2013. Twenty-four life histories of poor and non-poor Cambodians aged 40–74 were gathered and analysed using a grounded thematic approach.In the early lives of the respondents, almost all births occurred at home and were assisted by Traditional Birth Attendants. In modern times, towards the end of their lives, the respondents’ grand-children and great grand-children are almost universally born in institutions in which skilled birth attendants are available. Respondents recognise that this is partly due to the availability of modern health care facilities but also describe the process by which attitudes to institutional and homebirth changed over time. Interviews can also chart the increasing awareness of the risks of homebirth, somewhat influenced by the success of health education messages transmitted by public health authorities.The life histories provide insight into the factors driving the underlying cultural change: a modernising supply side; improving transport and communications infrastructure. In addition, a step-change occurred in the aftermath of the conflict with significant influence of extensive contact with the Vietnamese recognised.None. Up to 1 billion people live in fragile settings, with many of them among the world’s poorest and most vulnerable. By 2030, it is estimated that 43–60% of the world’s extreme poor will live in fragile and conflict-affected contexts ” .“Pregnant women were rarely brought to hospital to deliver the baby because it was too far, and they may give birth on the way. Another choice was to carry them with a hammock. There was nothing else” .“People in the past did not really believe in medical healthcare for giving birth; they believed in the TBA … [she] wrapped threads around the umbilical cord of the baby very tightly … and then cut them off using tailor’s scissors” .During this period, TBAs were popular; in rural areas where public facilities were rare as well as in urban areas, where public facilities were available. TBAs could be persons in a woman’s village or in neighbouring villages; family members or not; but those with extensive experience in assisting birth. The ‘TBA’ may not necessarily persons be clearly designated as such. The perceived difficulties associated with giving birth .Interviews showed that even when respondents lived close to a hospital, they still used TBAs when they perceived that giving birth would be safe, with no apparent complications (e.g. bleeding or prolonged labour pain).arb” (a kind of demon) would come to disturb the woman. We can’t see that demon, but the mother of the new-born can see it. Then, she would open her eyes widely and her body temperature would increase. She could die if no one can help” .“My mother died after delivering a baby … I was there when she died. Both she and her the baby died on the same day … . After giving birth, a woman is supposed to sleep on a warm bed above a stove with fire heating, and we have to stick a nail on the bed otherwise “One maternal death was reported by one respondent in this period, believed by the respondent to have been caused by a spirit.“Q: When did your first child die? A: She died when she was a half month old. She had oral thrush and she refused breast. Sometimes she drank my breast milk, but often vomited. After a period of time, she died” .New-born deaths were mentioned by three respondents. Deaths were often associated with illness of the new-born or was perceived to be caused by a spirit.“When we reached Prey Veng, my mum couldn’t walk any longer. She was pregnant, and her legs were swollen. So, we went into the village to rest there. We had planned to go to our hometown, but Pol Pot soldiers sent us in a different direction” .“I was moved [to a new place] three days before I gave birth to my fifth child. My husband went to [the TBA] for help when I was about to give birth. I looked after about ten kids when I was moved to that region. I was assigned to babysit those kids because I had just given birth and, thus, they let me do easier task. After two months, I returned to work, planting seedlings and rice harvesting” .During the Khmer Rouge regime, none of the interviewees reported giving birth at health facilities or hospitals. As noted earlier, where a small number of health facilities had survived, they were reserved for elite, revolutionary, categories. Even access to TBAs became difficult because TBAs were often assigned to work in different locations. In addition, due to forced labour– a common experience during the Khmer Rouge period - the interviewees moved often between work locations and were expected to work as normal, usually on a punishing schedule until the day of giving birth.“Even though I was getting morning sickness, I was forced to carry soil and dig canals … I did this work until I was pregnant for five months and then I was transferred to transplant rice seedlings [and after that] to husk the rice and then carry it to the kitchen. I worked until I couldn’t anymore and then I was allowed to rest at home until giving birth. I was crying while working because my stomach was getting pain when I worked too hard and I was trying to massage it to reduce the pain and then continued to work. Somehow, I didn’t dare to complain about this work because if it was heard I would be imprisoned and still forced to work as well … there wasn’t much Khmer medicine at that time and the elders told me to boil a kind of herb to ease labour … if smoke had been seen from our site, they would have come to check it so I hid the herb boiling from them. One elder boiled the herbs and the other stayed outside in case someone came to check the place. If we saw someone walking to us from the distance, we would have smothered the fire” .For one woman, there was no TBA, only the elderly women in her work group.“Q: When did you have the first child? A: After being married for 1 year, I had a daughter. This child died a week after delivery. At that time, before delivery, I was transplanting at the rice field. After I came out of the field, I went into labor and so I went to lie in bed to rest, but then I gave birth immediately” .The same woman mentioned the new-born death of her first child during this period.“At that time, there was still no hospital [in Angroka]. However, TBAs were available in the village since the Pol Pot regime had collapsed, and so people who were traditional birth attendants returned to live in the village” .“It was because there was no hospital here at that time. A hospital was available at the district when my wife had the third or the fourth children but even if a hospital/medical centre [was available] midwives were not … so people always delivered at home with TBA” .“All my seven children were delivered by traditional midwives. From 1979-1983 there were no doctors [and no] proper doctors from 1979-1990. There were some physicians in the commune, but not enough medicines were available” .During this period, new patterns of maternity services started to emerge, including homebirth with trained midwives; and giving birth at public facilities. Interviewees were still highly dependent on TBAs after the fall of the Khmer Rouge in 1979 through to the late 1990s, not least because they were available and close-by to offer immediate assistance.“There were hospitals only in [the] district towns but not … . where I was living. During that time there were still some remnants of Khmer Rouge … those remnants didn’t hurt civilians because they were afraid of the government’s troops. Sometimes they came to ask for rice … Because the distance was far, we were worried that I might deliver the baby on the way, and if it was so, we couldn’t find any TBA on time... there were landmines along the way as well. So, I tried to labour at home, but I didn’t know what time I delivered my child because I was unconscious” .The civil war between the remnants of the Khmer Rouge and the government troops continued until 1998 in Battambang province where one interviewee lived at that time. Landmines along the way to the district town also reduced the accessibility of public hospitals as reported by the interviewee.“Vietnamese troops lived there. However, people were afraid of [them] … we didn’t dare to go out at night. During the day, we needed a few people to accompany us or Vietnamese troops could harm us” .Another interviewee talked about the deployment of Vietnamese troops near the Cambodian-Vietnamese border (Takeo province) where the remnants of Khmer Rouge remained. She dared not travel outside the village to access public facilities, for safety reasons.“My neighbours, some elderly people, and the Vietnamese that lived near me advised me to go to hospital. They said “you should go to hospital; Vietnamese people never use TBA because they were afraid of risks of TBA. I listened to them, so I went to hospital and I could deliver baby safely. It’s near our house … when I was in labour, I rushed to hospital where they provided 24 hours service. All the medical staff were Vietnamese, and we had very few Khmer medics from the brutal regime” .“I did not know any hospital at that time. I only recalled that it was flooding season. We did not have money, so I was delivered the baby by a Vietnamese midwife” .“[I] delivered my son at the hospital. But I didn’t have a medical midwife to help me. [I] used only Khmer traditional midwife … Vietnamese physicians were busy treating injured people … After the birth, [I used] herbal medicines plus the help from the Vietnamese medical staff. They gave me some injections.” Two new-born deaths and one stillbirth were reported by respondents in the early 1990s. The reasons were illness of the new-born and heavy work done by women during pregnancy.The presence of trained Vietnamese midwives, medical workers or neighbours in 1980s to support childbirth and postnatal care of Cambodian women was also reported. One interviewee witnessed Vietnamese midwives providing services at hospital in 1980. She also recalled receiving advice on giving birth at hospital from a Vietnamese neighbour. In 1989, the same interviewee received support from a Vietnamese midwife to deliver her fifth child at home. Another interviewee recollected receiving postnatal care from Vietnamese medical providers in 1984.“There was a referral hospital at district as well as one just established about 2-3 km from home. But I didn’t have a motor bike … at that time we didn’t have a health centre in the community” .“Sometimes I thought of going to hospital, but I had no money … I witnessed some doctors not taking care of patients if they didn’t have money. Those doctors did not even look at the face of those poor patients. However, if patients had money, they were helped quickly. My sister experienced that” .By the late 1990s, hospitals were established at district levels in Kompong Cham and Takeo provinces where interviewees were living at the time. However, services were not yet available at community level. It was challenging for those who lived far from district towns to access public services. The combination of the cost of giving birth at a hospital, generalized household poverty at this time, along with a distrust of health worker motivations, also influenced decision-making.“We became aware of who, in former times, were midwives and asked them for assistance for giving birth …  their own equipment to assist us [ … ] unlike the TBAs” .