To describe expectant mothers’ experiences of fear of childbirth after a previous traumatic birth.Qualitative, individual, in-depth interviews were conducted with eight expectant mothers between September and November 2020. Data were analysed using a descriptive phenomenological approach.We identified four interconnected constituents: Suboptimal midwifery care, loss of control and agency; insufficient time and capacity to process a traumatic birth experience; “The baby has to be delivered!”, and finally, the path to a new childbirth with the hope of mastering fears.Findings reveal an association between a previous history of traumatic birth and a fear of childbirth in expectant mothers. The trauma they experienced whilst giving birth strongly impacted their subsequent pregnancy, making it difficult for them to deal with the new pregnancy and impending birth. Women who have experienced a traumatic birth need to have the opportunity to process the trauma. Routines must therefore be developed that identify, support and follow up with the women. If these women are identified and given the help they need, this may help prevent and/or alleviate fear of childbirth in their subsequent pregnancy. Childbirth is a significant event in a woman’s life. The act of giving birth often represents the most intimate and personal experience a woman will have. Giving birth is thus not only a medical event, but also a psychological, existential and social event Blåka, . AnxiousRecent international prevalence studies estimate that the prevalence of tokophobia is almost 14%, with significant differences across countries. In Norway, the prevalence of tokophobia is around 7% .Ten eligible women were invited to participate in the study, of which eight gave their informed consent. The women ranged from 22 to 39 years of age. Seven of the participants had completed higher education. They were all married or cohabiting and all reported that the pregnancy was planned. All the women had previously experienced a traumatic birth. The period between the traumatic birth and the new pregnancy ranged from 2 to 16 years. In the case of previous deliveries, six women had a normal vaginal birth and two had a caesarean section. The women were all multiparous; one was expecting her third child, while the remaining eight had one child and were giving birth for the second time. The gestational age of the new pregnancy at the time of the interview varied from week 20 to 35. All the women were receiving aftercare from a midwife at the counselling centre at the hospital where they planned to give birth. They had been referred by the specialist health service, a community midwife or a general practitioner, due to their need for follow up outside the primary care services.We conducted individual in-depth interviews from September to November 2020. We interviewed the participants face-to-face at the outpatient clinic, where the surroundings were familiar to them. All interviews lasted between 40 and 65 minutes. We developed an interview guide with open-ended and flexible questions, which we tested via two pilot interviews. The interviews commenced with the open-ended question “Do you want to talk about how you experienced your previous childbirth?”, to encourage participants to talk about their experiences from previous childbirths. They were then asked to describe their experiences from when they discovered they were once again pregnant to the present day: “Feel free to talk about the process from when you became pregnant until now—how has it been for you?” Questions were then posed to elicit their thoughts and expectations in relation to the impending birth: for example, “What thoughts do you have about the time leading up to your impending birth?” The final questions concerned their perspectives on what would be important during the birth and what would constitute a high standard of aftercare: “What are your expectations for this birth? What will be important to you during this birth, and what might be the best follow-up care?” Subordinate questions centred on their experience of the new pregnancy and dealing with everyday life, and their perceptions of their relationship with their loved ones. The interviews were audio recorded and transcribed verbatim.A descriptive phenomenological method was employed to analyse the data on participants’ fear of childbirth after a previous traumatic birth. This method is suitable for a phenomenological study and is closely linked to Husserl’s phenomenological philosophy. As recommended by Giorgi , the anaIn our analysis, we did not follow a strictly linear process; rather, it was a dynamic process involving movement back and forth between the various steps. When analysing the interviews, we critically examined and discussed the delineation and meaning of the different meaning units. We detected some initial differences with respect to the identified meaning in the text, which were resolved upon further reflection and discussion.The research team’s background, clinical experience and theoretical knowledge of birth anxiety can be viewed as a strength as well as a limitation when conducting a study on women’s lived experiences of the phenomenon. All authors in this study have a background as health professionals; four are midwives and one is a clinical psychologist. All have clinical practice caring for women and their families during pregnancy, birth and the postnatal period.epoché and phenomenological reduction, as described above. Through a disciplined, empathetic attitude (epoché), we sought the subjective experiences of the participants. By setting aside our own prejudices and asking in-depth questions, we opened up to the other’s experience of their lifeworld . To further ensure the validity of our findings, we conducted a systematic, transparent and descriptive analysis of the data.We recognized that, as researchers, our preconceptions about birth anxiety may inadvertently affect the research and presentation of findings. Our clinical experience was likely what initially sparked our interest and motivated us to conduct research on the topic. To ensure openness to the phenomenon, we engaged in a phenomenological approach involving We used in-depth interviews and a descriptive phenomenological method to analyse the data; this approach proved well-suited to illuminating the women’s experiences, as it allowed them to talk freely and openly about the phenomenon of fear of childbirth after traumatic labour Giorgi, . One limWe focused on the meaning of the women’s subjective experience, and did not include objective measures of birth trauma or fear of childbirth. While this may be seen as a limitation, in a phenomenological study, it is important to let the participants define these phenomena qua their experience, rather than rely on standardized criteria or theoretical construct-based questions. The eight women who responded to the invitation wanted to share their experiences and contributed with rich descriptions, providing sufficient information to illuminate the phenomenon . The women described their previous traumatic birth as an experience of heightened insecurity and loss of control. Their childbirth experience differed from their expectations, and they were unprepared for how painful and difficult it turned out to be. They linked the loss of control they experienced to inadequate or unclear information and absent midwives, making them feel alone. The participants also described a loss of agency, and felt that they were not seen or heard, nor were they included in the decision making. For some, this led to difficulties after the birth, in terms of having the emotional availability to feel warmth and love for their child; they also experienced a reduced capacity to actively participate in their role as a mother. This in turn evoked the feeling that they were not coping. The women felt that they had limited capacity to process the traumatic birth, and their coping strategy was to suppress the trauma and put it behind them. This strategy had severe implications for the women’s subsequent pregnancy, with flashbacks and a fear that their experience would be repeated. They struggled to deal with the traumatic birth, new pregnancy and impending birth. The participants also expressed ambivalence: they hoped that the birth would go well, while simultaneously feeling great uncertainty and fear that it would not. They called for autonomy and a wish to be heard, seen and included in their own birthing process.We identified four highly interrelated essential constituents in the general meaning structure that we have separated for the sake of analysis: Suboptimal midwifery care, loss of control and agency; insufficient time and capacity to process a traumatic birth experience; “The baby has to be delivered!”, and finally, the path to a new childbirth with the hope of mastering fears. These four constituents are described in more detail below. We present the constituents in chronological order, while illuminating their interconnectedness and relevance for the women’s experience of fear of childbirth.The women in our study had previously had a traumatic birth experience that evoked overwhelming memories when they were faced with a new pregnancy. The traumatic birth experience involved intense pain, a loss of control, insecurity, a fear of death and uncertainty about surviving the birth. They also expressed a desire to flee the situation. Contributing to the traumatic birth experience, they described periods with suboptimal midwifery care, in which they felt alone or like they were not treated with respect. Childbirth was not what they had anticipated, and they were unprepared for shortcomings in their care or dramatic complications that arose during the birth.I actually felt a bit like I was being ignored when they wouldn’t tell me anything about what was going on, I was just kind of told