Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity. The withdrawal of progesterone, either actual or functional, is thought to be an antecedent to the onset of labour. There remains limited information on clinically relevant health outcomes as to whether vaginal progesterone may be of benefit for pregnant women with a history of a previous preterm birth, who are at high risk of a recurrence. Our primary aim was to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome in their infants, with secondary aims of examining the effects on other neonatal morbidities and maternal health and assessing the adverse effects of treatment.n = 398) or placebo (n = 389). Participants and investigators were masked to the treatment allocation. The primary outcome was respiratory distress syndrome and severity. Secondary outcomes were other respiratory morbidities; other adverse neonatal outcomes; adverse outcomes for the woman, especially related to preterm birth; and side effects of progesterone treatment. Data were analysed for all the 787 women (100%) randomised and their 799 infants.Women with a live singleton or twin pregnancy between 18 to <24 weeks’ gestation and a history of prior preterm birth at less than 37 weeks’ gestation in the preceding pregnancy, where labour occurred spontaneously or in association with cervical incompetence or following preterm prelabour rupture of the membranes, were eligible. Women were recruited from 39 Australian, New Zealand, and Canadian maternity hospitals and assigned by randomisation to vaginal progesterone pessaries  (p = 0.912)—as was the severity of any neonatal respiratory disease . No differences were seen between study groups for other respiratory morbidities and adverse infant outcomes, including serious infant composite outcome . The proportion of infants born before 37 weeks’ gestation was similar in both study groups . A similar proportion of women in both study groups had maternal morbidities, especially those related to preterm birth, or experienced side effects of treatment. In 9.9% (39/394) of the women in the progesterone group and 7.3% (28/382) of the women in the placebo group, treatment was stopped because of side effects . The main limitation of the study was that almost 9% of the women did not start the medication or forgot to use it 3 or more times a week.Most women used their allocated study treatment , with median use similar for both study groups . The incidence of respiratory distress syndrome was similar in both study groups—10.5% (42/402) in the progesterone group and 10.6% (41/388) in the placebo group (adjusted relative risk [RR] 0.98, 95% confidence interval [CI] 0.64–1.49, Our results do not support the use of vaginal progesterone pessaries in women with a history of a previous spontaneous preterm birth to reduce the risk of neonatal respiratory distress syndrome or other neonatal and maternal morbidities related to preterm birth. Individual participant data meta-analysis of the relevant trials may identify specific women for whom vaginal progesterone might be of benefit.ISRCTN20269066.Current Clinical Trials  In a randomized controlled trial, Caroline Crowther and colleagues examine the effect of vaginal progesterone pessaries for pregnant women to prevent neonatal respiratory distress syndrome. Prevention of preterm birth remains a global challenge. Vaginal progesterone has been suggested to reduce the incidence of preterm birth in women at risk, but there has been limited assessment of the effects on relevant neonatal morbidity.The aim of our trial was to assess whether vaginal progesterone pessaries in pregnant women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome, other neonatal morbidities, and maternal health outcomes and if there were any side effects of treatment.Seven hundred and eighty-seven women were randomly allocated to receive vaginal progesterone or placebo from between 20 to 24 weeks’ to 34 weeks’ gestation.The rate of respiratory distress syndrome amongst infants in both treatment groups was similar, as were the outcomes for other respiratory measures and adverse outcomes.Maternal health outcomes and side effects of treatment were also similar between treatment groups.Vaginal progesterone pessaries did not reduce the risk of respiratory distress syndrome compared to placebo vaginal pessaries.Vaginal progesterone pessaries cannot be recommended in women with a history of previous preterm birth to reduce infant or maternal morbidity associated with any recurrence.These results provide robust evidence for health practitioners and consumers to make informed clinical decisions. The prevention of preterm birth remains a global challenge . Women wProgesterone has an important