Early onset sepsis (EOS) in preterm infants is associated with high morbidity and mortality. Improved characterisation of the haemodynamic presentation of EOS could lead to more effective and targeted treatments.We performed a retrospective observational study of preterm infants ≤32 week' gestation with EOS between 2010 and 2020 and gathered clinical, haemodynamic and echocardiographic data.Of the 2198 admitted infants, 27 infants  developed EOS with predominantly gram‐negative pathogens and the overall mortality rate was 33.3%. Besides hypotension, clinical signs were non‐specific, and over half of infants were normotensive in the first 72 h of life. Those with hypotension received more fluid resuscitation, inotropic support and had a higher mortality compared to the normotensive infants. Cardiac ultrasound was available in 18 infants and commonly revealed higher as expected cardiac output, pulmonary hypertension and diastolic dysfunction.Preterm infants with EOS had a high mortality rate, especially when they progressed from sepsis to septic shock. Echocardiography revealed a normal haemodynamic pattern, or one suggestive of vasodilatation and warm shock physiology. Targeting this pathophysiology earlier might improve outcomes. Perinatal infection is a primary cause of neonatal death in Australia and world‐wide.In particular, early onset sepsis (EOS) in preterm infants is associated with a high mortality.Recognition of clinical sepsis in this group is challenging.The clinical signs of preterm infants with EOS were difficult to distinguish from other causes of transitional hypotension.Preterm infants with EOS did not present with a haemodynamic pattern of vasoconstriction and cold shock physiology, but blood flows were higher as expected for post‐natal age and suggestive of warm shock.Targeting this pathophysiology with judicious fluids and vasoactive agents earlier might improve outcomes.To identify septic shock early, a cardiac ultrasound in the first 6 h of life could be considered in preterm infants with risk factors for EOS, irrespective of clinical examination findings.Early onset sepsis (EOS), or culture‐proven infection occurring at less than 72 h of age, is a major cause of morbidity and mortality in neonates. Studies have shown that those most at risk are very premature and/or very low‐birthweight infants. These high‐risk infants have an EOS incidence rate of 13.5 per 1000 live‐born very preterm infants,We performed a retrospective observational study in the neonatal intensive care unit of John Hunter Children's Hospital, Newcastle, New South Wales, Australia between 2010 and 2020. Our hospital is a tertiary‐care centre which has approximately 4000 deliveries per year. In addition to this, there are 11 rural birthing units as well as 6 large regional hospitals in the region that refer to unwell newborns. The study was approved by the local ethics committee.Eligible infants included those born at or below a gestational age of 32 weeks with EOS, which was defined as a positive blood or cerebrospinal fluid bacterial culture within the first 72 h of life. Infants who developed sepsis outside this time window or those with significant congenital heart disease or other birth anomalies were excluded from the study.Interpretation of cultures was as follows: a ‘positive’ culture was defined as single growth of pathogenic bacteria from blood or cerebrospinal fluid in a symptomatic infant, while a ‘contaminant’ culture was defined as single growth of coagulase‐negative staphylococcus, micrococci or other non‐pathogenic species with repeat negative culture within 48 h in an asymptomatic infant. Cultures demonstrating mixed growth in a symptomatic infant could be considered a ‘contaminant’ based on the opinion of the treating neonatologist as documented in the notes.Electronic medical records from eligible infants were reviewed. Extracted data included maternal and birth records, clinical examination, microbiological results, interventions and outcomes. Due to the dynamic nature of EOS and the transition from fetus to newborn, some of the data were serially collected over seven time intervals or epochs within the first 72 h of life .Cardiac ultrasound performed in the first 72 h after birth were analysed to calculate blood flows , left ventricular systolic function  and left ventricular diastolic function . Persistent pulmonary hypertension of the newborn was explored by reviewing tricuspid valve regurgitant jet velocity, shunt direction over the ductus arteriosus and ventricular septal flattening.Hypotension was defined as a mean arterial pressure in mmHg less than gestational age in weeks for more than 15 min. For the purpose of this study, septic shock was defined as clinical poor perfusion, hypotension or cardiovascular dysfunction on ultrasound requiring treatment  in the presence of sepsis.Local management of septic shock in our unit at the time advocated early fluid expansion . In fluid‐refractory cases, a vasopressor agent such as noradrenaline or dopamine was recommended. Dosing was titrated based on the clinical picture provided by physical examination, blood pressure monitoring and cardiac ultrasound when available.P value < 0.05 was considered significant.Descriptive data was gathered and analysed in Microsoft Excel. Data were graphically represented using GraphPad software  and one‐way ANOVA with multiple comparisons  was used to explore changes over time and a Staphylococcus (1), Micrococcus species (3) and viridans streptococcal species (2) that were deemed contaminants. Twenty‐seven infants (12.2 per 1000 live preterm born) with positive blood cultures were included in the final analysis.2198 infants born ≤32 weeks' gestation were admitted to the unit during the 10‐year study period. Thirty‐three blood cultures were positive within the first 72 h of life in this group, and 6 blood cultures grew coagulase‐negative Escherichia coli (12), followed by Haemophilus influenzae (4). The common gram‐positive pathogens were Group B streptococcus (3) and coagulase‐negative Staphylococcus (3). Other cultures included methicillin‐sensitive Staphylococcus aureus and Streptococci species.The antenatal and birth characteristics are presented in Table F = 5.75, P < 0.001). Significant tachycardia (>200 bpm) was seen in one infant in the first 6 h of life who received dopamine during this period. Median lactate values over the first 72 h of life ranged between 2.0 and 3.0 mmol/L  and the maximum lactate recorded was 19.0 mmol/L. The median ranges for systolic blood pressure, diastolic blood pressure and mean blood pressure were 42–51, 24–31 and 29–37 mmHg, respectively. Only systolic blood pressure changed significantly in the first 72 h after birth .The clinical signs in the first 6 h after birth were either non‐specific, or described respiratory deterioration and hypotension with or without poor perfusion. Figure A slight majority of the infants with EOS  were normotensive in the first 72 h of life. However, four were deemed to have clinical poor perfusion and received fluid treatment. Eleven infants (41%) developed sustained hypotension during the study period and received treatments. Ten of the 11 hypotensive infants received fluid boluses at a median (IRQ) volume of 30 (20–43) mL/kg and 7 infants received cardiovascular support with inotropes or vasopressors for septic shock, most starting within 24 h after birth. One infant received vasopressors for pulmonary haemorrhage on day 3.Eighteen out of 27 infants (66.7%) had an echocardiogram performed at a median of 25 h (range 4–42) after birth. The infants who received a cardiac ultrasound tended to be more unwell. The cardiac ultrasound parameters are presented in Table The overall mortality rate in this cohort was 33.3%. Four infants died before 72 h and five died after 72 h. One normotensive infant died from pulmonary haemorrhage. Eight of the 12 hypotensive infants died, representing a mortality rate of 66.7% in this subgroup. An individual patient overview of clinical findings, cardiac ultrasound findings and outcomes are presented in Table in‐utero and the individual host response, whereby the initial host response is vasodilatation and warm shock physiology. Only when this cannot be maintained cold shock will follow, similar to sepsis pathophysiology in adults.Various observational studies have assessed the haemodynamic response to LOS but few provided descriptive evidence of the haemodynamic presentation, clinical course of EOS and the progression to septic shock in this vulnerable age group.Recognition of clinical sepsis is one of the main pillars to help reduce mortality in sepsis.In our cohort, 59% of preterm infants with EOS progressed from sepsis to septic shock and this was associated with a significant increase in mortality. Considering the high mortality and the difficulty in diagnosing EOS clinically, one could argue that all preterm infants with risk factors for EOS should undergo routine assessment of vasodilatory changes, either with cardiac ultrasound or with alternative methods such as near‐red infrared spectroscopy.The approach of early diagnosis of sepsis phenotypes and earlier targeted interventions has led to improved outcomes in adults with septic shock.Our data showed that 1/3 of infants with EOS did not receive a cardiac ultrasound. Training and accreditation of bedside clinicians using this monitoring technique have increased in the last decade, but it remains difficult to provide around‐the‐clock cover in the neonatal setting. Given the limited time window and frequent haemodynamic changes in septic shock, there is a pressing need for more on‐site staff with bedside cardiac ultrasound skills. One proposed model of care might be to use on‐call neonatal experienced cardiac ultrasonographers. This model of care will likely lead to more general acceptance of integrating cardiac ultrasound findings into sepsis management. Developing a local cardiac ultrasound service will allow a collection of real time, longitudinal point of care information, assisting the clinician to understand the cardiac function and hemodynamic changes. This in turn allows targeting of cardiovascular support and monitoring of the response to treatment.There are several limitations to this study. This retrospective observational study gathered clinical and haemodynamic data from the medical records. Despite our high standard of medical documentation in our unit, we acknowledge the possibility of incomplete data impacting results. Secondly, few serial echocardiograms were performed and not in all patients which could also impact conclusions. Despite this, our data suggest that very preterm infants with EOS present with either warm shock or no symptoms of shock at all. Careful review with serial cardiac ultrasounds can help reveal early signs of septic shock, and earlier treatment needs further evaluation to help reduce the high mortality of EOS in very preterm infants.Preterm infants with EOS have a high mortality, expecially when progressing from sepsis to septic shock. Echocardiography can help phenotype sepsis and guide treatments.