that a gynaecologist was going to try suction and forceps. Then more of them just kept appearing. It was like all information was being withheld at the point when I was so in need of reassurance. (w4)It emerged that a lack of information contributed to feelings of insecurity and anxiety, and the women reported having received insufficiently clear communication and guidance. They described the trauma of their first birth as a sudden shift, from feeling as though they were coping to feeling a loss of control, as well as helplessness and insecurity.I woke up to a commotion; a doctor and several other people had entered the room. They didn’t talk to us, they just looked at the screen because at that point the baby’s heart rate had dropped quite a bit” (w3).The way the information was transmitted was important to the women. To be prepared, they wanted to be given proper information prior to any interventions. The women explained that their insecurity and anxiety was triggered when suddenly, without warning, various people appeared in the delivery room (as seen in the above quote). One participant described this as follows: “I kind of felt like I wasn’t allowed to be part of the things that were important to me, and it made me feel like I was watching myself in the room and was just an object that was going to deliver a baby … I felt like I was ignored and excluded from decisions made about my body. I felt I had lost myself. (w3)Several women reflected on their exclusion from the decision making surrounding their birth. They did not feel included in the decision being made about them, and found that it was the midwife who made the decisions. Participants also felt that they were not taken seriously. They described feeling ignored and that they lost control of the situation. Some also detailed how they felt robbed of the opportunity to make decisions about their own body—both during labour and in acute situations that resulted in a surgical delivery.parachuting without the parachute”, “going into a burning building” or a desire to flee the situation by “jumping out the window”. One participant described giving birth as if she had lost “the ground beneath her feet”. She said she instinctively closed her eyes, tuned out her surroundings and focused on surviving:That’s what’s so scary in a way—as long as you have control, you know what’s happening, but when you lose control, you lose the ground beneath your feet and no longer have that foundation, sort of, and instinctively I had to focus on surviving. (w8)The women likened their loss of control to ““I shut it out”: Insufficient time and capacity to process a traumatic birth experienceIt was intense and stayed with me after I came home without realising it” (w1). The women’s coping strategy was to put the trauma behind them. As one woman noted, “I just shut it out … My anxiety is that I really only—it’s there, but I’m not thinking about it” (w6). However, a sense of defeat and inability to cope after the traumatic birth overshadowed the joy of becoming a mother. The women struggled to find the emotional availability to feel warmth and love for their child, and felt they lacked the capacity to take an active part in their role as a mother.It was really tough, the birth—I was thinking I wasn’t happy about having him, I felt awful … I wasn’t able to take a proper interest in him, I couldn’t muster the energy to take care of him, you know … I’d had such a brutal experience. (w1)Everyday life as the mother of an infant was all-consuming and meant that the participants did not have the capacity to process their childbirth experience: “They didn’t think it was that unusual for the delivery to last that long or for me to lose so much blood … I really didn’t need to hear that. I needed to hear that this was a difficult experience, so that only made it worse. (w2)The participants described feeling inadequate, disappointed in themselves and disheartened. Although the postnatal period was a challenge, as seen in the quotes above, none of the women sought help to process their childbirth experience. Many never talked about the birth, nor the period that followed. One woman noted that, had she been offered counselling shortly after the birth, it would have helped her process the trauma. For those women who did speak to a healthcare professional after the experience, some reported that their experience was downplayed. This led to doubts as to whether their traumatic experience was real or whether they had overreacted. Several of the women pointed to validation, understanding and acknowledgement of their experience as important factors in their ability to process the trauma. One participant described how a lack of validation had tarnished her childbirth experience:I was adamant that I wasn’t going to have any more children … Then I got pregnant again. It came as a shock to me. Am I going to have to do this again?” (w7). One woman explained that her husband was keener to have children than she was, and he had talked her into getting pregnant again. She did not want more children, but at the same time she wanted a sibling for her child: “I have realized that it’s best to have a sibling … I just shut it out, it’s not up for discussion, yet here we are” (w6).Some participants also expressed a sense of shame and guilt. Several acknowledged that they had waited a long time to get pregnant again, following the traumatic birth, because they did not want to give birth again. Most expressed feelings of ambivalence and considered whether they wanted to go through another pregnancy: “It was actually very surprising—it came over me like a wave of fear—that I had to go through it all again, and I thought, my goodness … I couldn’t see another way out other than having an abortion, quite simply, because I can’t go through it again, and there was a feeling of shame given that I’d got myself pregnant of my own free will. (w1)They expressed a great need to work through the trauma, and that this realization emerged during the subsequent pregnancy. One woman described it as follows:“The baby has to be delivered!”: The new pregnancy triggers a fear of childbirth[t]he baby has to be delivered!” (w6). Another woman explained,It really does something to you. But now I’m pregnant again. Yes, that’s what I think is going to happen this time as well. That you won’t manage to save me. So that’s the biggest fear, I don’t care about pain … But it’s the fear that I’m going to die … That you won’t manage to save me. I’m so scared to go through that experience again … I don’t want to do it again. (w7)Participants described that their previous traumatic birth led to the fear that history would repeat itself, triggering a fear of childbirth. This affected their experience of this new pregnancy and their ideas and feelings about the impending birth. However, they highlighted that there was no escaping the fact that, as one participant stated, “I then started to really panic about giving birth. So the anxiety I felt about losing her then turned into an anxiety about getting her out, and that sometimes leads to slight claustrophobia, hyperventilating, you know—or I get stressed out. (w3)All the women expressed that their unease or fear about giving birth affected their everyday life. Their fear of childbirth manifested itself in the form of panic, hyperventilation, claustrophobia and stress.After my first conversation with the midwife, I realized that I have to deal with this and that I regretted having to give birth again” (w5). Others described a sense of fear for the child and for themselves, and some had nightmares. All the women had negative thoughts, to a certain extent. One woman described her thoughts as follows: “I keep thinking that I’m going to start bleeding on the way to the hospital, and that I’ll go into rapid labour again and that I won’t get there. All these thoughts about not getting there in time” (w7). Some of the women expressed a fear of dying: “It’s the fear that I’m going to die” (w7). Others feared that something would happen to the baby: “I think about the worst thing that can happen—a stillbirth” (w3). Some women expressed anxiety in relation to the unpredictability of the outcome of the impending birth: “But I think the anxiety I’m experiencing now, which I’m struggling with, is because I don’t know what the outcome will be—no one does. That makes me feel very panicky” (w3).One woman described how she was unable to think about the impending birth or talk to anyone about it. “There’s an obstacle in the way that makes me unable … I am looking forward to it, but it’s kind of, I don’t know …. I can’t seem to deal with it. People say things like it will be great to have a new baby in the house … I understand it will happen, but there’s something before that that has to happen and I just can’t face it. That’s the problem. (w6)The participants highlighted that fear of childbirth was a barrier to feeling happy about the pregnancy and preparing for the birth. Several said that they were procrastinating with regards to preparing for the new arrival. One woman reflected on how she did not feel emotionally invested in the pregnancy. She said that she had waited a long time before contacting the midwife and doctor after finding out that she was pregnant—she felt that was going through the motions of what she was supposed to do, but was not emotionally connected. She expressed sadness about this.Yes, it’s meant that I’m not having a very good pregnancy … I’ve been very focused on things like fear … It’s mostly been marked by fear … I’m not doing very well mentally. I feel very alone … No one knows how I feel. (w7)Another woman reflected on how her fear was preventing her from having a good pregnancy. She also expressed a sense of loneliness. She felt alone with her anxiety and wanted to talk to other women in the same situation who understood how she was feeling.I