“Q: You used the TBA so why did you invite the midwife? A: It was because it was a very long birth. I didn’t feel the pain and I didn’t really know when to push. After one baby was born, then they said that there was another baby coming. I lost my energy, so my husband went to invite a private midwife” .“Q: You chose to deliver the baby at home with the assistance of a trained midwife, but not a TBA? Why? A: There were some TBAs still, but most of them were getting old. Trained midwives started to be available at that time and people began to rely on them for giving birth. With the experience of my other sisters’ who had given birth, my mother suggested to ask a trained midwife to help me during birth. The medical midwife also had her own equipment such as scissors and knives” .Whilst TBAs continued to be popular, hiring private trained midwives to perform deliveries at home also emerged as a common behaviour during this period. One interviewee talked of hiring a former midwife (who had survived the Khmer Rouge regime) to assist his wife at home; four others recalled hiring newly-trained midwives during the late 1990s. The hiring of private midwives came after people became more aware of the risks of giving birth and availability of the service, and so they demanded reliable services as they faced inaccessibility to public facilities.“Before I went to Vietnam, I saw a neighbour who died after she delivered a baby at home and was bleeding. After I saw that, I wanted to go to hospital, and did not dare to deliver it at home … A village physician suggested I go to Vietnam and another physician knew Vietnamese, so he accompanied me” .Border residents reported seeking care in neighbouring countries for a complicated case, when their income allowed. Clearly, this also relied on improved roads and availability of transportation. One Takeo resident lived close to Vietnam and discussed giving birth to her 11th child.“Q: How was your third child [delivered]? A: In hospital. At that time, the transportation has improved a lot” .“Where was your second child born? A: The second child was born at the Red Cross Hospital near the Independent Monument … I started having prenatal check-up with my second child … When I moved here where I'm closer to medical staff, I heard them talking about pregnancy care. Then, I became worried, so I just went there to have prenatal test because it's also very close to my place. My elderly neighbour also advised me to have prenatal test” .An increase in public facility use in this period can also be observed from interviewees, especially among urban residents. Transportation also improved faster in urban areas and interviewees appeared more aware of risks in giving birth, gained through daily conversations with neighbours and friends. These accounts swayed five interviewees to deliver at a hospital.“[He] told me during my pregnancy that when I was in labour, I should inform him, and he would take me to military hospital so that I did not need to pay. I was even given food, scarf and towel. When I was in labour, he took me to the hospital by motorcar at midnight. I rested there for three days … I had my name as a wife of my nephew. He had a soldier certificate” .In the early post-conflict period, a family of military personnel could also gain free access to care in urban areas. For example, the interviewee below recalls how she gained free care through her nephew:“My brother suggested that I go [to a private clinic]. He said … he would pay for me. I didn’t know why he suggested this clinic, but all five children of my brother were delivered there. His workplace bought him an insurance there. My brother works for the International Red Cross” .During this period, interviewees reported four types of maternity services: homebirth with TBAs; homebirth with trained midwives; giving birth at a public facility and an emerging use of trained midwives at private clinics. Use of private clinics depended on slowly improving economic conditions for the household, the availability of private facilities, and a desire for better quality of service. Use, however, depended on household finances:“Most families would go to hospital now. However, there are still some families – one among 100 families, who are too poor to afford to go to hospital – still use services from TBAs. However, my family has money, so we go to hospital … the hospital asked us first if we had money or not” .“I did not have money to go to hospital... one bed cost 40,000KHR USD10.46)0.461 andThe interviews also revealed a declining reliance on TBAs that was linked to ability to pay for formal providers: interviewees, and the generations that followed them, who could afford the cost switched to public facilities. Those who were unable to pay continued to rely on TBAs.“The delivery of the second baby was smooth. She [my daughter] only went to the health centre [and] … didn’t spend any money for the maternity service because her family also shared the ID poor card with me” .Public hospitals became a service of choice for critical conditions or where complications in giving birth were anticipated. In this period, reference was also made to social protection schemes such as the Health Equity Fund for the poor, and Community Based Health Insurance.“Although the doctor did not ask money from me, I did not have money to buy food ... I did not have any means to travel too. I literally had nothing … [the midwives would want] 30,000KHR (USD7.38)“For me, I don’t want to go to hospital. I was also ashamed and shy of nurses and doctors. Health workers had bad words, so I didn’t want to go to hospital. Although I met a good doctor when I gave birth to my previous son, I was afraid that next doctors could be bad and blame me. When they blamed me, I was angry” .Other interviewees noted that, even with the ID poor card, they could not access hospital care due to continued high level of household poverty and health worker attitudes and behaviours.“Now we have media to raise awareness of people about pregnancy, that women should go to health centre for check-up when expecting a baby, or when they miss their period. The health care system before was far different from now … Now they advertise everything [ … ] and I am a village representative for the health network [ … ] I walk door to door and inform people [ … ] or we invite 10 people for a short meeting. We have 10 packs of washing powder to give to those 10 interviewees and 5000KHR (USD1.25)“Now young people prefer to deliver their baby at hospital and there are no TBAs. Giving birth in the hospital is safe because there are a lot of medicines and equipment. I know about this because I went to hospital to take care of my relatives and I observed it. I heard doctors talk about that to the patients. The doctor asked her to return home after staying in the hospital for 24 hours and the midwife came to our house to give her injections. The midwife didn’t allow her to take Khmer traditional medicines, so she drank only warm water. Now people trust trained midwives because they have enough equipment and medicine to help. In the previous time, people trusted TBAs. People’s belief and perception on health care have changed according to circumstances” .Younger interviewees showed greater pregnancy awareness and changing perceptions of the safest way to give birth, in part due to information and outreach programmes by the government, NGOs, media, community groups, and local authorities.Reduction in maternal mortality over the twenty-first century has been one of Cambodia’s success stories. The Maternal Mortality Ratio (MRR) dropped from 1020 per 100,000 live births in 1990 to 161 by 2015 [The interview results highlight the value of a life history approach, giving rich insights into how socio-cultural change takes place. They chart how attitudes to childbirth of individuals and community have changed, together with changed availability of options for assistance during birth; and how a maternal healthcare system has developed in the country over the last five decades, in tandem with economic security and infrastructure changes, during conflict and post-conflict reconstruction. The life histories highlight how change takes place, and show that change can be rapid, even within a generation .Through the majority of the regimes covered, from King Sihanouk to near present day, TBAs were the main birth attendant along with family members . This isThe horrors of the Khmer Rouge era have been documented elsewhere and are not the subject of this paper. The interview excerpts above convey starkly how isolated the people were during these times of mass genocide, displacement of families, forced labour, starvation, and malnutrition. Our interviews suggest that women giving birth in this era survived because of TBAs and each other. Also, with the extreme violence in the country, and overwhelming destruction of healthcare facilities, the risks of childbirth were simply an added complication to the many other risks women faced daily.The Vietnamese invasion of Cambodia in 1979 ended direct Khmer Rouge control, though civil unrest in the countryside continued for about 20 years , 18. AftThe UNTAC period instituted a wider rebuilding of the public health care system with TBAs still the main source of birth assistance over both regimes. However, with exposure to international attitudes, a change in Cambodian’s perceptions of TBAs is seen – TBAs are now thought limited in their scope and quality. This was accompanied by a shift in the perception of risk in childbirth and increased use of medicalized/formalized facilities in both the public sector and a nascent private sector suggesting that the post conflict periods can indeed be fertile opportunities for cultural change. Clearly, a step change in these attitudes occurred in the immediate post conflict period and is attributed to the influence of Vietnamese actors, both friends and neighbours; and authorities of the interim (Vietnamese) government.The proliferation of public health services accelerated from the year 2000, with significantly increased provision and use of public and private facilities. The commitment shown in the HSSPs to maternal care and the growing capacity and network of facilities indicates a return of the state and social contract with the population. The rising incomes of ordinary Cambodians can be observed along with improved transportation, enabling use of such facilities. By 2014, 89% of Cambodian births were supported by skilled birth attendants . HoweverIn this paper we have explored the changing experience of giving birth in Cambodia over a 53-year period, a time of extensive armed conflict, foreign invasion and civil unrest. We used life histories to trace changing responses to service supply during this period. They provided insight into some of the factors driving the underlying cultural change: a modernising supply side; improving transport and communications infrastructure. In addition, a step-change occurred in the aftermath of the conflict with significant influence of extensive contact with the Vietnamese recognised. In terms of health system strengthening, the interviews bear out the proposition that conflict and post-conflict periods can be periods where socio-cultural change can take place rapidly.