This study aimed to investigate midwives’ experiences of and perceptions about mother–baby separation during resuscitation of the baby following birth.A qualitative study was conducted using an author-designed questionnaire. Fifty-four midwives from two Swedish birth units with different working methods regarding neonatal resuscitation – at the mother’s bedside in the birth room or in a designated resuscitation room outside the birth room – completed the questionnaire. Data were analyzed using qualitative content analysis.Most midwives had experience of removing a newborn baby in need of critical care from the birth room, thus separating the mother and baby. The midwives identified the difficulties and challenges involved in carrying out emergency care in the birth room after birth and had divergent opinions about what they considered possible in these birth situations. They agreed on the benefits, for both mother and baby, in performing emergency care in the birth room and avoiding a separation altogether, if possible.There are good opportunities to reduce separation of mother and baby after birth; training, knowledge, education and the right environmental conditions are important factors in successfully implementing new ways of working. It is possible to work towards reducing separation and this work should continue and strive to eliminate separation as far as possible. Skin-to-skin care also promotes initiation of breastfeeding and babies tend to breastfeed for longer when on SSC immediately after birth2. Furthermore, SSC enhances mother–baby bonding2 and the physiological and psychological benefits of SSC have health advantages for the baby and the mother, in the short-term and long-term3. The World Health Organization (WHO) as well as the United Nations International Children’s Emergency Fund (UNICEF) recommend providing SSC immediately after birth5.The practice of skin-to-skin care (SSC) immediately after the birth of a healthy newborn baby is today standard care in many countries worldwide and it is well known that SSC promotes a more stable heart activity and enhances oxygen saturation in the newborn, as well as leading to less crying4. Despite this, Tasseau et al.6 found that many healthy newborn babies are separated from their mothers during the first two hours after birth, mainly for routine care. Separation can be caused by maternal factors where emergency care is needed, such as major postpartum hemorrhage or when the mother needs a surgical procedure in an operating theatre. Separation can also be due to factors necessitating neonatal resuscitation. The psychological effects of separation of mother and baby immediately after birth may include experience of being deprived of the first hours together and may disturb and postpone bonding7.Separation of the mother–baby dyad should be performed only when medically indicated9. When needed, neonatal resuscitation following birth can be performed on a neonatal resuscitation table, either at the mother’s bedside (termed ‘motherside resuscitation’) in the birth room, or in a room next to the birth room designed for neonatal resuscitation. Motherside resuscitation has been found to be valued by parents; it allows parents to see and touch their baby, and to observe what the clinical team is doing10. Further, it enhances an opportunity for early contact and involvement as it allows the parents to share the first moments of their newborn baby’s life11. Also, motherside neonatal resuscitation care allows the other parent to be both with the baby and the mother. In general, parents who have had the experience are positive to motherside neonatal resuscitation and do not regret having been present, despite strong emotions while watching their baby being resuscitated11. To avoid separation between mothers and babies after birth requires system changes including planning and organization of care, equipment, and design of units12.Neonatal resuscitation involves emergency care of a seriously ill/preterm baby after birth. Recommendations are available to guide caregivers on the structure of resuscitation actions10.A qualitative interview study reported that clinicians had some concerns regarding motherside resuscitation related to being observed closely by the parents. It described, however, that most of the interviewed clinicians were positive to motherside resuscitation13. However, considering the positive effects of non-separation of the newborn baby and the mother, it is important to further investigate midwives’ attitudes to neonatal resuscitation in different settings. Therefore, the aim of the present study was to investigate midwives’ experiences of and perceptions about baby–mother separation during resuscitation of the baby following birth.Regarding midwives’ experiences of and perceptions about baby–mother separation during resuscitation of newborns, one survey study reported that midwives in a Canadian hospital setting were reluctant to carry out motherside resuscitation because of practical and organizational obstacles14 to gain an increased understanding and knowledge regarding midwives’ experiences of and perceptions about mother–baby separation when the baby needs to be resuscitated after birth.This survey combined qualitative and quantitative dataThis study was conducted at two Swedish birth units (herein referred to as unit A and unit B) that are organized in different ways regarding neonatal resuscitation. At the time of the study, there were 46 birth units in Sweden and anecdotally practice differs among them regarding initiating neonatal resuscitation at the mother’s bedside on a designated table or while on SSC in the birth room, or in a designated resuscitation room outside the birth room. Further, no data on place of resuscitation in these units is available.At birth unit A, the newborn baby’s health is assessed by the midwife and evaluated for signs of respiratory disorder. If resuscitation is needed, SSC is stopped, and the baby is taken to a separate room with a radiant warmer where evaluations and resuscitation can be performed. The midwife always puts on an identity band on the baby before cutting the umbilical cord. At birth unit B, midwives, neonatal nurses, and neonatologists have for more than two decades performed neonatal evaluations and resuscitation in the birth room without separating the baby from the mother (motherside resuscitation). Some measurements, such as oxygen flow rate and oxygen saturation, are performed while on SSC on the mother’s breast, if possible, otherwise on a radiant warmer at the mother’s bedside, inside the birth room.Inclusion criteria were all midwives (n=81) working in birth units A and B; exclusion criteria were others working at the units, such as physicians and assistant nurses.13. To ensure content validity, the questions were pilot tested on four registered nurses and midwives working at a neonatal intensive care unit, but with experience of baby resuscitation both inside and outside the birth room. Thereafter, small adjustments were made. The questionnaires were in Swedish and contained a total of 16 items; six questions with fixed answer alternatives and ten open-ended questions. The questions with fixed answers concerned the midwives’ age and number of years in the profession, and questions such as whether they had ever participated in the resuscitation of a newborn baby, either on a resuscitation table in the birth room or SSC (yes/no question). The open-ended questions related to the midwives’ own experiences of situations such as taking a newborn baby out of the birth room to an emergency room or giving a baby initial assistance to support breathing immediately after birth. The open-ended questions also asked how the midwives felt about initial respiratory support for a newborn baby while on SSC or on a resuscitation table elsewhere in the birth room, as well as about the midwives’ opinion of advantages and disadvantages of referring a newborn baby to an emergency room versus neonatal resuscitation while on SSC or elsewhere in the birth room.The questionnaire was designed by the authors, based on their clinical experience and knowledge from current researchAll midwives who worked in the two birth units received oral and written information about the study from the head midwife, including an invitation to participate by answering the questionnaire (either on paper or as a web survey).15. Permission to perform the study was obtained from the medical directors and head midwife of the two birth units. The midwives received written information about the aim of the study, including the assurance that their participation would be voluntary and that they would have the right to withdraw at any time without giving any explanation. Anonymity was assured as the questionnaires were uncoded and the participants answered anonymously.This study was performed in accordance with the ethical standards of the Helsinki Declaration16. All answers to the open-ended questions were analyzed together and the analysis focused on finding similarities and differences in the text related to the study’s aim. As a first step in the analysis, meaning units were identified in the text; thereafter, the meaning units were given codes serving as titles for separate meaning units describing their contents. Categories were established by searching for similarities and differences in the codes and the text. The entire analysis took place in Swedish before everything was translated into English in connection with the manuscript writing. During the analysis process, the authors together reflected on and discussed the interpretation of the data.Qualitative data collected were analyzed using content analysis, as described by Lindgren et al.The quantitative data were analyzed with descriptive statistics, using SPSS  software.A total of 54 (67%) midwives completed the questionnaire, 36 (67%) from birth unit A and 18 (33%) from birth unit B. Their ages ranged 28–68 years (mean: 44), and they had worked as midwives for 1–42 years (mean: 13).The qualitative content analysis resulted in four categories  regardinIn all, 45 (83%) of the midwives stated that they had on some occasion separated mother and baby and taken the baby to a resuscitation room . There wAccording to responses to the open-ended questions, the reasons why the midwives chose to take a newborn baby out of the birth room included low Apgar score, the baby’s need for respiratory support, and critical illness of the baby, necessitating advanced care with help from the neonatal intensive care unit. Some midwives said that one reason for taking a baby to the resuscitation room was that the baby was expected to be in a bad condition, for instance when the baby was born preterm. One participant also mentioned