role in uterine quiescence ,9 and isAn initial systematic review of studies from the 1960s showed that use of progesterone may prevent preterm birth . Over thAt the time of planning our trial, there were 2 published clinical trials with relatively small sample sizes that included women with a previous history of preterm birth, and these studies had shown a reduction in preterm birth with the use of both natural vaginal progesterone  and intrThe primary aim of the PROGRESS randomised, placebo-controlled trial was therefore to assess whether the use of vaginal progesterone pessaries in pregnant women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome, thus improving the infant’s health. The secondary aims were to examine the effects on other respiratory outcomes; other neonatal morbidities; and maternal health outcomes, especially those related to preterm birth; and to assess any side effects of treatment.We conducted a multicentre, placebo-blinded, randomised controlled trial at 39 Australian, New Zealand, and Canadian maternity hospitals. This study is reported as per CONSORT guidelines . The stuWomen were eligible if they had a live singleton or twin pregnancy between 18 and <24 weeks’ gestation and a history of prior preterm birth  at greater than 20 weeks’ gestation and less than 37 weeks’ gestation in their preceding pregnancy where the onset of labour occurred spontaneously or in association with cervical incompetence or following preterm prelabour rupture of membranes. If the women had received progesterone therapy prior to 16 weeks’ gestation, they remained eligible. The protocol for this study has been published  S2 TextS2 Text.Women were ineligible if their preceding preterm birth at less than 37 weeks’ gestation was associated with placental abruption or placenta praevia, if it was a multiple pregnancy, or if there had been an iatrogenic decision for early birth, for example, related to fetal distress or preeclampsia.Women were ineligible if their current pregnancy, at consideration for trial entry, was associated with active vaginal bleeding requiring hospital admission at 18 weeks’ gestation or more, preterm prelabour rupture of membranes, active labour , known lethal fetal anomaly or fetal demise, progesterone treatment after 16 weeks’ gestation, or any contraindication to continuation of the pregnancy, such as chorioamnionitis requiring delivery, or contraindication to progesterone therapy . The PROGRESS Study protocol did not include the need for cervical length measurement at trial entry or during the pregnancy. The clinician responsible for care of the participant decided whether cervical length screening was undertaken.The study was approved by the Children’s Youth and Women’s Health Services Human Research Ethics Committee at the Women’s and Children’s Hospital, Adelaide, Australia, and by the ethics committee at each of the 39 collaborating centres .Eligible women were provided with written information about the study in the antenatal clinic, counselled by 1 member of the research team, and asked if they would participate. Recruitment started in February 2006 and was completed in September 2012.Women who gave written informed consent were randomly assigned to either ‘progesterone’ or 'placebo’ using a central telephone randomisation service. The randomisation schedule, prepared by an investigator not involved with clinical care, used balanced variable blocks with stratification by plurality of the pregnancy (singleton versus twin versus triplet) and collaborating centre. Participants, staff, and investigators were masked to study group allocation, and treatment packs appeared identical. The baseline information collected included maternal age, parity, ethnicity, body mass index, plurality, gestational age at trial entry, gestational age, and reason for the previous preterm birth.Women randomised to the progesterone and placebo groups were allocated a study number that corresponded to a treatment pack containing the allocated study treatment.Depending on the study treatment allocation, the treatment packs contained either a 14-week supply of progesterone pessaries  or similar-appearing placebo pessaries (in hard fat) bought for the study from Orion Laboratories, Western Australia. The manufacturer of the pessaries had no other involvement in the study. Women were asked to self-administer a vaginal pessary each evening from 20 weeks’ gestation, or from randomisation if this occurred after 20 weeks’ gestation, until birth or 34 weeks’ gestation, whichever occurred first. The maximum number of days treatment could be used for was 98 days.Women were reviewed in the antenatal clinic by the practitioner responsible for their care. Women