Echinococcus granulosus has been described as the common etiology of hydatid cysts in many parts of the world. A 54-yr-old female with lower abdominal pain referred to Gynecology Ward of Sari Imam Khomeini Hospital, Iran in 2016. Sonography was carried out and cysts in ovaries and liver were observed. The cysts of liver seemed to be hydatidosis but physicians were suspected about ovarian cystic mass. Anti-Echinococcus antibodies (ELISA) screen was positive. The operation was done on her and treatment by albendazole started one week before surgery and continued after discharge from the hospital. Pathology confirmed hydatidosis in ovary, also patient follow-up was performed for three months by abdominal CT scan that showed peritoan full of many small hydatid cysts. Uncommon locations for constitution of hydatid cysts such as ovary and peritoan often make the diagnosis very difficult. Hydatidosis is considered in differential diagnosis of any cysts of the entire body, especially in endemic countries such as Iran. Echinococcus granulosus has been described as the most common culprit of the hydatid cysts. Hydatidosis is very common in some parts of the world such as East Europe, South America, Middle East, East Africa, Australia and Mediterranean area  arising from pelvis with restricted mobility. Sonography of abdomen performed and cystic mass in both ovaries was seen. In addition, probably a cyst in liver hydatid was seen. MRI without contrast showed right ovarian simple cyst (80×50 mm) without internal septation and multiloculated left ovarian cyst (75×40 mm) was observed .Echinococcus antibodies (ELISA) screen was positive. However ovarian cystic mass might be hydatidosis but to rule out malignancy, oophorectomy and hysterectomy were conducted.All routine blood tests and tumors markers to be within the normal range such as CBC, biochemistry tests, CEA, CA125 and Alfa-Feto Protein performed were normal except ESR and LFT test that were abnormal. Anti-After bilateral oophorectomy, the cyst removed and sent to pathology laboratory. The pathology report confirmed hydatid cyst .Treatment with albendazole (400 mg) started one week before surgery and continued for three months. Postoperative follow-up was done for three months. CT scan performed for her indicated improvement of hydatidosis in liver but peritoan of this patient was full of many small hydatid cysts . AlbendaInformed consent was taken from the patient and the study was approved by the Mazandaran University of Medical Sciences, Sari, Iran.Generally, ovarian hydatidosis is very unusual (less than 1%). Typically this cyst presents a malignant tumor . In our Hydatid cyst in pelvic sites is a rare detection. The case of this paper presumably is a secondary hydatid cyst, due to rupture of liver cyst during surgery or spontaneously. Sterility, disorder of urinary tract system, distention and pain of abdomen and irregularity of menstruation are symptoms of pelvic hydatidosis . OvarianEchinococcus cyst makes it possible to avoid an intraoperative iatrogenic rupture, and when available, to administer previously an Albendazole-based therapy in order to decrease the risk of dissemination that can lead to recurrences (A high level of doubt or a preoperative diagnosis of urrences . Some ovurrences . Hydatidurrences . Pain isurrences .Hydatidosis can exist in all part of the body and no site is immune. Uncommon locations such as ovary and peritoan frequently produce nonspecific signs; consequently, hydatid cyst is considered in various diagnoses of all cysts of the body, especially in endemic countries such as Iran.


This paper explores the impact of shale gas and oil fracking wells on infants’ health at birth across Oklahoma counties. The empirical analysis makes use of the Dumitrescu-Hurlin causality test, as well as the (long-run) Pooled Mean Group method. The results clearly document that there is a unidirectional relationship between fracking activities and three alternative indexes of infants’ health at birth, as well as a significant impact of fracking on infants’ health indicators. In addition, the results illustrate the substantial role of fracking through the drinking water quality channel. Hydraulic fracturing (fracking) has been an important innovation in the energy sector, especially after 2006 in the case of the Oklahoma state. U.S. production of oil and natural gas has increased dramatically, leading to abruptly lower electricity prices, stronger energy security, lower carbon emissions, and better air pollution. As a result, thousands of fracking wells have been drilled from Pennsylvania to Colorado to Texas and to Oklahoma. Nevertheless, this innovative drilling activity has raised serious concerns about a number of negative impacts. In particular, many communities have reached very different conclusions about the benefits and costs. On the benefit side, there have been recent studies which find that fracking increases economic activity, employment, income, and housing prices , mother’s education , mother’s age , child parity , and mother’s residence location which is useful for estimating the distance from the fracking well. After filtering with missing information, we end up with 556,794 birth observations. In addition, the active drilled oil and natural gas wells in which fracking is applied measures shale gas and oil (fracking) activities, which provide a complete (active) set of shale gas and oil (fracking) drilling process. The data were collected from the Oil and Gas Division of The Oklahoma Corporation Commission. For each well, we got information on its location in the country. The dependent variable was tested through three alternative definitions: infant’s total weight, low weight (< 2500 g), and a composite health index that explicitly informs on multiple idiosyncratic characteristics of the infant , the mother’s race  technology. In that sense, the analysis divided the drilling wells that are within 1 km, 5 km, 10 km, and 20 km from mothers’ residence. As a result, we got 121,862 births within 1 km; 148,783 within 5 km; 157,664 within 10 km; and 128,485 within 20 km from the wells.The model specification yields:bit is the maternal birth i at time t, αi indicates county fixed effects, Xit shows a vector of maternal idiosyncratic characteristics, and eit is the error term. The control variable vector contains information on the mother’s race, mother’s education background, mother’s age, and children’s parity. Distance is defined as the number of (fracking) wells within 1 km from the mother’s residence, or 1–5 km, or 5–10 km, and 10–20 km. One of the referees has recommended that additional variables that could be considered are the mother’s drinking and smoking habits, substance abuse, obesity, and a variable that dictates for how long has the mother lived in proximity to the drilling site. In addition, the literature has put forward other  factors that have an impact on infants’ birth rates, such as the material living and working conditions, as well as the social conditions in which people are born, live, and work, certain structural drivers, i.e., residential segregation, social capital/cohesion, and behavioral factors, such as biological and psychosocial factors, e.g., social support (Boerma and Bicego where Estimates are drawn on Pooled Mean Group (PMG) estimators, developed by Pesaran et al.  and withBefore presenting the primary results, the analysis reports a second-generation panel unit root test so as to determine the degree of integration of the respective variables. The Pesaran  panel unThe results document that the effect of fracking wells on infants’ health at birth is negative in the cases where the health indicator is expressed through the infant’s total birth weight and the health index, while it turns out to be positive in the case where the health indicator is shown through the definition of low birth weight. Moreover, in relevance to the total birth weight, the results turn out to be significant only in the cases up to 5 km, with the stronger impact coming in the case where the distance is within 1 km. In relevance to the definition of total health index, the findings are significant across all distances, with the strongest impact occurring within the 1-km distance. For example, the coefficient − 0.067 within 1 km clearly indicates that births near a well site have a − 0.067 standard deviation decline in the health index. In relevance to the low birth weight, the findings highlight that the effect remains significant up to the 10-km distance, with the strongest value coming from the 1-km distance.The lowest part of Table Table Finally, after a referee’s recommendation, Table Table This study explored the impact of the fracking wells on infants’ birth health across Oklahoma counties. The findings indicated that the closer the mother’s residence at birth to fracking wells, the more negative are the effects on the infants’ birth health. The findings also documented the minor role of regular drilling activities in infants’ mortality prior to 2006, the threshold year that signified the importance of fracking activities in the case of the Oklahoma state. The results could be also explained through the impact of the fracking activities on the drinking quality index. These findings can motivate the rise of efficient regulatory actions with respect to both drinking water quality and to the shale gas industry.State as well as federal policymakers need to seriously and considerable evaluate such significant public health costs associated with fracking activities. In other words, priority should be the prevention of public health costs, before considering any potential benefits associated with other dimensions of the economy. Overall, regulatory mechanisms are not that strong to effectively monitor potential negative effects on the population. Therefore, policymakers must cope with the potential risk to underscore the production of unconventional natural shale gas and oil, which does not seem to receive strong support today, or to develop it without considering any potential harms on the population’s health quality. A stronger regulatory environment is a high priority.