feel that the hospital is taking me seriously now, and it’s made a huge difference” (w2). Some of the women had benefitted from writing a birth plan, which gave them a degree of predictability and reassurance. They also expressed the need to talk about their previous traumatic childbirth: “Being able to have a proper conversation with a midwife about the birth was really helpful” (w3).The offer of counselling during this new pregnancy had helped several of the women. They felt they were being taken seriously, with one explaining: “It’s extremely important for me to feel that sense of reassurance so that I can give birth, and it would obviously be best for me to manage it naturally … I need to go through the birth process. If I have a caesarean, I’ll never move on. (w7)Some of the women were motivated to have a vaginal birth. They were hoping for a good childbirth experience this time, but were unsure how it would go. One of the participants described how a vaginal birth was important for her ability to work through the trauma she had experienced:I want a caesarean section, and when I voice that, I feel much calmer within myself. Nothing is telling me that it’s wrong, I just know that it feels right, I become calmer, can plan things—it’s more predictable. (w8)The women seemed to be able to relate to this sense of ambivalence. For some, however, the fear of a vaginal birth was so heightened that they wanted a caesarean section to ensure predictability and regain a sense of control, despite knowing that this would increase the risk for themselves and their baby:So when they talk about a vaginal birth, I’m just not there, it kind of doesn’t apply to me. I can’t imagine anything other than a caesarean section” (w6).Another woman also expressed a clear desire to be approved for a planned caesarean and wanted a decision to be made rapidly about this so that she could mentally prepare herself for what would happen. She was unable to relate to a vaginal birth: “The most important thing is just that when they do their job … they remember that I’m there in a way. That I want to be involved and be seen and heard in a way” (w6).It was important for the women to feel seen, heard and included. They described a need for real involvement in the decision making. They did not feel that they had been given enough information to make autonomous choices during the pregnancy and in the preparations for the impending birth: “You’re supposed to sort of put your trust in the hospital, as it’s the only safety net you have really, but you don’t actually have that” (w4). However, some of the women did report having confidence in the healthcare professionals and their expertise: “I generally have a high level of confidence in those with the expertise and think things will go well and that they will take care of me, so I don’t have any concerns in that area” (w6).After previous difficult experiences with healthcare professionals, the women found it difficult to place their trust in them. They highlighted the paradox of being dependent on healthcare professionals in whom they had no confidence: “Finally, one woman expressed a hope and desire for more openness around the fear of childbirth.This phenomenological study investigated the phenomenon of fear of childbirth after a previous traumatic birth. Among the women in our study, the trauma of giving birth strongly impacted their subsequent pregnancy. They struggled to deal with the pregnancy, and the impending birth triggered considerable anxiety. However, they were hopeful that they would master their fears as their pregnancy progressed. In the following sections, we will discuss key findings in the context of relevant research: specifically, a fear of childbirth triggered by a previous traumatic birth; loss of control and the importance of relationships; insufficient capacity to process a traumatic birth experience; life’s vulnerability and predictability; and finally, a hope of mastering their fears in the impending birth.The first key finding is that the fear of childbirth was closely linked to and could be triggered by a previous traumatic birth experience. The situation that triggered participants’ traumatic memories and fears was an impending birth that was unavoidable. Every day, the women were reminded of their pregnancy and the certainty that they would once again give birth. This sense of being “stuck” was very challenging, and time marched on inexorably towards the situation they feared most. While the birth itself was inevitable, the outcome was unknown, making the fear of childbirth challenging for the women to deal with. This is consistent with other studies that highlight how the fear of childbirth can be a result of a previous negative birth experience (Dencker et al., The participants’ fear of childbirth stemmed from their fear of obstetric complications, of pain, of losing control, that something would go wrong with them or their baby, or not receiving adequate medical care during labour from the midwife or other healthcare professionals. Similar findings have also been described in other qualitative studies on fear of childbirth (Sheen & Slade, Pregnancy and childbirth are not only physical events that affect the body—they are also existential events during which women are touched on a deeper level that is connected to life’s vulnerability and unpredictability (Wigert et al., Loss of control was commonly reported by the participants as an important contributing factor to the trauma of the previous delivery. The association between loss of control and perceived trauma has been reported in several studies (Greenfield et al., Participants’ relationship with the midwife in particular, but also with other healthcare professionals, had a significant impact on the their experience of childbirth. They felt safe and that they had a sense of control, to the extent that they experienced the midwife as present and caring during labour, while adequate care involved receiving sufficient information and feeling included in their own birthing process. Unfortunately, the women experienced a lack of these factors in critical moments during labour, which contributed to the traumatic experience. The birth did not unfold as anticipated, and they therefore felt unprepared. Comparable with our findings, a recent Norwegian study found that a negative childbirth experience was associated with inadequate care, disrespect, and exclusion from decision making during labour (Henriksen et al., The women felt they were being listened to and were receiving good support from the midwife and doctor during this latest pregnancy, and this made them feel reassured and helped them access their own resources. Beck  emphasizParticipants expressed having insufficient capacity to work through their experience in the period after the traumatic birth. They felt overwhelmed and tired, both physically and mentally. The role of mother was all-consuming, and they struggled to be emotionally available for their baby. After the birth, they felt a sense of grief over not being able to cope with either the birth or the transition to motherhood, and several of the women described having lost confidence in healthcare professionals. Participants also expressed a strong need to suppress their traumatic experience, and “shut out” the event in order to move on. This is consistent with the findings of Nilsson and Lundgren , who repThe women in our study described how suppressing their feelings about their new pregnancy was a strategy they employed to avoid dealing with anything reminiscent of their previous childbirth trauma—and the fear that history would repeat itself. This is consistent with previous studies showing that women with a fear of childbirth try to avoid thinking about it and talking about their fears (Beck & Watson, Despite a severe fear of childbirth, the women expressed a hope of mastering their fears about the birth. They tried to prepare themselves by reinforcing their inner belief that they would be able to cope with the delivery, whilst recognizing that the birth experience for which they hoped was not guaranteed. Being asked about their expectations for the birth can empower women and help prepare them to deal with the unpredictable (Hildingsson, Our findings show that women who have experienced a traumatic birth need to have the opportunity to process the trauma. Routines are needed to identify, support and follow up with women who have experienced a traumatic birth. Future research should focus on how we can best help women work through a traumatic birth experience, with a view towards preventing fear of childbirth. Comprehensive and more adaptable service provision and treatment is needed for women with a fear of childbirth. Future research should therefore also focus on service provision and treatment for this group.In this phenomenological study, we explored and discussed women’s experience of fear of childbirth after a traumatic birth. We identified four interconnected constituents: Suboptimal midwifery care, loss of control and agency; insufficient time and capacity to process a traumatic birth experience; “The baby has to be delivered!”, and finally, the path to a new childbirth with the hope of mastering fears. The study sheds light on the association between a previous traumatic birth and a fear of childbirth in expectant mothers. The trauma of giving birth strongly impacted the women’s experiences of their subsequent pregnancy, making it difficult to deal with the new pregnancy and impending birth. Women who experience a traumatic birth need to be given the opportunity to work through the trauma. Routines are thus needed to identify, support and follow up with women who have experienced a traumatic birth. If these women are identified and given the help they need, it could help prevent and alleviate the fear of childbirth in their subsequent pregnancy.