that pediatricians sometimes request that a baby be taken to the emergency room for a specific reason.The midwives from birth unit B stated that they do not take newborn babies out of the birth room because the radiant warmer is located inside the birth room. They recalled a few isolated cases where a baby did need to be taken out of the birth room and separated from its mother and said that the most likely reason was that it was known before the birth that the baby would need neonatal care. Overall, the midwives expressed that in cases where there has been a normal pregnancy and birth, and where the mother is healthy and the baby is expected to be healthy but is tired after birth, they choose to wait and see, before taking the baby to a resuscitation table. They also described that they generally choose to wait for a baby to have normal tonus or pulse, and for cutaneous stimulation to take effect. One midwife stated that they also choose to wait and see when a baby is born preterm; she added that in such cases, the placental transfusion is extra important:‘Begin with cutaneous stimulation first to see if the baby is recovering within a reasonable time. If it does not go in the right direction, I cut the umbilical cord and take the baby out of the birth room, but I always try to give the baby a chance first.’Of the midwives, 21 (39%) had, at some stage, performed neonatal resuscitation in the birth room, and 7 (13%) had carried out resuscitation on SSC with the mother . Based o‘… If the conditions are met, I think that resuscitation can be done with the parents in the birth room.’In unit B, the routine for a long time has been that newborn resuscitation is performed in the birth room provided there is sufficient space. Answering the question about resuscitation of the baby during SSC with the mother, the midwives in unit B identified which procedures can be performed with the baby on SSC on the mother’s chest and which need to be done on the resuscitation table in the birth room. They described that initial respiratory support often occurs on the mother’s chest, and that even more advanced care, such as cardiac compressions, can be performed on the mother’s chest while on SSC. Intubation and umbilical catheterization were considered by many to be too complicated to perform while on SSC; these procedures, they said, should rather be performed at the mother’s bedside, but still in the birth room.According to the midwives, severe complications such as retained placenta took precedence over providing immediate care for the baby when on SSC with the mother. Sometimes, on the other hand, the mother’s need for care may be forgotten if the focus is on the care of the baby. In such situations, it may be difficult for a midwife to simultaneously care for both the baby and the mother, and to prioritize the care:‘If the mother herself needs urgent help, for example if she is bleeding a lot or if the placenta is sitting and you need to press the mother's stomach [uterus] while at the same time ventilating the baby lying there, this can delay the mother's care and make it difficult.’One thing the midwives highlighted was a lack of space in the birth room when a lot of staff were present, which could mean difficulties in getting a good working position and at the same time ensuring a good position of the baby to achieve effective ventilation. Lack of space was also perceived to pose a medical risk to the mother if in need of urgent care. Some suggested transferring the baby to a resuscitation table in the birth room in the event of the mother having an acute complication.Some midwives described how a mother can feel exposed and uncovered in connection with birth. During resuscitation of the baby, there can be many people inside the birth room, which could make the mother feel uncomfortable. Some midwives also expressed the importance of being attentive to the mother’s/parents’ wishes regarding whether the resuscitation of the baby should take place in another room instead of inside the birth room:‘… She can feel naked and vulnerable with many people around her. It is important to think about the [mother's] integrity and that she may need to “land” for a little while. Many women need that.’Resuscitation of the baby can be traumatic and scary for parents. The midwives described how the situation can be perceived as chaotic, where stressed staff are unable to provide support to the mother. They realized that a mother may experience fear that her baby will not survive and that she may feel inadequate as a mother. They concluded that resuscitation at the mother’s bedside may not be suitable for all mothers and families:‘Although I think many parents experience it as positive, I think it will stress others. I think it can lead to parents feeling that they are not enough, like they should be doing something …’In a resuscitation situation, parents who become worried and scared can distract staff from their focus on the baby and prevent them from working undisturbed. Many of the midwives suggested that certain staff should be dedicated to supporting and informing parents during the resuscitation process:‘Sometimes it is easier to work only on the baby without needing to inform the parents [about the procedure]. Then you can focus 100% on the baby.’Several of the midwives proposed that greater emphasis should be placed on midwives’ education and practical training to enable optimal care of the baby. The training of neonatal staff should also be intensified. Performing SSC breathing support on the mother’s breast, for instance, requires that the baby be held in a good position to optimize ventilation of the lungs. If this is not carried out properly, there may be a delay in the effect. The clinical service column in the birth room is located next to the birth bed, which, according to the midwives, enables quick interventions that would be delayed if the baby were transferred to an emergency room:‘The use of the equipment because “it is there” makes an emergency easier to deal with than if you had to wait for a minute to …’Several additional challenges of providing emergency care were mentioned. The midwives said that staff who do not adhere to the unit’s way of working, because they do not agree with the working method, can actually counteract the care. They also described concerns that collaboration with the staff at the neonatal intensive care unit could pose a problem. Further, they said that, at a resuscitation table, all the equipment is in place, but in the birth room, the equipment may be difficult to access or may not even be present in the room, which was described by some of the midwives in unit A. One midwife said that there was a risk of the baby falling to the floor in connection with the emergency care:‘[Neonatal staff] only see disadvantages in the form of this being “new” while we as midwives, we can do something constructive when we're not comfortable with a situation. More education and better collaboration are needed to make it work.’Introducing a new working method and new routines for emergency care entails a major reorganization in which it becomes important to collaborate with, and allocate work to, team members. Moreover, functioning technical equipment is a prerequisite, and so is the training of staff.Many of the midwives believed that there are no disadvantages, for the newborn baby, in performing emergency care on the mother’s breast or on a resuscitation table inside the birth room. When a baby is resuscitated in the birth room, it is possible for it to remain on SSC with the mother, according to several of the midwives. This gives the baby security, a connection, and warmth, and leads to improved breathing, faster recovery, good blood glucose levels, and a calmer baby. However, the midwives had differing opinions about what is of benefit to the baby. One midwife said that the benefits of a baby receiving resuscitation at the mother’s bedside were not clear, while another believed that some SSC can be maintained even outside the birth room if one parent is standing next to the baby. The fact that the baby can hear its parents’ familiar voices, which increases its feeling of safety, was also considered positive. Late cord clamping and sustained placental transfusion were seen as an advantage for the baby, as they would result in increased blood flow and a higher hemoglobin value in the long run. Some midwives answered the question about late cord clamping, saying that it gives better oxygen saturation and a faster recovery. One midwife also highlighted the benefit of late cord clamping to preterm babies, saying that it increases their survival rate.Most midwives considered it positive for the mother if resuscitation of the baby took place inside the birth room. It allowed the mother to feel more present with what was happening to her baby and what measures were being taken to help it. Obtaining direct firsthand information about the baby in this way, and thus avoiding uncertainty, was considered to increase security for both the mother and her partner. Participation in care and the increased security of not having to be separated from the baby were also described by many to improve the connection between the mother and her child, and to facilitate breastfeeding. Being present when the baby recovers, and then being physically close, was likewise considered positive:‘Not to be separated from their baby, to be able to see what is being done and what is happening … get the opportunity to be involved when the baby picks up and utters its first cry.’Many midwives thought that taking care of the baby in the birth room, and thus avoiding separation, reduces the traumatic experience that the baby is unwell and needs help to survive. The separation that occurs when the baby is transferred from the birth room was considered by some midwives to be more traumatizing than seeing what happens. Unrealistic notions about emergency care may then result. Further, when the partner follows the baby out of the birth room, this can, according to some midwives, reduce the feelings of security of the mother who remains behind. When both parents are present in the birth room, they have the opportunity to process the event together post-intervention and may not feel the need to question the procedure at a later point.11.This study is, to the best of our knowledge, the first to illuminate midwives’ experiences of, and perception about, mother-baby separation during resuscitation of the baby following birth. The experience of separating the mother–baby dyad, by taking the newborn baby out of the birth room when emergency care is needed, was described by most of the included midwives. However, it was clear that in unit A where resuscitation was performed