who presented with preterm prelabour rupture of the membranes after trial entry were advised to discontinue using the vaginal pessaries to reduce the risk of introducing infection. In the event of the development of serious depression or a medical condition that may have been aggravated by fluid retention , the clinician was to advise the woman to cease using the trial medication if he or she felt it would be in the woman’s best interests to do so.At 34 weeks’ gestation, women were asked to complete a questionnaire that assessed health-related quality of life , anxiety2O and/or fractional inspired oxygen [FiO2] < 0.4; moderate = MAP 7–9.9 cm H2O and/or FiO2 0.40–0.79; severe = MAP ≥ 10 cm H2O, and/or FiO2 ≥ 0.80 with need for ventilation).The primary outcome was the incidence of neonatal respiratory distress syndrome (defined as increasing respiratory distress or oxygen requirement or the need for respiratory support from the first 6 hours of life) and severity of neonatal respiratory disease (defined as mild = mean airway pressure [MAP] < 7 cm HThe secondary outcomes for the child were as follows:2 [%] within 12 hours of birth), need for and duration of mechanical ventilation (including maximum peak pressure [cm H2O] within 12 hours of birth), need for surfactant therapy, nitric oxide for respiratory support, air leak syndrome, and chronic lung disease  andother respiratory measures, which included the need for and duration of oxygen therapy (including highest FiOa composite adverse outcome for the infant that included 1 or more of the following: preterm birth (defined as birth at less than 37 weeks’ gestation), perinatal mortality , severe respiratory disease, chronic lung disease, Apgar score < 4 at 5 minutes of age, birth weight less than the third centile for gestational age at birth and infant sex, intraventricular haemorrhage on early cranial ultrasound, periventricular leucomalacia on later cranial ultrasound, inotropic support for the treatment of patent ductus arteriosus, proven necrotising enterocolitis, proven systemic infection within 48 hours of birth treated with antibiotics, and retinopathy of prematurity.The secondary study outcomes for the mother were as follows:significant health outcomes, particularly related to preterm birth, such as use of tocolytic therapy or antenatal corticosteroid therapy, defined by 1 or more of the following: maternal death, antepartum haemorrhage, pre-eclampsia, preterm prelabour rupture of membranes, prelabour ruptured membranes at or near term (defined as prelabour rupture of membranes after 36 weeks’ gestation), chorioamnionitis requiring antibiotic use during labour, postpartum haemorrhage, or antibiotic use after birth;length of any antenatal hospital stay or postnatal stay and psychological health  and if any of them were sufficient to stop treatment.Primary analyses were performed on an intention-to-treat basis, according to the study group allocated at randomisation. As prespecified, unadjusted analyses were performed and then adjusted for the potential confounders of gestational age at randomisation, gestational age of the previous preterm birth, and reason for the previous preterm birth.p < 0.05 level, and no adjustment was made for multiple comparisons. No adjustments were made for the 2 primary outcomes, as they were considered strongly related and expected to provide complementary information ) .2 values within 12 hours of birth, use and duration of mechanical ventilation, use of surfactant, use of nitric oxide, air leak syndrome, and chronic lung disease  (p = 0.765). A similar proportion of infants were born by caesarean section in both study groups. No differences were evident between the study groups for any of the other individual adverse infant outcomes that included low Apgar score, small for gestational age at birth, intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus requiring treatment, necrotising enterocolitis, proven early neonatal sepsis, retinopathy of prematurity, and need for admission to the neonatal intensive care unit and duration of the infant’s postnatal stay  . There w= 0.798) . The protal stay .p = 0.994) or in the individual health outcomes, particularly those related to preterm birth, including use of tocolytic therapy and antenatal corticosteroids prior to the birth, antepartum haemorrhage, preeclampsia, risk of rupture of the membranes preterm or at or near term, chorioamnionitis requiring antibiotics, and postpartum haemorrhage , including the overall physical and mental components, were similar in both study groups. No differences were seen in the proportion of women with a score on the Edinburgh Postnatal Depression Scale (EPDS) that was suggestive of depression (9.4% in the progesterone group and 9.0% in the placebo group), and the level of anxiety was similar in the 2 study groups .The proportion of women reporting any side effects of the treatment at 34 weeks’ gestation was similar between the study groups (134/394 [34.0%] in the progesterone group versus 118/382 [30.9%] in the placebo group), as was the proportion of women who stopped therapy because of side effects (39/394 [9.9%] in the progesterone group versus 28/382 [7.3%] in the placebo group) . A similThe PROGRESS Trial showed that in women with a history of previous spontaneous preterm birth, the use of 100-mg vaginal progesterone pessaries daily from 20 weeks’ gestation until 34 weeks’ gestation had no effect on the risk of the baby developing respiratory distress syndrome or on reducing the severity of any neonatal respiratory disease compared with placebo pessaries. In keeping with these findings, no benefits were seen relating to other respiratory outcomes or other neonatal morbidities.For women, the risk of having a preterm birth was not reduced with the use of progesterone, and the need for interventions related to preterm birth such as tocolysis and antenatal corticosteroids; the need for antenatal hospital admission; and, if admitted, the length of hospital stay were also not reduced. Over 36% of the women in both study groups in the PROGRESS Trial were given antenatal corticosteroids, appropriate for the 36% rate of preterm birth seen in our high-risk population. Although progesterone can suppress proinflammatory cytokines , there wWe found no effect of vaginal progesterone on the risk of preterm birth for women with a previous preterm birth, similar to the findings from the O’Brien Trial  and the The clear entry criteria for the PROGRESS Trial were specifically set to easily identify women at high risk of a recurrence of preterm birth based on their previous history and to assess the effects of vaginal progesterone on this population. Inclusion criteria for our study were based on a previous history of preterm birth—a strong predictor for subsequent preterm birth—and not dependent on assessment of cervical length. Women identified and recruited with a history of preterm birth in their preceding pregnancy were at high risk of recurrence, with 36% giving birth before 37 weeks’ gestation, although there was no difference in gestational age at birth or in the proportion born preterm between the study groups. The trial was masked for participants and investigators with a placebo, and the primary outcome of respiratory distress syndrome was reported for all babies.It is possible that the dose of 100 mg progesterone used may have been too low. However, the Da Fonseca Trial  used theOur pretrial sample size estimate, based on the reported effect of treatment with progesterone compared with placebo on neonatal respiratory distress syndrome , would pOf eligible women invited to participate in the PROGRESS Trial, only 41% chose to do so, not too dissimilar to the 52% consent rate in the OPPTIMUM Trial . WhetherIn any intervention study, compliance is crucial to ascertain true effect. Few other studies to date have reported on measures of compliance. In our study, most women started the allocated study treatment, and the median days of use was around 51 days. Nevertheless, a proportion of women in both study groups, almost 9%, either did not start the medication or forgot to use it 3 or more times a week, which was our measure of compliance. Within the OPPTIMUM Trial, compliance—defined slightly differently as 80% or more use of study treatment—was 69% . This isAlmost a third of the women reported side effects of treatment with the vaginal pessaries, the most frequent reasons given being headache, nausea, and pain or discomfort, although there were no differences in the proportion of women reporting side effects or the side effects reported by study group. For over 8% of women, these side effects were sufficient for them to stop their study treatment. Cessation of therapy because of side effects has not been well reported in earlier studies.There are ongoing differences in clinical practice recommendations as to whether to recommend use of progesterone or not ,18,19,20Our results do not support the use of vaginal progesterone pessaries in women with a history of a previous spontaneous preterm birth to reduce the risk of respiratory distress syndrome or other neonatal or maternal morbidity. IPD-MA of the relevant trials may identify specific women for whom vaginal progesterone may be of benefit. The search for alternative strategies for the prevention of preterm birth and its sequelae must continue.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.