To report values of the chest radiographic thoracic area (CRTA) in ventilated, term-born infants without respiratory disease and to evaluate whether CRTA is related to demographic data at birth.Retrospective, observational cohort study in a tertiary neonatal unit at King's College Hospital NHS Foundation Trust, London, UK.Newborn infants born after 36 completed weeks of gestation, ventilated for poor perinatal adaptation or hypoxic ischaemic encephalopathy without respiratory disease and admitted in a recent eight-year period (2014–2022).The CRTA was assessed by free-hand tracing of the perimeter of the thoracic area as outlined by the diaphragm and the rib cage excluding the mediastinal structures and was calculated using the Sectra PACS software.2 and was significantly related to birth weight , gestation at birth  and birth weight z-score .One hundred and twenty-one infants  were included with a median (IQR) gestation of 40 (38–41) weeks and birth weight of 3.41 (3.04–3.75) kg. The median (IQR) CRTA was 2,589  mmWe report values of the chest radiographic thoracic area in ventilated term-born infants which could be used as reference for determining respiratory disease severity. Quantitative assessment of the pulmonary parenchyma in neonatal intensive care has been undertaken by imaging and functional methods such as fetal magnetic resonance  or the mAlthough CRTA has been well-documented in pathological conditions, values in term infants without respiratory disease have not been reported. Such reference data would be important to establish the magnitude of the disease in respiratory disorders that are characterised by low lung volumes such as pulmonary hypoplasia due to prolonged preterm rupture of membranes  and dise2O. The study was registered as a service evaluation with the Clinical Governance Department of KCH and, as it was not a research study, informed parental consent was not required. The following information was collected from the medical notes: sex, mode of delivery, gestation (completed weeks), birth weight (kg), birth weight z-score  at King's College Hospital NHS Foundation Trust, London, UK were included in the study. The included infants were intubated and invasively ventilated for absence of respiratory drive at birth and had no supplemental oxygen requirement by 6 h of age. The starting point was selected as this was when the unit adopted volume-targeted ventilation as primary mode of mechanical ventilation. The infants were ventilated with a targeted tidal volume of 5 ml/kg and a positive end-expiratory pressure of 4 cm–5 cm H z-score .2 and 1.0 cm2 respectively . The software automatically adjusted for magnification errors. Free-hand tracing of the perimeter of the thoracic area as outlined by the diaphragm and the rib cage was undertaken and the CRTA was calculated by the software . The repectively .z-score were examined with the Spearman's ρ correlation coefficient. Differences in CRTA between male and female infants were assessed for statistical significance using the Mann-Whitney rank sum test. The relationship of the CRTA with birth weight was also examined with linear regression analysis to derive an equation to predict CRTA based on the birth weight. Statistical analysis was performed using SPSS software .Data were tested for normality using the Kolmogorov–Smirnov test, found to be non-normally distributed and were presented as median (interquartile range). The relationships of CRTA with gestational age, birth weight and birth weight z-score of 0.03 (−0.59–0.75). The median (IQR) CRTA of the right lung was 1,486  mm2 and of the left lung was 991  mm2. The total CRTA was 2,589  mm2 and was significantly related to birth weight  and birth weight z-score . The CRTA was not significantly different in male compared to female infants (p = 0.441). Following linear regression analysis, birth weight could predict the CRTA . The regression equation was:During the study period, 158 infants born after 36 completed weeks of gestation with poor perinatal adaptation or hypoxic ischemic encephalopathy were ventilated on the neonatal unit at KCH. Thirty-seven infants were excluded because of rotated radiographs, pneumothorax or concomitant respiratory disease. One hundred and twenty-one infants  were included with a median (IQR) gestational age of 40 (38–41) weeks, birth weight of 3.41 (3.04–3.75) kg and birth weight  = 0.003 ), gestat2 which is considerably higher than the 1,680 mm2 that we have previously reported in infants with CDH , compared with infants with congenital lung pathology   –7, some 986 mm2) . We shouOur study has strengths and some limitations. We included a large number of infants that were ventilated on volume-targeted ventilation. Infants ventilated for hypoxic ischemic encephalopathy are often receiving whole body hypothermia which might impact on respiratory function . VentilaIn conclusion, we report values of the chest radiographic thoracic area in ventilated term newborn infants which could be used as a reference for determining respiratory disease severity in diseases that are characterised by lung hypoplasia.


The variation on birth weight is associated with several outcomes early on in life and low birth weight (LBW) increases the risk of morbidity and mortality. Some environmental exposures during pregnancy, such as particulate matters and other traffic-related pollutants can have a significant effect on pregnant women and fetuses. The aim of this study is to estimate the effect of exposure to traffic density during pregnancy over birth weight in Spain, from 2000–2017. This was a retrospective, cross-sectional study using the information from Spain Birth Registry Statistics database. The traffic density was measured using the Annual average daily traffic. Multivariate linear regression models using birth weight and traffic density were performed, as well as a logistic regression model to estimated Odds ratios for LBW and GAM models to evaluate the non-linear effect. Our findings showed that increases in traffic density were associated with reduction of birth weight and increases of LBW risk. Moreover, exposure to high and very-high traffic-density during pregnancy were associated with reduction of birth weight and increase on LBW risk comparing with exposure to low number of cars trespassing the neighborhoods. The results of this study agree with previous literature and highlights the need of effective policies for reducing traffic density in residential neighborhoods of cities and towns. The World Health Organization (WHO) define children born with low birth weight (LBW), as a newborn who weigh less than 2500 g at birth . The var2.5) and those particulates with 10 μm or less in diameter (PM10), sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2) and ozone (O3) are associated with traffic-related air pollution (TRAP) [Pollutants and contaminants such as particulate matter (PM), especially PM of 2.5 μm or less (PMn (TRAP) ,5, what n (TRAP) ,7,8. It n (TRAP) . Also, tn (TRAP) ,12, and n (TRAP) . Recent n (TRAP) ,14,15 ann (TRAP) ,18,19,20n (TRAP) ,23,24,25Measuring traffic air pollution could be approached by different strategies, such as direct air quality monitoring, modeling air pollution, or distance to road or traffic density ,14,15. TPrevious studies have been conducted in Spain and similar countries ,29, neveWe carried out a retrospective, cross-sectional study using the information from Spain Birth Registry Statistics database from the National Statistics Institute (INE) was used. The initial population was 5,071,963 birth records from all the regions of Spain, between year 2000 and 2017, from which only pregnancy with one single live fetus born between gestation weeks 37 and 42 were selected. Children with missing data on birth weight or unplausible birth weight were excluded, resulting in a final population of 4,934,810 birth records.The annual average daily traffic (AADT) is a measure of the traffic density. It is expressed as number of vehicles per day and it is calculated as the total volume of transportation traffic of a road or highway for a year divided, by 365 days. AADT is a tool that is use to predict how active a road is and it is a useful instrument when assessing the effect of traffic density exposure.For the present study, AADT was measured using the Navteq cartography combined with the traffic density information provided by the Spanish Ministry of Public Words and Transport . Using tOutcome variables were birth weight (in grams) as a continuous variable and LBW as binary. The neonatal weight was collected using the birth records and registers with less than 2000 g or more than 4650 g were excluded, because we considerate those weights as little plausible birth weight for a term pregnancy. We created the binary variable LBW using the neonatal weight in grams and defined as low those babies that weighted less than 2500 g.We obtain information related to the mother, father, gestation and neonatal factors at delivery from the birth records. We collected data on infant sex, birth year, mother’s age, father’s age, autonomous community (18 regions) , and sizBefore the analysis, we categorized the AADT variable into four groups using the quartiles of the roads traffic average  and for the regression models; we use the lowest traffic density areas as the variable reference.First, we performed a descriptive analysis of the sociodemographic variables, by percentages for categorical variables and means and standard deviations for continuous variables.Then, in order to quantify the association between pregnancy’s exposure to traffic density and birth weight, we fitted multivariate linear regression