outside the birth room, midwives saw fewer benefits for the mother and baby. In organizations where separation is the norm, either because of cultural norms or for physical reasons (e.g. lack of space in the birth room), midwives might continue to practice cessation of SSC and separate mother and baby as motherside resuscitation is considered more difficult to perform compared to resuscitation in a separate room. This has also been highlighted in a cross-sectional descriptive study where some midwives described disadvantages of motherside resuscitation in hospital settings, primarily related to ergonomics and the resuscitation setup limiting adequate access to the infant with the cord intact17.The impact of the physical features of the birth room on the care provided following birth was described in the present study. For instance, the midwives mentioned that lack of space can lead to a suboptimal working position and can thus make it difficult to keep the baby in a good position when ventilation is performed while on SSC. Some felt that lack of space entailed challenges that made it difficult for staff to perform the emergency care in the birth room. The midwives also described the risk of forgetting the mother’s care needs. They emphasized the importance of respect for and responsiveness to the parents’ questions and requests, partly for the integrity of the mother, but also so that the family’s wishes regarding the care intervention were met. This was seen as difficult and as requiring experience and training for it to be performed properly2. Despite the consequences of separating mother and baby, the midwives in the present study demonstrated a difference in regard to the care culture, and mother–baby separation, between the two included units. The size of the rooms was equal in units A and B, but routines and working methods differed. Some of this difference was due to how the units were differently designed, mainly regarding where the resuscitation table was located. In unit A, the organization of newborn emergency care was not in accordance with best evidence, and as a result, staff at this unit continued to separate the mother–baby dyad. A recent study reports that motherside resuscitation is possible when wanting to make care as optimal as possible for the newborn baby and the mother18. To separate the baby from its mother must never jeopardize medical safety. Before motherside resuscitation is possible, the rooms must be rebuilt to make this possible. To not separate is of huge importance, but the care must be medically safe, both for the baby and the mother, and all necessary equipment inside the delivery room must be there so that resuscitation can be possible, without delays. This would be best practice.It has previously been reported that separation interferes with optimal care for the newborn baby19. It is well known that it can be difficult to change practice in well-established organizations and that the success of implementation of new working methods is dependent on behavior change among the healthcare personnel, such as the midwives in our study20. Therefore, translating research evidence into practice is not easy, but the midwives who work with the mothers and babies have a central role in this process. Winston Churchill once famously said, ‘We shape our buildings, and afterwards our buildings shape us’. Perhaps it is the same with emergency care of a baby after birth: if we build new birth units where all resuscitation can be performed motherside, this will change the midwives’ working methodology and their knowledge about, and attitudes to, this procedure. A new working methodology and new work routines also present challenges for the healthcare personnel. As Porter and Macintyre21 remark, women tend to assume that whatever system of care is provided has been well thought out and is therefore likely to be the best one and where they express a preference, it is generally for whatever arrangements they have experienced rather than for other possible arrangements.Many factors influence midwives’ decisions when a newborn baby is critically ill following birth, experience and intuition are important factors in this decision-making process, and, if clinical practice and guidelines are changed, the decision-making will be considerably affectedFurther, change of practices need to be supported by all members of the multidisciplinary team , not just the midwives. This will require education and support from, and for all, stakeholders.2. However, contemporary childbirth/neonatal care should be family-centered as well as evidence-based. To justify separation at birth by highlighting the need for resuscitation should no longer be accepted. A growing body of evidence reports that intact cord resuscitation supports the process of physiologic neonatal transition and is beneficial for non-vigorous newborn infants23. If motherside resuscitation cannot be practiced for maternal reasons, specially designed equipment or trolleys can facilitate resuscitation, in the same room, with the placental and cord circulation intact18.The practice of separating mother and baby has been the custom for many decades, since the introduction of incubator care and the use of infant formula13 discuss whether the midwifery perspective, that separation should only be performed if there is compelling evidence, means that midwives prioritize evidence differently from other care providers when considering policies and procedures. In line with the opinion of several of the interviewed midwives, it has been emphasized elsewhere that the midwife should strive for zero separation and promote SSC after birth wherever possible2. The results of the present study show that unit B managed to achieve zero separation to a greater degree than did unit A, partly because there is no resuscitation table in the birth rooms in unit A, and mother and baby may therefore need to be separated to perform emergency care of the baby.It was also described in the present study that the midwives who had experience of taking compromised babies to the emergency room, sometimes awaited urgent decisions and actions when they felt that the baby was recovering. Fulton et al.24. When a mother is separated from her newborn baby, she may experience being deprived of the first minutes with the baby, which can make bonding more difficult7. Separation can be traumatic for the mother just as for the baby, since it involves an imposed stress, which in turn can affect the baby’s brain development25. The midwives expressed that if the parents were present at the resuscitation table this could enhance bonding; however, it was also suggested that parents when witnessing resuscitation of their newborn may experience it as traumatic. Previous studies have addressed this and report that parents are generally positive about witnessing resuscitation. Knowing what is happening and seeing the staff doing their best can comfort them. Also being able to touch and see their baby can make them feel involved, as a family, in the first moments of their baby’s life11. However, further investigation of mothers’ and parents’ perceptions of what they think is beneficial for babies/mothers/parents in regard to mother–baby separation during resuscitation of the baby following birth, is warranted.The midwives in both units agreed that separation of mother and baby after birth should be kept to a minimum, which is reinforced by research that shows that SSC and, therefore, no separation, is an important part of the newborn’s transition to extrauterine lifeIn this study, we invited all midwives working in units A and B to participate, aiming to include all midwifery experiences, both positive and negative. This strategy has given breadth to the findings, which is a strength of the study. On the other hand, the study did not include, for example, nurses from the neonatal ward. Including them might have given a wider perspective on the work towards reducing separation between mother and baby after birth, as nurses are a staff group involved in neonatal emergency care that could be started both inside and outside the birth room.14.The questionnaires were sent to 81 midwives in unit A and unit B and the response rate was lower in unit B than in unit A. The reason for the lower response rate in unit B is unknown as the midwives did not have to give a reason for not wanting to participate. The assurance that they would participate anonymously gave the participants a greater sense of security when responding to questions and therefore possibly resulted in more honest answers, as responses could not be traced back to a specific midwife. The answers tended to be brief and curt, which made the analysis challenging. Short sentences and single words can mean lost information, which can lead to misinterpretation. An interview method would have provided the opportunity for follow-up questions, possibly leading to more detailed answers. The study is based on both quantitative and qualitative data, an approach that contributes to a wide range of findingsContinuous education and training are needed to respond to midwives’ concerns and uncertainty about new working methods and routines. If this education and training is not provided, anxiety may prevent the midwives from carrying out emergency care in the birth room, which may mean that they instead choose to transfer the baby to the emergency room and thus separate mother and baby. Further, this education and training needs to include all team members who care for mother and baby at birth , not just midwives. Different conditions prevail in the neonatal units in Sweden regarding resuscitating a newborn inside the birth room, including the possibility of having video surveillance as well as space for resuscitation tables in some, but not all, of the birth units. Therefore, the care is not equal. To achieve equality, all birth units should be evidence-based. They should aim to reduce the separation between mother and baby after birth as far as possible. To broaden knowledge about the cooperation with other health professionals in the birth room, further research may be needed.There are good opportunities to reduce separation of mother and baby after birth; training, knowledge, education, and the right environmental conditions are important factors in successfully implementing new ways of working. In a birth unit where separation is the norm, midwives might continue to practice cessation of SSC and separate mother and baby, as motherside resuscitation is considered more difficult to perform than resuscitation in a separate room. It is important that birth units carefully think through and plan for their approach to neonatal emergency care, including separation or not of the mother–baby dyad.