As greenness indicators, we considered maternal residential proximity to green spaces and the Normalized Difference Vegetation Index (NDVI) within a 100 m buffer around each woman’s residential address. We enrolled 56,576 newborns (5.1% preterm). The effect of a 1 °C increase in temperature on the daily number of preterm births was higher in women with low SEP (+2.49% (90% CI: 1.29–3.71)) and among those living within 100 m from green spaces (+3.33% (90% CI: 1.82–4.87)). No effect modification was observed for NDVI or PM10. SEP was an important effect modifier of the heat-preterm birth relationship. The role of greenness in modifying this association between heat and preterm delivery should be further investigated.Urban green spaces have been associated with health benefits, but few studies have evaluated the role of greenness on pregnancy outcomes. We examined how the association between short-term exposure to heat and air pollution on the probability of preterm delivery is affected by the spatial variation of socioeconomic position (SEP) and greenness. We analyzed a cohort of newborns in Rome, from April to October of 2001–2013, defining preterm as births between the 22nd and the 36th week of gestation. We used a time series approach, with maximum apparent temperature (MAT), PM Preterm birth children, representing the 5–9% of the total births in Europe, are more likely to experience adverse health outcomes throughout childhood and into adulthood. The rates of preterm birth are increasing in many countries, reaching 11% ,3,4. The10), with effect estimates comparable to those of heat but more persistent and delayed in time [Climate change has been widely regarded as the greatest global threat for human health in the 21st century. As extreme meteorological events  are predicted to increase in frequency and magnitude in the future, it is important to identify the potential health effects of these meteorological conditions among vulnerable subpopulations such as pregnant women ,9,10. In in time . 10 during the warm season. Furthermore, specific subgroups of women, with low education level and of young age, were more susceptible. However, other important risk factors were not analyzed. When evaluating the relationship between air pollution, ambient temperature, and preterm births, the potential role of different measures of socioeconomic position (SEP) should also be considered. It is well recognized that socioeconomic inequality plays a key role in pregnancy outcomes and that low socioeconomic groups can also be more exposed to environmental stressors and be more vulnerable [In a previous study, we analyzed the effect of short-term exposure to temperature and air pollutants during warm and cold seasons on the probability of preterm births . We founlnerable ,24,25,26lnerable . In thisGreen spaces can mitigate the urban heat island, absorbing solar radiation and cooling through evapotranspiration, and can create differential heat patterns within a city, especially at night . However2, and most of the inhabitants are located within the Main Ring Road . Then, we geocoded each woman’s residence at the time of delivery ) focusing only on residents within the Main Ring Road.We defined preterm birth as a live birth between the 22nd and the 36th week of gestation. We computed gestational age as the difference between the date of delivery and the first day of the last menstrual period.We used daily maximum apparent temperature (MAT), which is an index of discomfort that includes both air and dew-point temperatures ,30. Appa10), nitrogen dioxide (NO2), and ozone (O3) measured by the Lazio Environmental Protection Agency  at three monitoring sites (a background and two urban stations). We assigned daily values of PM10 (24-h mean), NO2 (24-h mean), and O3 (maximum eight-hour running mean) to all mothers. We analyzed particulate matter with an aerodynamic diameter of 10 um , with a spatial resolution of 30 m × 30 m  as a measure of surrounding greenness and a surrogate for general outdoor greenness . NDVI ram × 30 m C, for thWe considered a small area-level indicator of socioeconomic position (SEP): the index is based on data from the 2001 census in Rome, derived from a factor analysis that included education, occupation, home ownership, family composition, crowding, and immigration at census block level  . We cateWe used Poisson generalized additive models to check the linearity of the relationships and to estimate the associations between environmental exposures and the daily proportion of preterm births. We included the daily number of pregnancies at risk as offset in the models. We adjusted the models for long-term trend and seasonality , and holidays . We first studied MAT and each pollutant separately, and we considered the adjusted models only when collinearity did not arise. We checked for collinearity among the exposures using the variance inflation factor (VIF) with values of VIF > 10 indicating presence of collinearity. 2, and O3, while a lag of 12–22 days before delivery was considered for PM10. Each exposure was included in the model as a linear term at the chosen lag. In our previous study, we studied the lag structure of the relationships with a distributed lag model (DLM), allowing a lag structure of up to 30 days . In accop-value less than 0.10 as threshold. We also stratified by each potential effect modifier considered in this study (green indicators and SEP) and maternal age and education. To identify whether greenness and small-area SEP modified the effect of MAT and air pollutants on the probability of preterm birth, we included an interaction term in the model between each potential effect modifier and the environmental indicators, considering a www.r-project.org).We used SAS 9.2  and ArcGis 9.1  to create datasets while we carried out the analyses with R software   were preterm. The maternal residential address was available for all women included in the study. In our cohort, 28,946 (51%) mothers lived within 100 to 500 m from a green space with 5.2% preterm births, while only 16% (9013) lived within 100 m of a green area and had a 5.4% of preterm births. No relevant differences in preterm birth distributions were found by NDVI . As shown in 3 showed the highest variability among the pollutants (3 (ρ = 0.6) and between PM10 and NO2 (ρ = 0.5) (The percentile distribution of daily MAT and air pollutants between 1st April and 31st October 2001–2013 is reported in llutants . We obseρ = 0.5) .10 was associated with an increased probability of preterm birth; for an IQR increase (11 μg/m3) in PM10 with a lag of 12–22 days before the delivery, the percent change in the proportion of preterm births was equal to 8.16 (90% CI: 2.38–14.26). For NO2 and O3, no significant effect on preterm births was observed  in the proportion of preterm births per 1 °C increase in MAT in women living within 100 m from green areas, while those living further away from green spaces (>500 m) showed a significantly lower effect of temperature on preterm births of 1.03% (90% CI: −0.19–2.28) compared to women living within 100 m (reference group) . For SEP, women with low SEP were more susceptible to the effect of temperature on the probability of preterm birth (2.49% increase per 1 °C increase in MAT (90% CI: 1.29–3.71) than women with high SEP (1.01% increase per 1 °C increase in MAT (90% CI: −0.15–2.18)) . No effe10 on the preterm birth probability  per 1 °C increase in MAT compared to women with high SEP living within 100 m   .p-value of interaction term = 0.082; Considering the double interaction between residential proximity to green spaces and maternal age, we found a 4.4% increase (90% CI: 2.47–6.42) in the proportion of preterm births among women aged 30–36 years and living within 100 m from green areas for a 1 °C increase in MAT vs. a 1.3% increase (90% CI: −1.23–3.90) in women aged 37 and over living within 100 m . This study is one of the first to evaluate the association of maternal exposure to high ambient temperature and urban air pollutants with the probability of preterm birth by analyzing the spatial variation in SEP and green spaces as effect modifier. Although we considered a longer time series adding three years to previous analysis , our res studies ,22. As fThe effects of heat and air pollution on preterm births have been discussed in several studies and reviews ,17,20,22Less is known on the individual characteristics that may worsen or mitigate these effects. Even if our study adopted a time series design, we were able to analyze socioeconomic position and closeness to major green areas at residential address of each mother as potential effect modifiers, considering residency from population registry data. We found an interaction between residential proximity to a major green space and temperature: women living within 100 m from a green area had a greater probability of preterm birth for every 1 °C increase in temperature