Evidence supporting the practice of skin‐to‐skin contact and breastfeeding soon after birth points to physiologic, social, and psychological benefits for both mother and baby. The 2009 revision of Step 4 of the WHO/UNICEF “Ten Steps to Successful Breastfeeding” elaborated on the practice of skin‐to‐skin contact between the mother and her newly born baby indicating that the practice should be “immediate” and “without separation” unless documented medically justifiable reasons for delayed contact or interruption exist. While in immediate, continuous, uninterrupted skin‐to‐skin contact with mother in the first hour after birth, babies progress through 9 instinctive, complex, distinct, and observable stages including self‐attachment and suckling. However, the most recent Cochrane review of early skin‐to‐skin contact cites inconsistencies in the practice; the authors found “inadequate evidence with respect to details … such as timing of initiation and dose.” This paper introduces a novel algorithm to analyse the practice of skin to skin in the first hour using two data sets and suggests opportunities for practice improvement. The algorithm considers the mother's Robson criteria, skin‐to‐skin experience, and Widström's 9 Stages. Using data from vaginal births in Japan and caesarean births in Australia, the algorithm utilizes data in a new way to highlight challenges to best practice. The use of a tool to analyse the implementation of skin‐to‐skin care in the first hour after birth illuminates the successes, barriers, and opportunities for improvement to achieving the standard of care for babies. Future application should involve more diverse facilities and Robson's classifications. They would then be categorized as “No: Emergent Care for Mother or Infant.” If the separation results in a delay of less than 5 min, the pair is categorized as yellow—a caution for the hospital to review—but the dyad continues on the blue best practice path.The next element of the model considers continuous SSC during the full first hour or so. If the newborn is removed from SSC either for emergent or routine care any time within the first hour or so after birth, it is recorded.The algorithm considers the standard of uninterrupted or undisturbed SSC next. Dyads are recategorized if staff interfere with the newborn during the first hour or if the mother or family interferes with the newborn's innate behaviours. Staff “helping” the newborn to latch would be considered interrupting, because the SSC standard includes newborn crawling, familiarizing, and self‐attaching.Best practice is ultimately measured through the achievement of Widström's 9 Stages during the first hour or so after birth. Immediate, continuous, and uninterrupted practice optimizes the infant's ability to achieve this goal.If a dyad experienced immediate, continuous, uninterrupted SSC for the first hour or so after birth and progressed through Widström's Stages and suckled, they have achieved the standard of best practice.33.1Analysis of the Japanese dyads is presented in Figure All 14 babies were immediately placed in SSC with their mother. None were removed due to hospital policy or emergent care. Thirteen of the 14 babies received continuous SSC with their mother. One baby was removed at 50 min. Seven of the 13 remaining newborns were interrupted by staff who “helped” the newborn to breastfeed during the first hour. Six newborns were uninterrupted. One of the newborns who had immediate, continuous, uninterrupted SSC progressed through Widstrom's 9 Stages and achieved the standard of self‐attachment and suckling. The other five newborns did not progress past the Activity Stage (Stage 4).3.2Analysis of the Australian study is presented in Figure One baby was immediately placed in SSC with mother. Seven were placed in SSC with mother within 5 min of birth. Twelve received SSC later than 5 min after the birth (between 5.01 and 65.05 min), and one did not receive any SSC within the first 2 hr after birth. Seven of the mothers who received immediate SSC, or SSC within 5 min of birth, did not experience continuous SSC because they received less than 45 min of initial SSC with mother. The newborns were removed from the mother for routine care. One baby was not removed for routine care. One mother requested the baby to be removed, and it was recorded as “interrupted” on the algorithm. None of the babies met the standard for SSC—immediate, continuous, uninterrupted SSC for at least an hour, progressing through Widström's 9 Stages, self‐attaching to the breast and suckling.44.1The algorithm allows us to examine SSC during the first hour after birth in relation to the international standard of immediate, continuous, uninterrupted SSC with the goal of progressing to self‐attached suckling followed by sleep. By using the HCP‐S2S‐IA, the hospital can review practice in order to better understand their barriers to