It is rarely seen that neonates with congenital macrocystic lung malformation (CMLM) presenting with respiratory distress require emergency intervention. No consensus has been achieved concerning the best policy facing such condition. This study aims to evaluate the efficacy and safety of our strategies in treating neonates with CMLM presenting with respiratory distress.We retrospectively reviewed the data of six neonates with CMLM presenting with respiratory distress from April 2020 to October 2022 for whom drainage-prior-to-surgery strategy were adopted and favorable outcomes were obtained. The relevant data was reviewed and analyzed.All the patients were prenatally diagnosed with congenital lung malformation and postnatally as congenital macrocystic lung malformation via CT scan. Each neonate accepted percutaneous thoracic catheter drainage prior to surgery. The first and fifth neonates with macrocystic lung mass experienced prompt open lobectomy and delayed thoracoscopic surgery due to failure of air drainage, respectively. The other four patients obtained good drainage of the large air-filled cyst, thus gaining the opportunity for elective thoracoscopic surgery within median 45 days.For neonates with macrocystic lung malformation presenting with respiratory distress due to mediastinal compression, percutaneous thoracic catheter drainage is worth a shot for elective thoracoscopic surgery due to its feasibility and safety. The majority of children diagnosed with CPAM are asymptomatic at birth, and elective pulmonary resection beyond the neonatal period is recommended and associated with favorable outcomes –5. In ad2.2.1.A retrospective chart review was performed to evaluate the congenital macrocystic lung malformation (CMLM) neonates presenting with respiratory distress in the Department of Pediatric Surgery, West China Hospital, Sichuan University, from April 2020 to October 2022. The study was approved by the Research Ethics Board of Sichuan University West China Hospital. All subjects participating in the study gave written informed consent. We included prenatally diagnosed CMLM neonates presenting with progressive respiratory distress after birth due to mediastinal shift and lung compression caused by large space-occupying lesions. We excluded those with concomitant diseases that can also cause respiratory distress, such as pneumonia, congenital cardiac anomalies, and upper respiratory tract obstruction. Medical and operative records were retrieved for data analysis. Patient data including sex, weight, Apgar score, lesion size, CPAM volume ratio(CVR), timing of respiratory distress onset, age at PTCD, age at surgery, surgery type, time to discharge after surgery and complications were extracted and analyzed. Postoperative complications were defined as pneumothorax, tube dislodgement, failure to drain, broncho-pleuric fistula, persistent air leak (≥7 days), major bleeding, and subcutaneous emphysema.2.2.2.2.1.After lidocaine infiltration a pigtail tube was used through Seldinger manoeuvre, based on preoperative CT scan images. Success of the PTCD maneuver was defined as continuous drainage of trapping air from the lung cyst via the tube, and complete relief of respiratory distress was obtained (SpO2 increase to above 95% without pure O2 uptake). Failure to drain included (1) tube was placed in pleural cavity rather than in large cyst and (2) Tube was placed in the cyst not connecting to the bronchi. At this time, another attempt was reasonable. Thoracoscopic lobectomy through the hilar approach was applied in elective surgery, and thoracotomy in emergency surgery. The details of lobectomy have been described in our previous study 3.2 could not be maintained above 95% by oxygen mask ventilation. Therefore, they promptly underwent PTCD on the first day after birth and obtained good drainage of the large air-trapping cyst  immediately after birth. Neonates (Case 1 and 5) seemed to respond well with respiratory support in the first one to two weeks and underwent first PTCD at d 19 and d 8, respectively. The remaining patients  presented tachypnea (60 times per min above) and the SPOing cyst , thus gaing cyst . This paing cyst . Pneumoting cyst , thetubeing cyst . HoweverCatheter dislodgement occurred 3 weeks after PTCD maneuver in case 2 and 3 days after PTCD in case 6, respectively. Replacement of chest tube were successfully performed and maintained for a few weeks. They all recovered well, and the relevant data are shown in 4.In fact, emergency thoracotomy worked as the most frequent intervention , 16–20 wIn the literature, PTCD was performed on a clinical basis with CT image navigation , 14 or un = 2), catheter displacement (n = 1) and failure to drain (n = 1). They reported pneumothorax occurred due to use of a non-pigtail catheter (chest tube or angiocatheter). Similar to the complications of PTCD reported above, Pneumothorax (n = 1), catheter displacement (n = 2), failure to drain (n = 2) and broncho-pleuric fistula (n = 0) occurred in PTCD using pigtail catheter in the current study. We noted that failing to drain both occurred in the two cases (case 1 and case 5), the former case had faster postoperative recovery than the latter one  even though open surgery was performed in case 1. Maybe the duration of respiratory distress prior to surgery (23 days vs. 36 days) could explain. We assume that the shorter the duration of respiratory distress was, the less impairment to the remaining lung was, the faster the neonate recovered, which needs to be verified in further study.Indeed, PTCD of a lung cyst is different from thoracocentesis to some degree. Most likely, the puncture needle can easily penetrate the cyst wall. However, the pigtail tube could fail to advance along the guidewire because the cystic wall is, unlike the thoracic wall, elastic and unfixed while it advances. Retrospectively, the failure of PTCD in case 1 could be attributed to this explanation. The puncture site, angle and adequate depth of advancement are of great importance. To avoid complications pertaining to lung injury, the puncture point should be a proper surface site to which the target cyst wall is mostly adjacent with the least lung parenchyma interposition between the inner thoracic wall and the cyst. The needle should be perpendicular to the cyst surface. Oh SH et al.  reportedMaintaining the chest tube after discharge needs careful parental care to avoid a significant number of severe complications. In this study, 2 babies experienced tube dislodgement, thus causing recurrence of respiratory distress. Fortunately, the respiratory symptom relieved again by reinserting another tube along the external opening of the fistula at the thoracic wall, which lasted couple of weeks prior to surgery. To a certain degree, we overestimated the parents' nursing abilities in securing the chest tube at home for a long time (4–8 weeks).Although Oh SH, et al.  reportedIt is worth mentioning that Cass DL and colleagues  reportedSeveral caveats regarding this study should be acknowledged. Firstly, this was a retrospective, single institution series with a relatively short follow-up period (median 18 months). Secondly, the study population was rather small due to the low morbidity rate. Thirdly, a lack of control will no doubt degrade the evidence level of this study. Last but not least, since the majority of neonatal units' standard policy is to remove the chest tube before discharge, the clinical algorithm mentioned in this study can not be referenced in many low and middle income countries. Despite these limitations, this was the first paper that exclusively delineated an algorithm of prenatally diagnosed CMLM that may cause respiratory distress after birth. Case control study with larger sample size is anticipated in the future.5.For neonates with macrocystic lung malformation presenting with respiratory distress due to mediastinal compression, percutaneous thoracic catheter drainage is worth a shot for elective thoracoscopic surgery in selected cases, which is deemed as a safer alternative to direct emergency thoracotomy.


Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages.In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway  to nationwide hospital data . Gestational age was categorised as 23–27, 28–31, 32–33, 34–36, 37–38, 39–41, and 42–44 completed weeks. The analyses were stratified by age at follow-up: 0–11 months and 1–5, 6–14, 15–29, and 30–50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk.Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28–31) and late preterm (34–36) to full-term (39–41 weeks), RRs  for hospitalisation for any infectious disease at ages 1–5 were 3.3 (3.0–3.7) and 1.7 (1.6–1.8), respectively. At 30–50 years, the corresponding estimates were 1.4 (1.2–1.7) and 1.2 (1.1–1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs.Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vaccinations and other prevention strategies should be investigated.10.13039/501100011769St. Olav's University Hospital and 10.13039/100009123Norwegian University of Science and Technology, 10.13039/501100005416Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, 10.13039/501100006306Sigrid Jusélius Foundation, 10.13039/501100005744Foundation for Pediatric Research, and 10.13039/501100004325Signe and Ane Gyllenberg Foundation. Birth before full-term is associated with higher infection risk in childhood, but it is not known whether this risk persists in adulthood. We searched PubMed using the keywords  AND “infection” AND  for articles in any language from its inception up to October 19, 2022. The search returned 1592 articles, of which 15 concerned admissions due to infectious diseases among infants and children. We did not identify any studies on gestational age related to hospitalisations for infectious disease among adults.The risk of admissions due to infections increased gradually with lower gestational age. The increased risk was most pronounced in childhood but persisted into adulthood, although the estimated gap between those born preterm and full-term narrowed with increasing age. Higher hospitalisation rates in adults born preterm were evident for any infection and for both respiratory tract infections and infections not related to the respiratory tract.Birth before full term is a risk factor for infections in childhood, adolescence, and adulthood. Future studies should explore potential mechanisms including the roles of early life development of the microbiome, the immune system, and respiratory organ function. Preventive measures like vaccination strategies should be tailored to high-risk preterm born. Meanwhile, current knowledge may be used to optimize hygiene habits and vaccination guidelines, and to reduce known modifiable risk factors for severe infections such as smoking and obesity.,Host factors, including modifiable factors and genes, are increasingly recognised as important risk factors and targets for the prevention of infections.,Worldwide, 15 million babies are born preterm every year, and complications following preterm birth are the leading cause of death in children aged <5 years, causing 1 million annual deaths.in utero, and immune responses continue to develop after birth and are influenced by environmental exposure, which may differ according to the length of gestation. Thus, birth before full term may disturb the long-term immune response to infection.Recently, infections were identified as the primary cause of excess hospital contacts in children born preterm in the UK, pointing to a research priority on preventing infections in this group.Given the known link between preterm birth, alterations in the immune system and childhood infections, we hypothesized that this association persists into adulthood. This study aimed to determine hospitalisation rates for infectious diseases at different ages, from infancy up to 50 years, by comparing individuals born at different gestational ages.,,We used data from the Medical Birth Registry of Norway (MBRN), which contains complete coverage of all live and still births in Norway since 1967.The study and data linkage were approved by the Regional Committee for Medical and Health Research (Rek-Midt 2018/32) and the registry-keeping authorities.All individuals born in Norway from 1967 and through 2016 were eligible. Individuals were excluded if their identification number was missing; gestational age was outside a range which would typically have been actively treated ; stillborn; birthweight missing. To reduce the impact of incorrect measures of exposure, we excluded individuals with a birthweight of >6000 g or <350 g, a birthweight for gestational age standard deviation (SD) score >4 or < −6 from expected or maternal age >55 years.Information on gestational age in days was obtained from the MBRN. Gestational age was estimated based on ultrasound examination or the last menstrual period, if ultrasound was not performed. In the case of assisted reproduction, estimation from embryo transfer was preferred over ultrasonography. Gestational age in days was converted to completed weeks at birth and categorized as extremely preterm (23–27), very preterm (28–31), moderately preterm (32–33), late preterm (34–36), early term (37–38), full-term (39–41), and post-term (42–44 weeks) and gestational age was also treated as a continuous variable based on completed days of gestation.The primary outcome was inpatient hospitalisation for infectious diseases based on the International Classification of Diseases (ICD-10) discharge diagnoses assigned by specialists only and collected for administrative purposes from the NPR database. We also studied admissions due to respiratory tract infections (RTIs) and non-RTIs separately and any infection caused by specific viral or bacterial agents separately. Furthermore, bacterial and viral infection-related admissions were studied separately for RTIs and non-RTIs. All ICD-10-codes used to identify infections are listed in Analyses were performed separately for five age groups: 0–11 months, 1–5 years, 6–14 years, 15–29 years, and 30–50 years. Associations between gestational age at birth and hospitalisation for infections were quantified by calculating the hospitalisation rates  and hospitalisation rate ratios and comparing individuals born in different categories of gestational age. We calculated the person-time at risk for hospital admissions due to infectious disease from 2008 to 2017 that each individual contributed within their respective age-groups, and the corresponding number of hospitalisations. For example, an individual who was born on January 01, 1967 was considered at risk from January 01, 2008 through December 31, 2017 when counting hospitalisations in the age category of 30–50 years. We subtracted the time spent in hospital for an infection from the time at risk, as patients would not be at risk of having a new admission for infection during this period. Individuals did not contribute with person-time after emigration or death. Using this design, different birth-year cohorts were followed up at different ages . HospitaAll statistical models were estimated using Stata version 17.0.We evaluated consistency using additional analyses, adjusting for maternal educational level at birth, maternal country of birth, birthweight SD score and birth months in two categories of Spring–Summer (March–August) and Fall–Winter (September–February). These were complete case analyses. The number of individuals excluded in addition to the main analyses, are reported in relation to each figure in the addition analyses, and in The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Authors KR, JV and SMN had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors take final responsibility for the decision to submit the report for publication.A total of 2,937,580 births were registered in Norway from 1967 to 2016. After all exclusions, the study population consisted of 2,695,830 individuals , lowest at ages 6–14 years (5.5) and increased slightly into adulthood (11.8 at ages 30–50) . For allAmong adults aged 30–50 years, hospitalisation rates were higher in the earlier categories of preterm birth. For very and late preterm compared with full-term, the aRRs (95% CIs) were 1.4 (1.2–1.7) and 1.2 (1.1–1.3), respectively. In this age group, the estimate was imprecise for those born extremely preterm. For any infectious disease hospitalisations, the aRRs per 30 days longer gestation were gradually less pronounced with older age groups, but remained evident in adulthood: 0.62 (0.61–0.63) at 1–5 years, 0.84 (0.81–0.87) at 6–14 years and 0.94 (0.91–0.97) at 30–50 years .Table 2TOne in three hospitalisations for infectious diseases were classified as RTIs , declining thereafter; among adults, there was <1 hospitalisation for viral RTIs per 1000 person-years . CompariIn adulthood, hospitalisation rates for bacterial RTIs were considerably higher than those for viral RTIs, and the patterns of associations for lower gestational age groups for bacterial RTIs were comparable but with an overall higher precision than that of viral RTIs .Overall, 41,067 (13.1%) hospitalisations due to infection could be attributed to viral agents  and 76,0For infections not classified as RTIs, the results also indicated a gradient pattern for gestational age that was attenuated by age