compared to women living beyond 500 m. No effect modification was found when considering NDVI within 100 m from each residential address. Although there is a growing literature on the beneficial health effects of urban green spaces, existing evidence on pregnancy outcomes and surrounding greenness is still inconsistent ,35,46,4710-preterm birth association. This is coherent with literature showing that vegetation could absorb particles decreasing the levels of air pollution, and with studies showing a lower traffic density nearby green areas [Our study suggested a potential mitigating effect of residential proximity to green spaces on PMen areas . We coulIn our study the association between MAT and preterm birth was also modified by SEP with a higher effect in women with low SEP, equal to about 3% in the daily proportion of preterm birth for every 1 °C increase in MAT. A similar increased probability was found in women with primary school vs degree in our previous study in which we considered maternal education . AlthougSome limitations of this study have to be discussed. Since there was no universally accepted definition of urban green space, we decided to use two indicators of greenness—one derived from satellite data (NDVI) and one based on the distance between residential address and the nearest major green area provided by Municipality of Rome. For NDVI, we considered a single satellite image taken at a single day in July. Although we did not account for the potential temporal variation in greenness, a previous study conducted in Rome showed negligible changes in the quantity of greenness during the study period . NeitherAlso, we used an indirect assessment of exposure: meteorological data were retrieved from a fixed monitoring weather station located in Rome (Ciampino Airport), and pollutants were derived from three fixed monitoring stations within the city. Therefore, an average measure of outdoor temperature and of air pollutants for all women residing in the municipality of Rome, within the Main Ring Road, was used. This could have induced non-differential misclassification of exposure because it was unrelated to the outcome, thus biasing the estimated effects toward the null value. Furthermore, it is important to take into account that personal exposure may be modified by the amount of time spent indoor, by the use of air conditioning, and by residential mobility, which we were, at this stage, unable to consider. Moreover, both effect modifiers (SEP and greenness) might have been affected by a potential misclassification due to the implicit assumption of residential stability during pregnancy. Our research relied on maternal residential addresses at the time of delivery, and we were not able to reconstruct residential mobility during pregnancy.Finally, the different spatial resolutions between the main exposures  and the effect modifiers  could have probably inflated the bias concerning the studied interactions. A major improvement in the analysis could be the use of the individual exposure levels through spatio-temporal models for both temperature and air pollutants to catch the true role of green areas and SEP as effect modifier.10 is associated with a short-term increase in the preterm-birth probability. This association appears to be modified by socioeconomic position and closeness to green spaces. Contrary to expectations, living close to green areas seems to increase the preterm birth probability when exposed to heat, especially in women of low socioeconomic position. The study confirms that maternal exposure to heat and PMIt is interesting to note that, while the existing evidence confirms a general salutary impact of greenness on health, much remains to be clarified on the particular pathways involved and, above all how these may change by social context, subgroups, and pregnancy outcomes. For all these reasons, the role of greenness as potential modifier of hazardous exposures in urban areas should be further investigated.


No differences in SLF microstructure were found between groups using DTI, nor were differences in CST microstructure observed across groups regardless of hemisphere or diffusion model. Our data are consistent with the view that motor impairment characteristic of DCD may be subserved by white matter abnormalities in sensorimotor tracts, specifically the left and right SLF. Our data further highlight the benefits of higher order diffusion MRI (e.g. CSD) relative to DTI for clarifying earlier inconsistencies in reports speaking to white matter organization in DCD, and its contribution to poor motor skill in DCD.Previous studies of white matter organization in sensorimotor tracts in developmental coordination disorder (DCD) have adopted diffusion tensor imaging (DTI), a method unable to reconcile pathways with ‘crossing fibres’. In response to limitations of the commonly adopted DTI approach, the present study employed a framework that can reconcile the ‘crossing fibre’ problem  to characterize white matter tissue organization of sensorimotor tracts in young adults with DCD. Participants were 19 healthy adults aged 18–46: 7 met diagnostic criteria for DCD  and 12 were controls . All underwent high angular diffusion MRI. After preprocessing, the left and right corticospinal tracts (CST) and superior longitudinal fasciculi (SLF) were delineated and all tracts were then generated using both CSD and DTI tractography respectively. Based on the CSD model, individuals with DCD demonstrated significantly decreased mean apparent fibre density (AFD) in the left SLF relative to controls (with large effect size, Cohen's  •All previous diffusion studies of white matter in DCD have employed a tensor model•We employed a non-tensor model to characterize microstructure in adults with DCD•The non-tensor model showed atypical white matter organization in the SLF in DCD•The tensor model failed to detect microstructural group differences for any tract•Motor impairment characteristic of DCD may be subserved by white matter abnormalities•We need to move beyond the tensor model in characterizing white matter in DCD ConvergfMRI)  .Until now, only four studies have explored white-matter tract microstructure in DCD . Across Firstly, a variety of approaches have been used to analyze diffusion MRI data including manual delineation of 3D tracts via tractography e.g. , automatWith respect to behavioral relevance, in some of the above studies alterations in white matter organization coincided with poorer motor performance in the DCD group. However, the direction of the correlation coefficients have also been mixed/unexpected in some studies . For exab-values (b ~ 1000 s/mm2) , which requires only moderate numbers of encoding directions (a minimum of six) and relatively low 0 s/mm2) . Accordi0 s/mm2) . Briefly0 s/mm2) , it is n0 s/mm2) . Hence, In response to limitations of DTI, there have been considerable efforts in recent years to develop higher order non-tensor approaches to diffusion MRI  sequence and CSD. With respect to the latter, in order to control for partial volume effects and reduce isotropic signals  we emplo22.1MAge = 23.29; SDAge = 4.31) and control groups . All individuals with DCD and all but one control (who reported being ambidextrous) were self-reported right handers. The ambidextrous control participant, however, showed a right-hand preference during standardized motor assessment (described below). Participants gave written informed consent and the project received ethical approval from the Deakin University Human Research Ethics Committee.Consistent with earlier diffusion MRI studies of samples of individuals with DCD, participants were 7  who met the DSM-5 criteria for DCD, and 12 controls  aged between 18 and 46 years. No difference was detected in mean age between the DCD  and ADC child scale (CI95%: 4.26 Mean +/− 0.86). Those participants who met Criterion A (described above) and fell above the CI95% cut off for the Total  and child  were deemed to have met criteria B and C respectively. Initially 8 participants had motor skill ≤ the 16th percentile, but one of these failed to meet Criteria B and C as described here. A further participant met Criterion C according to the ADC, but failed to meet Criterion B. However, this participant verbally stated that their poor motor skills negatively impacted their performance of motor related daily tasks so we were confident of their meeting Criterion B and their subsequent inclusion in the DCD group. One participant who met our criteria for DCD had a previous diagnosis of Dyspraxia/DCD. Since all participants were either recruited through the University setting or had completed an undergraduate degree, they were deemed to have had intelligence at least in the normal range (Criterion D). Further, no participants reported a previous diagnosis of a neurological or medical condition affecting movement . Finally, no participant reported a diagnosis