achieving the standard of care and more clearly identify where to direct interventions aimed at improvement.A review of the algorithm Figure  represenHospital practices were also successful at supporting the continuous aspect of SSC. Only one infant was removed and that was for routine care at 50 min. Hospital practices could be reviewed to determine whether staffing issues or staff education would help to ensure continuous SSC for at least 60 min, or until the newborn falls asleep (around 90 min after birth), for all mothers.More than half of the mothers in the Japanese data set were subject to interruption by staff during the first hour after birth. Two of the newborns were moved by the staff. The other five were moved and then latched by the staff to the mother's nipple. We speculate that this may be a result of the historic understanding Step 4 of the BFHI, “Help mothers initiate breastfeeding within a half‐hour of birth.” This could easily be interpreted as assisting a mother to latch her baby within 30 min of the birth. In 2009, WHO clarified this step, emphasizing SSC during the first hour or so after birth, although the wording of the step itself was unchanged .Examination of uninterrupted SSC in the Australian data set indicates that the single mother who did not have her newborn removed for routine care by the staff asked for the newborn to be removed due to nausea. According to analysis, 20 of the 21 Australian newborns were unable to complete at least 60 min of SSC due to hospital policies or routine care. The tool provides feedback to the hospital regarding the current barriers in implementing immediate, continuous, uninterrupted SSC after elective caesarean birth.4.34.3.1The algorithm allows review and deeper understanding of the barriers to best practice of immediate, continuous SSC during the first hour after birth. The first question concerns immediate SSC between the mother and baby. Was the newborn placed immediately (within 5 min) on the mother's chest? What could be preventing this implementation of best practice? This could be the case if the hospital has a protocol, for example, that includes babies born by caesarean in the classification of those who should not be eligible for immediate SSC. This was the case for a number of mothers in the Australian study. Other challenges could be a policy about births that occur in the Emergency Department or if certain anaesthesia was used. Perhaps the hospital has no policy about SSC as best practice, and implementation is based on staff preference or mother request. Does the facility not allow for staffing the required number of nurses to enable SSC? Perhaps swaddling or washing or routinely assessing every baby while on a warming table was required by protocol, or conducted by staff choice, before SSC could be started. These would be included as No: Hospital Policy or Protocol on the algorithm. This categorization could highlight for the hospital the barriers to best practice.None of the separation in our two example cases revealed prevention of immediate SSC due to emergent care for the mother or infant. This would have been the categorization if newborn did not have an initial birth cry or had a low 1‐min Apgar requiring transfer to the NICU team, rather than to the mother's chest, or, the mother has haemorrhaged, requiring the newborn to be placed elsewhere. It is vital for a hospital to recognize if the lack of immediate SSC contact is due to hospital policy or a need for emergent care. Each reflects opportunities for more in depth review or quality improvement projects.The next element of the model considers continuous SSC during the full first hour or so. Continuous SSC is vital for the warmth, respirations, and colonization of the newborn. Because the newborn will need to begin again the progression through Widström's 9 Stages after separation from the mother, any separation can be problematic because the newborn has limited time before falling asleep after birth. It is important to understand why the separation is occurring. Are there concerns about the infant's respirations? Are there concerns about the mother haemorrhaging? These would be examples of Emergent Care. None of the infants in these two examples were removed during the first hour for emergent care. If they had been, it would highlight a concern about the status of the mother and/or infant immediately after birth. Were the newborns removed for routine care? This occurred both in the Japanese data set and the Australian data set. Routine care during the first hour after birth can and should be conducted while mother and infant remain in SSC. This pathway of the algorithm highlights an opportunity for staff education.The algorithm considers the standard of uninterrupted or undisturbed SSC next. Dyads are recategorized if staff interfere with the newborn during the first hour or if the mother or family