models using birth weight as the dependent variable and traffic density as explanatory variable, in both forms as continuous and categorical. For LBW, we estimated Odds ratios (OR) and 95% confidence intervals (95% CI) using logistic regression. First, for both models we fitted an initial unadjusted model and then an adjusted model including gestation age, infant sex, birth year, maternal and paternal age, maternal autonomous community and size of municipality of residence, and maternal socio-economic condition and economic activity rate. We tested the potential modification effect of infant sex by including the interaction between traffic density and infant sex in the models. Finally, we fitted GAM models over the continuous variable to evaluate potential risk in a not linear fashion.p-value ≤ 0.05 was considered as the significant statistical level. The data was analyzed with the statistical program R 4.0.2.For all analyses and tests a The study included 4,934,810 birth records and their neonatal and parental characteristics distribution are shown in p < 0.01).Detailed analyses of the unadjusted and adjusted association between each covariate and the birth weight of this analysis can be found in the annexes on the p < 0.01), however, when the effect was evaluated by measuring the traffic density in quartiles, it shown more clearly that as the traffic density increments, the risk of LBW also increments exponentially, with a risk of 9% in the crude model and 8% in the adjusted model, in the group exposure to a very high traffic density compared to the group with the lower traffic density in the roads near their homes (p < 0.01).Finally, This study focused on the association between exposure to the traffic density over birth weight in Spain, considering traffic density close to the home address of pregnant women as proxy of traffic-related pollution exposure. Based on our results, an increasing number of cars trespassing near the mother’s home residence seems to be associated with a small reduction of weight at birth, nevertheless the effect over LBW risk is more obvious and exposure to high and very high traffic-density during pregnancy showed increased risk of LBW in comparison with exposure to low traffic density. Moreover, this study showed that the newborns with higher risk of LBW were also associated with mother’s residence in cities with more than 100,000 inhabitants.2.5 and PM10, and other pollutants, such as SO2, CO, NO2 and O3, nearby the study groups [As regard to the different proxies to the exposure, several studies investigated the effect of traffic-related air pollution using prediction models to estimate air pollution by calculating daily concentrations of PM, specifically PMy groups ,34,35,36y groups .A recent meta-analysis published in 2020, described positive associations between air pollution due to a higher traffic density and LBW, finding an OR of 1.013  for the risk of LBW with an increment of 5000 vehicles/day in traffic density, similarly to our results. In addition, they evaluated studies that treated traffic as a binary variable depending on the distance to the road. A positive effect between LBW and the distance to road was found as well, showing an OR of 1.044  when the cut-off point was 50 m and an OR of 1.023  with a distance of 100 m .A Japanese study that evaluated the association between maternal residential proximity to major roads and adverse birth outcomes, determinate that living within 200 m from a major road increased the risk of preterm birth by 1.5 times and LBW by 1.2 times. It also pointed out that mothers with lower individual socio-economic position (SEP) showed higher ORs for term LBW  compared with those with higher individual SEP ; compara2.5 exposure during the entire pregnancy and head circumference at birth, as well as an association between maternal NO2 exposure and shorter length at birth [Another meta-analysis from 2018, which reviewed 15 studies of the association between air pollution exposure during different phases of pregnancy and fetal growth and anthropometric measurements at birth. Described a negative associated with Maternal PMat birth . However2, suggested an association between maternal exposure to outdoor air pollution and birth outcomes. Its results showed an increased odd of being born small for gestational age (increased by 37% when ambient NO2 levels increased 10 μg/m3 during the second trimester) and being born at risk of lower length (reduction of −0.27 cm) or weight (reduction of −40.3 g) with a NO2 exposure above 40 μg/m3 during the first trimester [Previous studies showed that inhalation of pollutants during pregnancy, in particular those that are associated with traffic contamination, is associated with systemic inflammation, oxidative stress-induced DNA damage and, blood coagulability and viscosity alterations. All these can affect the placenta or the embryo directly, leading to LBW and others adverse birth outcomes ,37,38. Arimester .2 and PM2.5 surfaces near the mother’s postal code during pregnancy. The authors estimated that LBW and term birth weight was strongly associated with both pollutants  [In 2016, a study about the association between TRAP and adverse pregnancy outcomes was conducted in Canada by mapping the NOppb NO2) , similarppb NO2) .2.5 [One study based in Brazil presented an interaction between infant sex and the exposure of pregnant women to air pollutants. This study suggested that sex of the newborn played a paper in the association of air pollutants exposure during pregnancy and LBW. Specially, exposure of ozone in the period of 30 and 90-day window prior to the birth, showed that female newborns presented a bigger susceptibility  to maternal exposure to air pollutants than male newborns. Conversely, a different study claimed to find a contrary result, suggesting that male fetuses are more sensitive to air pollution exposure, especially to PM2.5 . NeverthAs usual, this study has some limitations to mention. A main one is the no inclusion of data on previous maternal health history, substance use or complications or diseases during pregnancy that may affect the newborn’s weight. Other limitation is the use of the maternal home address as listed in the municipal registry at the moment of birth as location point of exposure estimation. Pregnant women could be out of home working or somewhere else and we did not include those other locations in the study that can led to inexact results if people’s mobility is not considered as stated in some studies ,42. We uIn addition to these limitation, we much point out that the traffic density levels have improved in the Spanish main cities during the last few years, mostly due to changes related to traffic implemented policies and increased use of environmentally-friendly cars, as well as growing network of renting public electric cars, bicycle and skateboard around the center of major cities in Spain ,44,45,462, 66% for NOx, 30% for non-methane volatile organic compounds, 21% for ammonia and 50% for PM2.5 [It is crucial to reduce TRAP and improve air quality by adopting and promoting effective policies to reduce air pollution emissions, as well as to increase awareness of the consequence of this exposure, especially to the population of reproductive age that live nearby high pollutant areas. Several initiatives have been taken place internationally, as well as at a European and national level related with this matter. One major key initiative was the creation of National Air Pollution Control Programme (NAPCP), approved in 2019 by the Council of Ministers . The NAPor PM2.5 .The results of this study agree with previous literature and finds association between exposure to high traffic density and LBW risk. This result highlights the need of effective policies for reducing traffic density in residential neighborhoods of cities and towns.


Teaching Point: Cystic nerve enlargement near a joint should evoke an intraneural synovial cyst and lead to the tracking of the articular connection for confirmation, where ever the location within the body is. A 55-year-old male was referred to our radiology department to perform a head and neck MRI as part of the staging of a palatine tonsil squamous cell carcinoma with a necrotic adenopathy (not shown). Besides the tumor and the adenopathy, the MRI scan showed an ipsilateral bilocular cystic lesion within the masticator space running along the V3 nerve , arrow. There was no enhancement of the pure cystic lesion , arrow, The patient wasn’t symptomatic so therapeutic abstention was chosen.Intraneural synovial cysts  are rare benign mucinous cysts contained within the external sheet of peripheral nerves. Several studies have recently provided evidence for an articular  pathogenesis: the cysts are formed from a capsular defect of a joint, propagate through the epineurium of an articular neural branch toward the parent nerve and their divisions. The cyst expansion depends on articular pressure and pressure fluxes . It can Close examination of the images is essential and may permit to identify the articular connection of the cyst, which is often very thin. Contrast medium injection in the nearby articulation followed by a CT-scan or an MRI showing propagation in the cyst confirms the articular origin. Disconnection of the articular branch of the cyst is the main principle of the surgical management of the pathology, and statistically helps to prevent recurrence.Although very rare in the head and neck region, ganglion cysts could be a clinically relevant pitfall in oncologic treatment planning mistaken for perineural tumor spread or missed as a potentially treatable cause of trigeminal neuropathy.


Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity.We performed a nationwide study of Swedish women diagnosed with IBD 1990–2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation . We also examined pregnancy outcomes in 2007–2016 of women with vs. without clinically active IBD  <12 months before pregnancy . Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth  and small-for-gestational age .Of infants to women with vs. without histological inflammation, 9.6% (n = 117) and 6.5% (n = 41) were preterm, respectively . Histological inflammation was associated with preterm birth in ulcerative colitis (UC) , especially extensive colitis , but not in Crohn's disease . Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA . Clinically active disease before pregnancy was linked to preterm birth , but not to SGA birth . Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth .Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity.Swedish Society of Medicine.The  On June 23, 2022, we searched PubMed using the following search string:  AND  AND "pregnancy"[All Fields]". The search generated 21 studies; however, none of the studies concerned histological activity of inflammatory bowel disease (IBD) to pregnancy outcomes. We then searched PubMed for articles published between Jan 1, 2000, until June 23, 2022, using the following search string:  AND ("activity"[All Fields] OR "flare"[All Fields] OR "relapse"[All Fields]) AND "pregnancy"[All Fields]" This second search generated 250 studies, of which a large proportion were outside the scope of this study concerning aspects of IBD management and drug safety during pregnancy.Based on almost 2000 births of women with IBD with a pre-pregnancy colorectal biopsy, this nationwide study found an almost 50% increased risk of preterm birth of infants to women with histological inflammation in IBD, particularly in ulcerative colitis. Histological inflammation in IBD was not linked to other adverse pregnancy outcomes.Our data support recommendations to objectively assess IBD remission status before conception, to optimise management and prevent adverse outcomes of pregnancy and IBD.Inflammatory bowel diseases (IBDs), represented mainly by Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions, impacting patients' quality of life and imposing high societal costs. Clinical remission and mucosal healing during endoscopic evaluation are key therapeutic targets of IBD.,IBD diagnosis usually coincides with childbearing years.Using a nationwide IBD cohort with histopathology data,,We defined IBD as having either ≥2 International Classification of Disease (ICD) codes in the National Patient Register (NPR)We identified 7374 women diagnosed with IBD in 1990–2016 who, after diagnosis, gave birth to 11,374 children in 1990–2016 . 1990–20I.Our primary exposure was histological inflammation  documented 0–<12 months (≤365 days) before the start of pregnancy. In line with recent consensus reports,,,II.Our secondary exposure was clinically active IBD (vs. quiescent IBD). Motivated by a previous study,,High-quality data on pregnancy outcomes were retrieved from the Medical Birth Register, which contains information on all births in Sweden since 1973.Our primary outcomes considered the risk of preterm birth  and small for gestational age  birth. Gestational age was determined by second-trimester ultrasonography  or the last menstrual period as reported at the first maternity health care visit. Birth date and gestational age data were used to define the start of pregnancy.Secondary pregnancy outcomes included very preterm birth , low birth weight (<2500 g), low 5-min Apgar score (<7), induction of labour, instrumental delivery, caesarean section , stillbirth , gestational diabetes and pre-eclampsia as defined in As detailed in Several of the researchers of this study care for patients with IBD. However, in this register-based study no patients were directly involved in the design, recruitment or conduct of the study.We used generalised linear models to estimate risk ratios (RRs) and their 95% confidence intervals (CIs) for adverse pregnancy outcomes of women with histological inflammation  and clinically active IBD (vs. quiescent IBD), respectively, 0–<12 months before the start of pregnancy. All analyses accounted for maternal clustering due to multiple or repeated births and were further adjusted for maternal age at delivery, parity, education level, country of birth, comorbidities, early-pregnancy smoking status, and BMI.We present complete case analyses, which ignored observations with incomplete covariate data. However, in sensitivity analyses for the outcomes preterm birth and SGA we used multiple imputationOur primary outcomes of preterm birth and SGA were examined by IBD subtype  and the extent and location of disease at diagnosis. The risks of preterm birth and SGA were also analysed stratified by year of IBD diagnosis , duration of IBD diagnosis at delivery , age at delivery , parity , maternal education level , and country of birth .Exposure window restricted to 0–<6 months before or during pregnancy .Histological inflammation in women without clinically active IBD. We determined the possible incremental effect of residual histological inflammation in women without clinical disease activity. Restricting data to births from October 1, 2007, through 2016, we estimated the risk of preterm birth and SGA in women with histological inflammation, but without clinical disease activity .Outcome definition. To test the robustness of our findings, SGA was also defined as below −2 standard deviations of weight for age and sex.Stratified analyses of histological inflammation and preterm birth by use of corticosteroids: Restricted to births between October 2007 and December 2016 for which Prescribed Drug Registry data were available, we stratified our analysis on histological inflammation  and preterm birth by pre-pregnancy use of corticosteroids.Data were analysed using SAS version 9.4 .The Stockholm Ethics Review Board approved the study and waived the requirement of informed consent.The funding sources did not influence any aspect of the study , its writing or the decision to submit it for publication. JFL, JS and OO had full access to all the data in the study. All authors accepted responsibility to submit the paper for publication.This study included 7374 women diagnosed with IBD between 1990 and 2016 who, after their diagnosis, gave birth to 11,374 children (up until 2016). Restricting our sample to women with ileal-colorectal biopsies collected 0–<12 months before pregnancy, there were 1223 births to 1164 women with histological inflammation and 630 births to 611 women with histological remission . Median Overall, 35.4% of the children were born by women with CD, 60.9% with UC, and 3.7% with IBD-U. Women with histological inflammation more often had a high degree of endoscopic inflammation and a higher risk of IBD-related surgery or hospitalization in the year before pregnancy than those in histological remission . Until dThe preterm birth rate was 7.8%  in the overall sample of IBD women. Among those with histologic inflammation within 12 months before pregnancy, 9.6% (n = 117) of births were preterm compared to 6.5% (n = 41) in women with no inflammation corresponding to an almost 50% increased risk of preterm birth  and represents one extra event per 32 births in women with histological inflammation. Adjustment for maternal age, smoking habits, BMI, education level, and comorbidity exerted negligible impact on results (adjusted (a)RR 1.46 , and especially elevated in those with extensive colitis . In contrast, histological inflammation in CD was not associated with preterm birth . While the absolute risks of preterm birth were highest in nulliparous women, young women (15–24 years), and those with low education level (≤9 years) , the RRsWomen with pre-pregnancy histological inflammation gave birth to 116 (9.6%) SGA infants and those without to 56 (8.9%)  . Neither inflammation 0–6 months before pregnancy  nor inflammation during pregnancy  was significantly associated with SGA . HistoloFrom October 1, 2007, and until 2016, approximately one third (n = 