of ADHD or similar neurodevelopmental disorder.Project advertisements were placed on University websites at an Australian University and on social media . Participants with DCD were screened in accordance with DSM-5 criteria and recent guidelines for identifying DCD in adults . SpecifiControls were free of self-reported medical or neurological impairment. None self-reported motor difficulties and where possible, the motor ability of control participants were assessed using the BOT-2. Accordingly, 8 controls performed the BOT-2 with all presenting with motor ability above the 20th percentile.2.23, acquisition matrix 256 × 256, FoV = 240 mm, 192 contiguous slices with an acquisition time of 4:26 min. High angular resolution diffusion imaging (HARDI) was conducted using a single shot EPI sequence with the following parameters: TR = 8500 ms, TE = 110 ms, flip angle = 90°, voxel size = 2.5 mm3, acquisition matrix 96 × 96, FoV = 240 mm, 60 contiguous slices. A total of 64 non-collinear diffusion weighted directions with b = 3000 s/mm2 were captured, and 8 non-weighted images (b = 0 s/mm2) interleaved between the weighted images. Acquisition time was 10:32 min. The higher b-value adopted here relative to previous studies of white matter organization in DCD was used to improve the resolution of distinct fibre orientations for tractography  with a 32-channel receive only head coil. High resolution T1-weighted 3D MPRAGE images were acquired for each participant using the following parameters: TR = 1900 ms, TI = 900 ms, TE = 2.49 ms, flip angle = 9°, voxel size = 0.9 mmtography .2.3b-matrix rotation and echo planar imaging (EPI) correction  were applied when reconstructing tracts for an individual regardless of whether the CSD or DTI model was used. However, as expected, the two models often produced different fibre projections. Therefore, where anatomically spurious fibres were detected, the incidence and location of spurious fibres often differed across models and hence exclusion ROI's differed. Finally, while all efforts were made to ensure that participant identity was masked while ROI's were delineated, this was not always possible. Though ROI's were applied using the highly reproducible methods described in the methods above (e.g. as per 3), mean fractional anisotropy (FA), mean diffusivity (MD), mean apparent fibre density (AFD) (The following diffusion metrics were obtained from the reconstructed fibre tracts: mean tract volume (mmty (AFD) .2.63), mean FA and mean MD for each tract and hemisphere.In order to compare diffusion metrics between CSD and DTI derived tractography, two-way mixed ANOVAs with Group as the between-subjects factor (2 levels: DCD vs Control) and diffusion MRI model as the within-subject variable (2 levels: CSD vs DTI) were conducted on mean tract volume  and DTI derived metrics  for each tract. We corrected for multiple comparisons using the False Discovery Rate (FDR) of 0.05   . Where gas pFDR) , renderias pFDR)  and adolas pFDR) ]. Hence,Finally, in light of evidence that group differences in diffusion metrics have shown to alter along the length of white matter tracts e.g. , it is u3F = 62.64, p < .001, partial η2 = 0.79], and right CST as well as increased mean diffusivity in the left CST when parameters were estimated using the CSD model compared to DTI. With respect to the SLF, main effects analysis demonstrated significantly higher tract volume for both the left and right SLF, as well as lower FA for both the left and right SLF when parameters were estimated using the CSD model relative to DTI.Two-way ANOVA (group x diffusion MRI model) on mean tract volume, mean FA and mean MD failed to reveal any interaction effects with group for either the left or right CST, or left or right CST. Main effects for diffusion MRI model (CSD vs DTI) are presented in t-test revealed that mean AFD of the left SLF was significantly lower in individuals with DCD  than controls , t(17) = −2.70, p = .015 (0.039 FDR), d = 1.32. Further, individuals with DCD  showed a trend for decreased tract volume in the right SLF relative to control  (p = .137). No other group comparisons reached statistical significance. For a summary of group comparisons and group descriptive statistics for diffusion metrics, see rS = 0.442, p = .049  relative to controls. While none of these comparisons survived FDR correction, the data show a clear trend for lower mean AFD of the SLF that was select to, or accentuated, immediately anterior to the arcuate fasciculus. Finally, no systematic along tract group differences were observed for any DTI modelled tract.Along tract group comparisons for each tract modelled using CSD and DTI are summarised in 4d = 1.32), and a trend towards reduced tract volume in the right SLF . Interestingly, DTI-based reconstruction of SLF tracts failed to reveal any group differences and no group differences were observed for the CST regardless of tract laterality or diffusion MRI model . Given the methodological advantages afforded by CSD relative to DTI (e.g. addressing the ‘crossing fibre’ issue) and that all previous accounts of white matter organization in DCD have adopted DTI, our study highlights the added value of CSD as a method for clarifying previously inconsistent findings speaking to the profile of white matter organization in DCD. Taken together, these data are broadly consistent with the view that the motor difficulties symptomatic of DCD may be subserved by microstructural tissue differences in sensorimotor tracts, specifically the SLF. They further highlight the benefits of moving beyond the tensor framework for characterizing white matter tissue properties in DCD. These conclusions and their implications are discussed next.This study was the first to investigate white matter organization in young adults with DCD using CSD-based tractography. As predicted, young adults with DCD showed divergent white matter organization to controls in the SLF, with CSD modelling revealing significantly decreased AFD in the left SLF relative to controls  in the left hemisphere appear to be particularly important for the representation of purposive actions (often referred to as praxis), regardless of handedness . Given tWhile previous evidence is mixed, those studies that have reported differences in SLF microstructure between individuals with and without DCD did so using DTI-based tractography. While we detected group differences in SLF white matter organization in adults with DCD using the CSD-based tractography, unlike earlier work we failed to do using DTI-based tractography. Below we elaborate on methodological considerations which we argue likely account for differences in the CSD based analyses of the present study to DTI based analyses of earlier work.No significant differences in diffusion metrics were observed in the CST between those with and without DCD regardless of diffusion model (DTI vs CSD). This finding sits in the context of mixed findings in earlier work. While one previous study included young adults with DCD , the remGiven the well-established role of the CST in supporting motor performance, our finding of preserved white matter organization in young adults with DCD may seem counter-intuitive at first. However, even in severe developmental neurological disorders of movement such as cerebral palsy (CP), reports of CST damage are common at the group level , yet inc4.2The findings reported here parallel evidence suggesting that CSD produces anatomically superior tracts, and may be more sensitive for detecting white matter abnormalities in patient groups e.g. . Indeed,We argue that the aforementioned limitations of DTI have likely contributed to previously inconsistent finding speaking to the role of white matter connectivity in reduced motor skill in DCD. Further, while our sample size is in-keeping with available diffusion studies using samples of individuals with DCD, we acknowledge that it is nonetheless modest. Regardless of this, however, since ours is the first study to model white matter organization in DCD using CSD we argue that our data provide one of the more robust accounts of white matter organization in DCD, at least as it pertains to young adults. Most importantly perhaps, our direct comparison of CSD and DTI derived diffusion metrics, highlights the added value of higher order models in characterizing white matter properties in DCD and the need to move beyond the tensor.The current sample involved adults with DCD. As eluded to above, the developing brain is not simply a ‘mini’ adult brain, and thus we must be circumspect about generalizing the findings of the present study to children and adolescents with DCD. Indeed, the trajectory of white matter maturation is often varied depending on the tract, with commissural (e.g. CC) and projection (e.g. CST) tracts reaching maturation by early adolescence (e.g. 10 to 15 years), while association fibres (e.g. SLF) follow a more protracted developmental period spanning into early adulthood . Taken wWhile theoretically justified, we opted for a conservative approach in identifying two tracts of interest given the exploratory nature of the study. Hence, while our data are consistent with the view that poor motor skill in DCD may be subserved by white matter tissue organization, they can only speak to potential role of the SLF and CST. Should future larger-scale studies occur, a more detailed account of alternative tracts  may shed light on the broader role of microstructural tissue properties in DCD symptomatology. The degree to which these contribute to the psychosocial corollaries of impaired motor function should also be the subject of future work.Future studies should consider a fixel based analysis (FBA) framework to distinguish macroscopic morphology of fibre bundles, including the density of axons within a particular fibre and the change in the cross-sectional area perpendicular to the corresponding fibre bundle . Howeverb-values such as those used in the present study  and a Wellcome Trust Strategic Award (104943/Z/14/Z).KC is supported by a Career Development Fellowship from the