but was still evident in adulthood, but with overall less pronounced estimates than for RTIs . For virWe adjusted for birthweight SD scores , maternaA summary of the estimates for the very preterm and late preterm groups for all infectious groups in early childhood (1–5 years) and adulthood (30–50 years) is shown in In this study of 2.7 million individuals, we found a gradual increase in infection-related hospitalisation risk with a lower gestational age at birth. The association was very strong in childhood, persisted throughout adolescence and adulthood, was robust to adjustment for perinatal and maternal factors, and could not be explained by congenital malformations or severe neurological conditions. In the very preterm group, there was three-fold increase in the risk of hospitalisation for any infection in childhood, whereas this association was attenuated to a 30–40% increased risk in the adult groups. At ages 30–50, the pattern of gradually increasing infection-related hospitalisation risk with lower gestational age at birth was most pronounced for bacterial and viral RTIs and for bacterial infections that were not RTIs.,Our study is the first to assess the risk of adult infection across the entire gestational age spectrum. Our finding that preterm birth is associated with increased risk of hospitalisation for infections in childhood corresponds well with those of previous studies, although most previous studies were typically follow-up studies of extremely preterm groups and not population-based. Studies on preterm children show an elevated risk of neonatal sepsis and severe infections until the age of 12 years, particularly in the extremely preterm group.,While previous studies have focused on infections in children and adolescents, this study determined the risk of infections from birth until the age of 50 years. A Swedish population-based study of 674,820 persons born between 1973 and 1979 who were followed for up 36 years found that preterm birth was associated with increased mortality attributed to infections after 6 years of age but lacked power to conclude about risk among adults.The immature immune system of preterm infants may increase their susceptibility to infection. The immune system undergoes significant maturation in the last trimester of pregnancy. Hence, preterm infants do not have the same level of immune competence and defence against microbes as full-term infants. Moreover, preterm infants may be exposed to several interventions such as caesarean section, prenatal and neonatal antibiotics and corticosteroids, intravenous lines, and invasive ventilatory support, potentially affecting their microbial composition, shaping of the immune system and organ development. Programming of the immune system is further supported by observations of lower rates of atopy in adults born preterm and at very low birthweight.32,,,The link between preterm birth and long-term risk of respiratory infections, particularly lung infections, seems plausible because preterm birth is strongly associated with lung immaturity and the need of ventilatory support in the neonatal period.Understanding the link between shorter length of gestation and increased risk of severe infections can help tailor preventive and therapeutic measures, such as vaccinations, diagnostics, and medical interventions. This knowledge is particularly valuable during epidemics and pandemics when the identification of risk groups and prioritization of resources is necessary.Advancements in prenatal and neonatal care have improved the survival rates in preterm births. In high-income countries, this development has been particularly related to improvements in the treatment of neonatal lung disease with surfactants since the 1990s.,,From a global and population perspective, survival rates have improved, particularly for those born in the moderate to late term.Misclassification of gestational age is a potential limitation although we applied inclusion criteria based on possible SD scores for birth weight related to specific weeks of gestation to reduce this risk. Further, different methods of estimating gestational age may influence the accuracy of the estimates of gestational age.,Another limitation is the relatively low proportion of infections identified as being caused by specific microbes. We applied a strict definition where a specific pathogen or a typical clinical syndrome  had to be specified by the specialist care doctor at discharge for an infection to be classified as bacterial or viral. In clinical practice, the specific pathogen can often not be identified. In patients hospitalized with pneumonia, a pathogen could be identified in 40–60% of cases even with comprehensive microbiological testing,In conclusion, children, adolescents, and adults have a gradually higher risk of infection-related hospitalisations with shorter gestational age at birth. The risk patterns were similar across infectious disease groups, such as bacterial and viral infections, and were not only evident for RTIs but also for infections not classified as RTI. The mechanisms involved are mainly understudied but may be linked to early life immune system and organ system development. Nevertheless, current knowledge may be used to emphasize preventive lifestyles, such as avoidance of smoking and obesity, optimization of hygiene habits, and further develop relevant risk stratified immunization recommendations.KR is the guarantor of the study and affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted. All authors participated in critically reviewing the analyses and the report and interpreting the findings. JV and SMN analyzed the data, interpreted the data, drafted the initial manuscript, and revised the manuscript. KR, SMN, SS, ES, TR, AA designed the study and statistical methods and analyses and reviewed and revised the analyses and manuscript for important intellectual content. HD, SO, JKD, EK, JM planned the study, and reviewed and revised the analysis and manuscript for important intellectual content. KR is responsible for the Norwegian data, designed and planned the study design, drafted the initial manuscript, revised and approved the final manuscript. KR and ES were resposible for conceptualization and funding. KR, JV and SMN had full access to all the data in the study, verified the data, and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors take final responsibility for the decision to submit the report for publication.www.helsedata.no).Data protection law precludes us from sharing the data used in this study. Access to the data can be requested from the Norwegian Health Data service (All authors declare no competing interests.


Stable isotope studies were performed, using D3-leucine, to determine the apo(a) FCR and PR. As expected, plasma Lp(a) concentrations were inversely correlated with wIS . The wIS had a modest positive correlation with apo(a) FCR  and a negative correlation with apo(a) PR . The relationship between wIS and PR became significant when we controlled for self-reported race and ethnicity (SRRE) ; controlling for SRRE did not affect the relationship between wIS and FCR. Apo(a) wIS plays a role in both FCR and PR; however, adjusting for SRRE strengthens the correlation between wIS and PR, suggesting an effect of ancestry.Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined by the number of Kringle IV Type 2 repeats. Previous studies report a strong inverse relationship between Lp(a) levels and apo(a) isoform sizes. The roles of Lp(a) production and fractional clearance and how ancestry affects this relationship remain incompletely defined. We therefore examined the relationships of apo(a) size with Lp(a) levels and both apo(a) fractional clearance rates (FCR) and production rates (PR) in 32 individuals not on lipid-lowering treatment. We determined plasma Lp(a) levels and apo(a) isoform sizes and used the relative expression of the two isoforms to calculate a “weighted isoform size” ( Lipoprotein(a) [Lp(a)] has two main protein components: each particle has one apolipoprotein B100 (apoB100) molecule covalently bound to one apo(a) molecule . High leA distinct feature of this apoB100-containing lipoprotein is the variability of apo(a) size, with masses that range from 300 to 800 kDa , 10, duewIS) for each subject, support previous studies indicating the isoform size is more closely related to PR than to FCR and that ancestry, as assessed by SRRE, impacts the association between isoform size and PR.Previous studies have shown a consistent and strong inverse relationship between plasma Lp(a) concentration and isoform size , 14; higThe study subjects had participated in one of three separate stable isotope studies examining the effects on lipoprotein metabolism of (1) an apoB100 antisense, (2) an inhibitor of cholesteryl ester transfer protein, or (3) a monoclonal antibody against PCSK9 , 25, 26.3-leucine dissolved in 0.15 M NaCl (10 μmol/kg body weight) immediately followed by a constant infusion of D3-leucine dissolved in 0.15 M NaCl (10 μmol/kg body weight/hour) for 15 h. EDTA blood samples were collected at 18 predefined times over 24 h and plasma separated and stored at −80°C. Aliquots of these banked samples were utilized for this study; the samples