2110) of the study infants were born to women with clinically active IBD and two thirds (n = 4993) were born to women with clinically quiescent IBD. Almost 90% of those with clinically active IBD were identified through their use of IBD-related drugs . Charactduring pregnancy  of births were preterm compared to 6.5% (n = 325) of births to women with clinically quiescent IBD . There was a higher risk of preterm birth in women with clinical IBD activity during pregnancy  and 416 (8.4%) infants born to women with and without clinically active IBD <12 months before pregnancy, respectively, were SGA . Active IBD before pregnancy was also not significantly associated with SGA within patient subgroups of varying education levels, ages, etc . HoweverIn a sensitivity analysis of 726 children to women with clinically quiescent IBD, the presence of histological inflammation (vs. no inflammation) was not significantly associated with preterm birth  vs. without (24.3%) clinically active IBD ; Restricting our cohort to children born between October 2007 and December 2016  we reran our analysis on histological inflammation and preterm birth while stratifying for corticosteroid use. However, these analyses yielded largely similar estimates across strata .The association of histological inflammation vs histological remission and clinically active vs quiescent IBD with SGA and preterm birth were largely unchanged when adjusting for alcohol-related diseases and disorders  as well In this nationwide study of maternal IBD, histological inflammation was associated with preterm birth, but not other adverse pregnancy outcomes. The increased risk for preterm birth was confined to women with UC and histological inflammation, particularly extensive colitis. However, histological inflammation was not significantly linked to preterm birth in women with clinically quiescent disease. Our data support recommendations to objectively assess endoscopic and histologic disease remission before conception,,Clinical and endoscopic remission are the main therapeutic targets of IBD. However, histological remission may further improve clinical outcomes beyond these therapeutic targets, particularly in UC, where it has been proposed as a potential adjunct treatment goal.,This study links histological inflammation with preterm birth. Excess risks were seen in UC, but not in CD, with the highest risk increase in women with extensive colitis . Our contrasting UC and CD findings are consistent with previous research showing that a high degree of endoscopic inflammation was linked to hospitalization in UC patients.In our study, aRRs for spontaneous preterm birth were only slightly lower than preterm birth overall, indicating that this association is not merely explained by preterm labour induction. Indeed, considerable data implicate inflammation in the pathogenesis of preterm birth,,,,We and others,,We exploited population-based histopathology data as an objective measure of disease activity in IBD. More than 1800 births to women with IBD biopsied <12 months before pregnancy were identified. Earlier validations have shown a positive predictive value of 93%–95% for our IBD definition,This study has several limitations. As in any observational study, causality cannot be inferred. However, a study randomizing pregnant women (or women desiring pregnancy) to histological or clinical disease activity would be unethical and unlikely to be performed. Thus, while we adjusted for the potential confounding of maternal age, education level, comorbidities, smoking, BMI, and birth country, we recognize that residual confounding cannot be ruled out. Furthermore, the consistency in our findings across patient subgroups, defined by age and calendar year of diagnosis, does not support confounding by indication, i.e., an association related to the indication for biopsy  as a sole cause of our findings.Another limitation is the lack of data on the clinical indication, symptoms and biomarkers, that could have prompted the histological assessment of IBD. However, women with histological inflammation vs histological remission were more likely to have features of clinically defined disease activity, such as prior IBD-related surgery or hospitalization , which sWe acknowledge that clinical IBD activity defined by IBD-related hospitalization, surgery, or medication escalation may identify patients with moderate-to-severe disease activity. Patients without these features may not have reached complete clinical or endoscopic remission. Similarly, we recognize that routine histological assessments may not capture the full burden of IBD activity, above all in CD patients, where intramural or segmentally distributed intestinal inflammation may be misclassified as histological remission. In addition, UC patients may be histologically misclassified given that microscopic activity can vary within and across colonic segments, especially after therapy. Finally, in this nationwide study, misclassification may also be related to interobserver variability between clinical pathologists. Importantly, however, the prospective nature of this study ensures that any misclassification of histopathological data should be unrelated to pregnancy outcome. While such non-differential misclassification may attenuate risk estimates, it is unlikely to cause spurious associations. Our data originate from Sweden, a high-income country of mainly Caucasian people with a high incidence of IBD. The generalizability of our findings to other countries is unknown.Using nationwide prospectively collected data, we showed that histological inflammation in IBD, particularly UC, was associated with an increased risk of preterm birth. While our results suggest that targeting histological remission of women with UC may reduce the risk of preterm birth, further research is needed to determine the importance of pre-pregnancy histological appearance in women without clinically defined disease activity.JFL and OO designed the study, collected study data and are responsible for data integrity. JS analysed the data. JFL, JS, and OO had full access to all the data in the study and verified the underlying data for our results. KM and JFL wrote the first draft of the paper. JS, OS, JA, JH, GB, JM, and OO contributed to the writing of the paper. KM, JFL, and OO obtained funding. JFL supervised the project and is the guarantor of the article. KM, JS, OS, JA, JH, GB, JM, OO, and JFL interpreted the data, agreed with the manuscript's results and conclusions, approved the final version of the paper and accepted responsibility to submit it for publication.No additional data are available due to Swedish regulations.Dr Ludvigsson has coordinated an unrelated study on behalf of the Swedish Quality Registry for IBD (SWIBREG). That study received funding from the Janssen corporation.Dr Olén has been PI for projects (unrelated to the current paper) at Karolinska Institutet financed by Janssen, Takeda, AbbVie, Ferring, and Pfizer grants. Karolinska Institutet has received fees for lectures (OO) and participation on advisory boards (OO) from Janssen, Ferring, Bristol Myers Squibb, Galapagos, and Takeda.Dr Halfvarson has served as a speaker or advisory board member for AbbVie, Celgene, Celltrion, Dr. Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Janssen, MEDA, Medivir, MSD, Novartis, Olink Proteomics, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, ThermoFisher Scientific, Tillotts Pharma, Vifor Pharma, and UCB. He has also received grant support from Janssen, MSD, and Takeda.Dr Axelrad has received research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Abbvie, Pfizer, and Janssen; and holds U.S. patent 2012/0052124A1.Dr. Bröms has participated in projects at Karolinska Institutet financed by grants from Janssen, Pfizer, and UCB. Lecturer for Takeda.Dr Marsal has served as a speaker, consultant, or advisory board member for AbbVie, Bayer, Bristol-Myers Squibb, Hospira, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, and Union Chimique Belge and has received grant support from AbbVie, Calpro AS, Fresenius Kabi, Pfizer, SVAR Life Science, and Takeda.The other authors report no conflicts of interest.