We describe a successful surgical approach with cyst unroofing and careful evacuation of the multiple daughter cysts by aspiration, and the effective management of the residual cavity by the combination of all three aforementioned techniques.Diagnosis and treatment of liver hydatid cysts may be challenging. Many surgical techniques have been proposed for the treatment of liver hydatid cysts, but the problem of the residual cavity still remains controversial and challenging, especially in giant liver hydatid cysts which are rare entities that have not been widely described in the literature so far. Capitonnage, external tube drainage and omentoplasty are the most commonly used techniques. Herein, we report the case of a 70-year-old man with a mild upper quadrant pain that proved to have a giant liver hydatid cyst, 21*14 cm Cystic echinococcosis is a zoonotic parasitic disease that is caused by Echinococcus granulosus . Liver h2, marginated hydatid cyst, occupying the entire right lobe of the liver with multiple daughter cysts inside the primary cyst  revealed a large solitary cyst at the right lobe of the liver with multiple cysts inside the primary cyst. The features suggested hydatid aetiology. The diagnosis was confirmed with serological tests, where positive IgG and IgM antibodies were found. An abdominal computed tomography (CT) scan showed a giant, 21*14 cmary cyst . CommuniWe decided not to perform a radical surgical procedure such as cystectomy or major hepatic resection, because of the large size of the hydatid cyst and in order to preserve the liver parenchyma. A small Kocher incision was conducted and the operative field was protected from any spillage to reduce the risk of intraperitoneal soiling and contamination by using gauze packs soaked in 20% hypertonic saline. Cyst unroofing and careful evacuation of the multiple daughter cysts by aspiration with a closed system suction device was performed. 10% povidine iodine was also injected in the giant hydatid cyst for 10 minutes. Biliary orifices were sutured with 3/0 PGA (polyglycolic acid) sutures. Because of the large size of the giant hydatid’s cyst residual cavity capitonnage was not enough and a combination of capitonnage, omentoplasty and external tube drainage was performed. First, the anterior wall of the cyst was sutured in the middle of the posterior wall with absorbable sutures. The rest of the cavity was managed with the drainage tube and a viable pedicle flap of omentum, which was sutured on the cyst’s anterior and posterior wall with absorbable sutures.The postoperative recovery was uneventful and the patient’s tube drainage was removed on postoperative Day 5. There was no bile fistula. Albendazole 10 mg/kg for 3 cycles was initiated to avoid recurrence. The patient was discharged on postoperative Day 5. After 1 year of follow-up the patient is well and the giant’s hydatid cyst residual cavity has obliterated.Treatment of cystic echinococcosis can be divided into interventional and non-interventional methods. The first consist of surgery and percutaneous procedures (PAIR), while the second is based on administration of antiparasitic drugs such as albendazole, mebendazole and praziquantel that are used for inoperable patients or for decreasing the recurrence after surgery . SurgeryThe management of the hydatid cyst’s residual cavity still remains a challenging problem, especially in giant hydatid cysts. Many ways of managing the residual cavity have been proposed depending on the size and location of the cyst, the presence or absence of complications and the surgeon’s experience: omentoplasty, external drainage, capitonnage and different combinations of them , 7. OmenIn conclusion, setting the diagnosis of liver hydatid cysts may be challenging as mild pain may only exist. In our patient the size and the location of the giant hydatid cyst led us to decide using a combination of capitonnage, omentoplasty and external tube drainage for managing the residual cavity. There are only a few reported cases of giant liver hydatid cysts and there is not an established consensus in managing the residual cavity in those situations, but using the combination of omentoplasty, capitonnage and external tube drainage seems to be a safe and effective way in selected patients.The authors declare no competing interests.


Birth defects are important causes of neonatal morbidity and mortality. A good understanding of the etiology is a vital step toward developing improved treatment and preventive strategies. We conducted an audit of medical records of newborns with birth abnormalities in a tertiary hospital over a 10‐year period, using a Pro forma designed to collect information on obstetric history, antenatal history, sociodemographics of parents, and the type of birth abnormality. Of the 180 medical records reviewed, female babies were 92 (51.1%) and male babies were 86 (47.8%). The mean age of the fathers was 38.2 + 6.2, and mothers 31.8 + 4.9. Majority 115 (63.9%) of the mothers had records of acute illnesses, and 23 (12.8%) chronic illnesses during pregnancy. Unspecified febrile illness 44 (38.3%), malaria 40 (34.8%), typhoid 8 (6.9%), hypertension 13 (56.5%), pregestational diabetes 4 (17.4%), and HIV 3 (13.0%) were the commonest maternal pathologies. Most of the documented birth abnormalities were Down's syndrome 34 (15.2%); congenital hydrocephalus 32 (14.3%); acyanotic congenital heart defect 30 (13.4%); deformity of the digits 26 (11.6%); and ventricular septal defect 20 (8.9%). The prevalence of maternal pathologies calls for concern, as these may be implicated in birth defects, therefore should be further investigated in future studies. ACHDacyanotic congenital heart defectCHDcongenital heart defectLUTHLagos University Teaching HospitalSVDspontaneous vertex deliveryTTtetanus toxoidVSDventricular septal defect1Congenital malformation otherwise known as birth defects or congenital abnormalities are structural, functional, genetic, or behavioral anomalies, including metabolic disorders that occur during fetal development and can be diagnosed prenatally, at birth or later in life.According to the US Center for Disease Control, major birth defects occur in one of every 33 births,About 50%‐60% of all congenital malformations have no specific cause, while others are associated with known causes or risk factors.Some of the public health measures recommended by the WHO to decrease the frequency of certain birth defects include adequate dietary intake of vitamins and minerals, particularly folic acid in adolescent girls and mothers, preventing maternal exposure to harmful substances, adequate prenatal vaccination, rational prescribing in pregnancy, amongst others.Understanding the etiology of birth abnormalities is a vital step toward developing improved treatment and preventive strategies of congenital defects.2The study center, Lagos University Teaching Hospital (LUTH) is a major tertiary hospital in Southwestern Nigeria, which often serves as a referral center for patients in Lagos State and its environs. Most of the cases of birth abnormalities in this hospital were referred from other hospitals. At the Medical Records Department, eligible cases were identified from the birth defect registry; the file numbers were used to recover the case files, and the cases were thoroughly reviewed one after the other by the investigator. Relevant information such as the demographics of the babies and their parents, antenatal and obstetric histories, parents’ social histories, specific diagnosis made with regard to birth abnormalities, types of birth abnormality, time birth abnormality was diagnosed, pathologic state of the parents, exposure to known teratogens during pregnancy, and pregnancy outcomes (whether live birth or