had not been previously thawed or refrozen.Complete details of the stable isotope studies on the metabolism of apoB100 and apo(a) have been previously published , 25, 26.Plasma lipids  were measured on an Integra400plus (Roche) from samples obtained at baseline. Plasma low density lipoprotein (LDL)-C levels were calculated using the Friedewald formula (no subject had a TG level >400 mg/dl). Plasma apoB100 levels were measured by a ELISA kit # 3715-1HP-2, from Mabtech, Inc, Cincinnati, OH.3-leucine was measured as described by Zhou et al. (Apo(a) enrichment with Du et al. . In brieLp(a) plasma concentration was measured using the isoform-independent sandwich ELISA developed by the Northwest Lipid Metabolism and Diabetes Research Laboratory . Apo(a) wIS. Each expressed isoform can potentially have a different FCR , say, k1 and k2 for the two isoforms. As apo(a) is a slowly turning over protein and we use a primed constant infusion protocol in our studies, the apo(a) enrichment, when expressed as a fraction of the precursor plateau, goes up nearly linear during the 15 h infusion period and the rising slope, as a fraction of the plateau enrichment, equals the FCR or fractional synthetic rate. If E1, the enrichment of isoform 1, goes up with slope k1, and E2 goes up with slope k2, it can be seen that the overall enrichment E, which equals m1E1 + m2E2, goes up with slope m1k1 + m2k2, where m1 and m2 are the relative masses  of the two isoforms, with the total mass denoted by M.Most individuals express two apo(a) isoforms in plasma, and these are inversely correlated with Lp(a) plasma levels, with smaller isoforms generally dominating . To asce1 = a + bS1 and k2 = a + bS2. It follows, then, that the combined apo(a) FCR, which is m1k1+m2k2, equals m1(a + b S1) + m2(a + bS2), which simplifies to a + b(m1S1 + m2S2). We define m1S1 + m2S2 as the wIS. Substituting, we see that the combined apo(a) FCR, termed kc, follows the relationship kc = a + b wIS. Thus, when we estimate a single apo(a) FCR, it bears the same linear relationship with wIS as the isoform-specific FCR would bear with the corresponding isoform size. Further, if we look at the total PR, which is the sum of the two isoform-specific PR1 and PR2, where PR1 = m1Mk1 and PR2 = m2Mk2, it follows that PR = m1Mk1 + m2Mk2 = M(m1k1 + m2k2) = Mkc. That is, the total PR equals the total mass multiplied by the FCR we estimate from the total enrichment data. When we calculate a single apo(a) PR, it bears the same relationship with wIS as the isoform-specific PR would bear with the corresponding isoform size.If there is a linear relationship (with intercept “a” and slope “b”) between isoform-specific FCR, termed k, and the corresponding isoform size, termed S, it means k = a + bS. Applying it to the two isoforms 1 and 2 above, the relationships become k1 and M2, so total Lp(a) mass is M = M1 + M2. If the two isoform sizes are 20 and 30, with relative expression of 70% and 30%, respectively, the wIS is 0.7∗20+0.3∗30 = 23. If now, the two isoforms are cleared with rate constants k1 = 0.4 and k2 = 0.2, then, by the formulas above, PR1 = 0.7∗M∗0.4 = 0.28 M; PR2 = 0.3∗M∗0.2 = 0.06 M; kc = 0.7∗0.4 + 0.3∗0.2 = 0.34. We see that total PR = PR1 + PR2 = 0.34 M = kcM.Example: Say the two isoform masses are MThe apo(a) enrichment data were modeled as previously described , 25, 26.wIS in the three SRRE groups was studied by analysis of covariates (ANCOVA).All data were analyzed using standard R software functions  invoked by our cufunctions package . Variabl2. Lipid and apoB100 levels were within normal ranges.The subject demographic data as well as plasma lipid and apoB100 levels are shown in wIS of 22.8 ± 4. As expected from published data, Black subjects had a higher median Lp(a) concentration. In our cohort, 9 of the 32 individuals (28%) had only one detectable isoform. Mean ± SD FCR and PR of apo(a) were 0.18 ± 0.08 pools/day and 0.57 ± 0.40 nmol/kg/day, respectively (The study population had median Lp(a) levels of 54.6 nmol/L (interquartile range 36.8–119.0) . Plasma ectively . IndividwIS  , SRRE group differences were not statistically significant . The lack of significance may be due to the small number of subjects in each SRRE group. The relationship between individual apo(a) isoforms and the Lp(a) levels associated with each isoform in the combined cohort of all subjects  was also statistically significant (P < 0.0001) (wIS with the kinetics of apo(a).As observed in larger population data sets, our subjects had an inverse relationship between Lp(a) levels and = 0.002) A. Lp(a)  0.0001) . IsoformR2 = 0.07, P = 0.16) was not statistically significant  (wIS with FCR (The relationship between Lp(a) levels and apo(a) FCR (nificant . When we = 0.08) A. Controwith FCR B.Fig. 2RwIS showed a negative trend with apo(a) PR (P = 0.06) (P = 0.03)  C and thi = 0.03) D.wIS and FCR were positively correlated  but no correlations were found between the single isoforms and PR  .The results above comprised all 32 subjects, including 9 individuals who expressed only a single isoform . In this = 0.23) A, B.High plasma Lp(a) levels are associated with an increased risk for ASCVD , 23. Theet al. and Rader et al. found that PR, but not FCR, correlated with Lp(a) levels (Previous reports support a role of production and/or clearance regulating Lp(a) plasma levels; these have been reviewed , 34, 35.) levels , 43. Our) levels . Similar) levels . These s) levels  support LPA gene. Early studies in cultured liver cells, using both steady state labeling and pulse chase analyses, showed that the endoplasmic reticulum residence time of secreted apo(a) isoforms is determined by their size, and that this accounted for the inverse relationship between isoform size and level of secretion. The authors concluded that apo(a) posttranslational stability is a major determinant of the levels of plasma Lp(a) in baboons  in studies using endogenous labeling of Lp(a) with stable isotopes  FCRs, the latter similar to our current findings. These previous studies did not determine and take into account participant SRRE.As previously stated, an individual’s plasma Lp(a) level, with few exceptions, is highly regulated by the number of KIV-2 repeats present in their apo(a) isoforms, which are determined by the  baboons . Additio baboons , 47, 48. baboons  or varyi baboons . The latisotopes . SubjectwIS (see Methods), which captures the contribution of each isoform to the Lp(a) level in the circulation. The use of isoform expression to calculate isoform specific Lp(a) plasma levels has been applied in earlier studies . We found that wIS had only modest correlations with both PR and FCR. Our results are consistent with previous reports that found strong relationships between allele size and PR but also identified trends with FCR . Relevant to our current findings, a sub-analysis by Chan et al. (Advances in mass spectrometry and methods to isolate Lp(a) have enhanced our ability to interrogate the mechanisms that regulate Lp(a) . In this studies . Calculawith FCR , 49, 50.n et al.  of the bn et al. . The autn et al. . Importan et al. . Mipomern et al. . Anacetrn et al. . The resn et al. . Lastly,n et al. , 34, 35.n et al. . The latn et al. , 55.wIS and PR was statistically significant.Due to clear racial differences in the relationship of isoform size and plasma Lp(a) levels , 57, it wIS after various therapies that lower apoB100 and apo(a) (Lp(a) lowering with nontargeted and targeted treatments decreases both isoforms. Of interest, the relative expression of apo(a) isoforms does not change after Lp(a) levels are lowered using ASO apo(a) treatment . The latd apo(a) . A recend apo(a) . Recent d apo(a) , 61 .LPA gene within the KIV2 region that are linked to high and low Lp(a) levels. The allele frequencies of these SNPs have been found to differ across SRRE groups  present in the E groups , 62, 63.et al. examined the role of isoforms in larger diverse cohorts  isoforms have a significant yet modest contribution to the mechanisms regulating apo(a) FCR and PR. Although we did include subjects with different SRRE in this study, our study population was small, with 17 of our 32 subjects identifying as Black, leaving very few subjects in the other groups. Mechanistic studies are costly and labor extensive, hence it will be difficult to perform studies in large populations with adequate sample size for different SRRE groups. Our results, however, highlight the need to recruit diverse cohorts when designing these studies. Berglund  cohorts  showing pathways .wIS. We examined the kinetics of apo(a) isolated from LDL or LDL+HDL fractions. However, the apo(a) PR and FCR from LDL-only or from LDL plus HDL fractions were not statistically different  isoforms and calculate their unique FCR and PR; instead, we used the relative expression data from gel electrophoresis to estimate their contributions to the ifferent  and the ifferent  and not ifferent , howeverAll the data generated during and/or analyzed during the current study are available from the corresponding author and are included in this published article and its supplementary information file.This article contains The authors declare that they have no conflicts of interest with the contents of this article