Patients suffering from childhood acute lymphoblastic leukemia (ALL) are at risk of late adverse treatment-related effects. The examination of targeted biomarkers could be used to improve the diagnosis and prediction of life-threatening ALL sequelae. The purpose of this cross-sectional study was to search for treatment-related alterations in apolipoprotein (Apo) levels as potential markers of the occurrence of obesity in subjects treated for ALL, and to assess the relationships between weight, gender, anticancer treatment, and Apo concentrations. Fifty-eight ALL survivors were included in the study. The mean time of follow-up after treatment cessation was 5.41 ± 4.29 years. Serum levels of apolipoproteins were measured using a multiplex assay kit. Among ALL survivors, we observed a significant correlation of Apo-C1, Apo-C3, Apo-H, and Apo-J levels, depending on body mass index (BMI). Marked differences were observed in the area under the curve of Apo-A1, Apo-A2, Apo-C1, Apo-D. In our study, patients with a history of childhood ALL developed alterations in their Apo profile. Furthermore, this is the first study revealing that some apolipoproteins may act as valuable biomarkers useful in the prognosis of metabolic imbalance. We believe that this paper, at least partially, will highlight the importance of long-term prognosis of metabolic complications associated with the anticancer chemotherapy used to treat hematological malignancies in children. Today, acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 75% of leukemias and 25% of all cancers ,2. DespiThe childhood survivors of ALL constitute a group of patients with a particularly high risk of the development of late effects due to anticancer treatment. Anticancer therapy is radical and intense, including cytostatic agents, high doses of glucocorticoids and, in selected cases, total body irradiation (TBI) and/or cranial radiotherapy (CRT) ,10. It iIt has been shown that the diagnosis of late sequelae of ALL is often delayed, which has a negative impact on the overall health status and further prognosis of the survivors ,16. ThusAbnormalities in Apo levels are associated with the development of metabolic syndrome components . The mec2. All of the patients were classified into one of three groups in terms of weight status: normal weight (53.45%), overweight (29.31%), and obese (17.24%).p < 0.05; p < 0.05; p < 0.05; The data analysis of Apo concentrations within ALL study participants and the control group is presented in p < 0.05; p < 0.05; p < 0.05; p < 0.05; As shown in p = 0.111; The 58 qualified patients consisted of 27 females and 31 males, and showed greater level of Apo-A1 in females than in males, but this difference did not achieve statistical significance . Additionally, we also observed that overweight and obesity among ALL survivors were positively correlated with the levels of Apo-C3, apolipoprotein H (Apo-H), Apo-J, and CRP .The Spearman’s rank correlation estimates for the ALL group by weight status are presented in p < 0.05) in the area under the curve (AUC) of apolipoprotein profiles were observed in Apo-A1 (AUC 0.80), Apo-A2 (AUC 0.68), Apo-C1 (AUC 0.68), Apo-D (AUC 0.87), and CRP (AUC 0.90), as presented in Based on the Apo concentrations, the receiver operating characteristic curves to predict overweight and obesity in childhood cancer survivors were calculated . Statistp < 0.05; p < 0.05; p < 0.05; The multiple Spearman’s rank correlations were performed regarding the selected characteristic features of all of the patients with ALL . We obseThe treatment of ALL during childhood, involving anticancer chemotherapeutics, irradiation, and corticosteroid therapy , is highly associated with the development of MetS components—especially abnormal alterations in lipid profiles, such as hypertriglyceridemia and hypercholesterolemia ,26. NumeIn our study, significantly increased serum concentrations of Apo-A1 and Apo-A2 were observed in the whole ALL group—which included participants with normal weight, overweight, and obesity—in comparison with healthy peers. The main roles of Apo-A1 are the removal of cholesterol from cells and enhancing the activity of lecithin–cholesterol acyltransferase (LCAT), which results in efficient reverse plasma cholesterol transport. In turn, Apo-A2 regulates LPL activity through HDL-C proteasome modulation ,30. ThusAn important question is whether CRT—another commonly used treatment mode—might cause lipid abnormalities among ALL survivors. CRT is widely known for the induction of long-term side effects in ALL survivors, including impairment within the hypothalamic–pituitary (HP) axis and cardiovascular complications , althougIt is important to note that the alteration in lipid profiles—especially in the composition of lipoproteins—can be a prognostic factor in patients with active leukemia, and may also be a reliable marker of remission in the long-term effects on childhood ALL survivors ,44. In oThere are several limitations to this study. First, it was a single-center analysis with a relatively small number of participants. It should be noted that apolipoproteins are molecules that guide the formation of lipoproteins, as well as acting as activators and inhibitors of enzymes involved in the lipoproteins’ metabolism . AlteratIn total, 58  White childhood cancer survivors (CCS) in complete continuous remission were involved in the study. All of the participants were diagnosed with ALL, and were treated at the Department of Pediatric Oncology and Hematology of the Medical University of Bialystok in Poland. The mean age at diagnosis was 5.01 ± 3.46 years. Additionally, the mean time of follow-up after cessation of treatment was 5.41 ± 4.29 years. The basic characteristics of the study group are shown in 2). In accordance with the OLA/OLAF centile charts of BMI for Polish children, individuals were assigned to particular weight groups, i.e., normal weight, overweight, or obese. The BMI indicative of overweight was considered when the value exceeded +1 standard deviation (SD), while obesity was considered when the value exceeded +2 SD [During the follow-up visit, all of the patients underwent anthropometric measurements and clinical examinations. Their height and weight were measured using a Martin anthropometer and a digital scale , respectively. In order to calculate BMI, the weight expressed in kilograms was divided by height expressed in squared meters  with the Cobas 6000 c502 Roche , following the manufacturer’s protocol.The concentration of apolipoproteins—i.e., Apo-A1, Apo-A2, Apo-B, Apo-C1, Apo-C3, Apo-D, Apo-E, Apo-H, Apo-J—and CRP were measured using the Immunoassay Kit .g for 15 min at 4 °C to remove particulates. Thereafter, the samples were diluted in three steps with sample dilution buffer  . This multiplexing method is based on sensitive covalently coupled magnetic beads. Firstly, standards, blank, and samples were added to the appropriate wells of a 96-well assay microplate. Subsequently, the capture beads were applied to each well and incubated while protected from light for 1 h. Next, the microplate was washed three times using a diluted assay buffer. The detection antibodies were applied to each well, and then the plate was incubated again for 1 h. After addition of streptavidin–phycoerythrin (SA–PE) solution, subsequent incubation, and a series of successive washes, the resuspended beads were added to each well and shaken for 30 s. Finally, the levels of the selected parameters were determined using the Bio-Plex 200 System . The Apo concentrations were calculated with consideration of the appropriate standard curve.Before performing the multiplex assay, the sample dilutions were prepared following the manufacturer’s protocol. The serum samples were centrifuged at 1000× t-test test . Spearman’s rank correlation coefficient was used to correlate results between selected parameters. Optimal cutoff points and determination of the diagnostic value of apolipoproteins were evaluated using the ROC method. The association between Apo levels and the independent variables was established using multivariate regression models. The results were considered statistically significant with a p-value < 0.05.The data are presented as mean ± standard deviations (SD). Statistical analysis was conducted using GraphPad Prism 8.2.1. software . The normal distribution of the values was assessed by the Shapiro–Wilk test. Statistical comparisons were performed with the non-parametric Mann–Whitney U test  or the parametric In conclusion, this study showed that patients with childhood ALL and history of anticancer treatment are at high risk of the development of alterations in their Apo profiles. Moreover, the composition of Apo-A1, Apo-A2, and Apo-D was discovered to be notably changed in ALL survivors compared to the normal-weight, healthy individuals. Furthermore, we found a significant correlation between increased BMI and elevated Apo-C1 concentration in patients with a history of anticancer treatment targeting ALL. It should be noted that this is the first study to reveal that apolipoproteins—specifically, Apo-A1, Apo-A2, Apo-C1, and Apo-D—might constitute valuable biomarkers of metabolic imbalance, which could be used for the long-term prognosis of the development of overweight and obesity among ALL survivors. The possibility that abnormal Apo composition may lead to the onset of MetS—including significant weight gain, hypertriglyceridemia, and hypercholesterolemia—cannot be excluded; therefore, systematic follow-up for this condition is necessary in this population. Considering the role of the changed Apo composition in the development of MetS among children after ALL treatment, we believe that this paper, at least partially, highlights the importance of long-term prognosis of the occurrence of metabolic complications that are directly associated with anticancer treatment for hematological malignancies.