stillbirth), were extracted using a well‐structured Pro forma.2.1The ethical approval for this study was granted by the Health Research Ethics Committee of LUTH, Idi‐araba, Lagos, on April 21, 2017. Approval Number: ADM/DCST/HREC/APP/1564.2.2Relevant data were entered into Microsoft Excel spread sheet to check for accuracy. Thereafter, data were coded and loaded into Statistical Package for Social Sciences IBM SPSS, Version 20.0  for analysis. Descriptive statistics on sample characteristics such as frequency and percentages were computed. Chi‐square test was used to determine if important covariates such as booking status, medical condition in pregnancy, acute illness in pregnancy, self‐medication, or prescription drugs use during pregnancy have statistically significant association with the number of birth abnormalities.33.1The full obstetric history of the babies is presented in Table 3.2The sociodemographics of the parents are presented in Tables The mean age of the fathers was 38.2 ± 6.2. Most of the fathers 97 (53.9%) were 31‐40 years old. Middle aged fathers (41‐50 years) were 41 (22.8%), while 17 (9.4%) of the fathers were between 21 and 30 years old. Paternal age was not documented in 20 (11.1%) of the cases. Unlike the mothers, most of the fathers were professionals 45 (25.0%), artisans and traders were 38 (21.1%), and 40 (22.2%), respectively. Paternal occupations were not documented in 21 (11.7%) of the cases. Just like the mothers, most of the fathers were nonsmokers 151 (83.9%), nonalcoholics 132 (73.3%), and do not use social drugs 157 (87.2%).3.3The full maternal antenatal history are presented in Table 4Previous studies have reported that certain prescription drugs included in the case notes of the studied subjects, such as anti‐epileptics, anticonvulsants,We observed that nearly all the mothers, all through the period of antenatal were prescribed routine prenatal multivitamin product containing folic acid 0.4 mg, elemental iron 17 mg, Vitamins B1 3 mg, B2 2 mg, B6 10 mg, B12 6 μg, Niacin 20 mg, Vitamin C 70 mg, Vitamin D 400 IU, Vitamin E 4 mg, Zinc 15 mg, Copper 1000 μg, Selenium 30 μg, Magnesium 150 mg, Vitamin K 70 μg, Iodine 140 μg, Natural mixed carotenoids 2 mg, Biotin 150 μg, and Pantothenic acid 6 mg. A systematic review of Cochrane database reported that prenatal supplementation with iron or iron plus folic acid given daily or weekly is effective in preventing anemia and iron deficiency at term, but there was no significant association between prenatal iron and folic acid supplementation with reduction in substantive maternal and neonatal adverse clinical outcomes.In the scientific literatures, there appears to be some conflicting information regarding the safety of multivitamin use in pregnancy. For instance, one study reports that maternal periconceptional intake of vitamin E is associated with congenital heart defects (CHDs),In the present study, unspecified febrile conditions, hypertension, and pregestational diabetes, were the most documented maternal pathologies. However, a causal relationship between these pathologic conditions and the documented birth abnormalities could not be directly established because of possible effects of the medications used in managing these disease states. However, in a population‐based retrospective cohort, febrile illness with no multivitamin use was associated with generally increased risk of some birth defects including orofacial, central nervous system, cardiovascular, limb, and abdominal abnormalities.Our study has potential limitations. Aside from the incomplete documentations on maternal medication, this work is an audit of medical records; the documented congenital abnormalities were based on the clinician's assessments. This may be limited by the clinician's level of experience in managing birth defects. However, most of the assessments were supported by adequate laboratory and other clinical investigations including X‐rays, ECG, ultrasound scan, CT scan, appropriate blood test, amongst others. Finally, it suffices to mention that our current findings contribute to the existing body of literature evidence that certain maternal pathologies may contribute to the development of birth abnormalities.5In conclusion, this retrospective audit of medical records of newborns with congenital abnormalities at the LUTH reports prevalence of maternal acute and chronic illnesses such as malaria, typhoid, hypertension, and gestational diabetes, suggesting that these pathologies or their drug treatment during pregnancy may be implicated in the development of birth abnormalities. We therefore recommend that the aforementioned pathologic states and their drug treatment during pregnancy be further investigated in future case‐control studies to fully understand their involvement in the development of birth abnormalities.None declared.


Midwives’ practices during the second stage of labour vary nationally and internationally. We aim to retrieve evidence that supports high-quality intrapartum care by conducting a systematic review of the literature.EMBASE.com, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Maternity and Infant Care Database (through MIDIRS), and The Cochrane Library will be searched to identify studies that meet the inclusion criteria. No language or publication date constraints will be applied. Articles that pass the two-stage screening process will then be assessed for risk of bias and have their reference lists hand searched.Electronic bibliographic databases including PubMed, A midwife’s practice can be influenced by education and cultural practices but ultimately it should be informed by up-to-date research evidence. By analysing and synthesising the results of the studies, this systematic review will provide valuable insight into high-quality evidence-based midwifery care, which can inform practice, education and future research.CRD42018088300PROSPERO The online version of this article (10.1186/s13643-018-0916-1) contains supplementary material, which is available to authorized users. Labour and birth constitute significant and memorable life events for a woman and her wider family. How a woman experiences birth has both short- and long-term effects on health and wellbeing for both herself and her baby , 10, 14.As far back as 1997, the WHO defined physiological birth as spontaneous onset, low risk at the commencement of labour and continuing so for the remainder of labour and birth. The infant is born spontaneously, between 37 and 42 weeks of pregnancy with a cephalic presentation. Following birth, both mother and infant are in good condition . Labour can be divided into three stages: the first, second and the third stage of labour. The WHO (2018) have recently defined the first stage of labour as the time period characterised by regular painful uterine contractions until full dilatation of the cervix and the second stage of labour as the time period between full dilatation of the cervix and the birth of the baby, whilst the woman is experiencing an involuntary urge to bear down, due to expulsive uterine contractions. The third stage is recognised as the period after the birth of the baby ending with the birth of the placenta and fetal membranes [Midwives can facilitate the process of physiological labour and birth by enabling the interplay of reproductive hormonal and neuro-hormonal mechanisms by their kind and respectful caring practices, which promote oxytocin release for effective uterine contractions during labour and the relaxation of the birth canal , 13. HowTherefore, we plan to undertake a systematic review to identify pertinent evidence related to intrapartum midwifery care, focusing specifically on care during the second stage of labour.This leads to our structured research questions which were formulated using the PICO  framework for quantitative research and the PEO  question format for qualitative research questions: “How do midwives facilitate women to give birth during physiological second stage of labour?” and “What evidence supports good quality intrapartum care during the second stage of labour?”The aim of the systematic review is to collate, analyse and synthesise the international evidence that supports high-quality intrapartum care during the second stage, which will inform midwifery practice, education and future research and positively influence this aspect of midwifery care for women.www.prisma-statement.org) , PsycINFO (via Ebsco) and The Cochrane Library (via Wiley) from inception, i.e. no publication date restrictions will be applied. An additional search will be performed in the Maternity and Infant Care Database (through MIDIRS). The search strategy will include the Boolean terms OR and AND, the search terms will include controlled terms  as well as free text terms and truncations (*). We will use free text terms only in The Cochrane Library and synonyms and variations of the keywords in all databases  statement