interferes with the newborn's innate behaviours. This could be subtle or significant. It is possible for staff to shift a newborn, to take vital signs, for mother to eat and shift position all without disturbing the newborn through the progression of the nine stages. It is possible to move the mother from an operating table to the stretcher without separating or interfering with newborn behaviour. On the other hand, it is possible to disrupt a newborn when checking vitals or helping a mother to shift position. Staff gently helping to reposition a newborn's head to maintain a clear airway could be done in a way that does not interrupt the newborn. Flipping a baby over and rearranging the newborn's body could be very disruptive. Staff “helping” the newborn to latch would be considered interrupting, because the SSC standard includes newborn crawling, familiarizing, and self‐attaching. It is this “help” that is highlighted in the Japanese data, presenting an opportunity for staff education on the latest understanding of best practice.The ultimate goal of immediate, continuous, uninterrupted SSC during the first hour after birth is manifested through the instinctive behaviour of the newborn during this time. If needed, this can be observed closely as Widström's 9 Stages. However, even when unobserved, this is the neurological pattern of behaviour that infants progress through during the first hour. Video allows us to examine this closely, but a secure knowledge of the instinctive behaviour allows us to understand when a newborn has, or has not, achieved all of the stages. Each stage is clear, even without close observation. Did the newborn open their eyes? Did the newborn move their arms and shift their body? Did the newborn progress to the breast? Did the newborn lick the nipple? Mothers, partners, and health care providers can know and understand whether the newborn progressed through the stages and achieved suckling and sleeping, without needing to stand over the dyad for the full hour. If a newborn has not achieved these stages—why would they not open their eyes? Why would they not crawl? Why would they not lick? Why would they not suckle?—needs to lead to further examination of these newborns, perhaps by examining their exposure to labour medications  combines Robson's criteria for obstetric classification, parameters for best practice of SSC  along with Widström's 9 Stages in order to evaluate the experience of mothers and babies in the first hour after birth. Although the exemplar sample sizes were small, differences could be discerned, and opportunities for practice improvement can be elucidated. Larger samples with more varied Robson classifications are likely to assist hospital staff further in understanding the barriers within more discrete populations of mothers. Because every birthing facility has unique strengths and challenges, use of the algorithm periodically will allow new barriers to be documented and progress celebrated. This simple algorithm for hospitals to follow could have far‐reaching impact on making practice visible, auditing, and reporting practices enabling the achievement of best practice, as well as providing a consistent measure for future research.The authors declare that they have no conflicts of interest.KB and KC substantially contributed to the creation of the algorithm. JS substantially contributed to the data and analysis, with KB and KC, of the Australian caesarean data into the algorithm. YT substantially contributed to the data and analysis, with KB and KC, of the Japanese vaginal birth data into the algorithm. All authors contributed to the writing of the paper. All authors contributed to the interpretation of the data, drafting and revising the article, and final approval of the version to be published.


Effects on costs were examined in regression models.Mean total costs for participants with PCHL and the HCG were £15 914 and £5883, respectively , primarily driven by a difference in educational costs. Compared with the HCG, additional mean costs associated with PCHL of moderate, severe and profound severity were £5916, £6605 and £18 437, respectively. The presence of PCHL and an additional medical condition (AMC) increased costs by £15 385 (95% CI £8532 to £22 238). An increase of one unit in receptive language z-score was associated with £1616 (95% CI £842 to £2389) lower costs. Birth during periods of UNHS was not associated with significantly lower overall costs .The societal cost of PCHL was greater with more severe losses and in the presence of AMC and was lower in children with superior language scores. There was no statistically significant reduction in costs associated with birth in periods with UNHS.ISRCTN03307358, pre-results. The consequences of permanent childhood hearing loss (PCHL) can include impairment in language skills and academic achievement which become more marked with more severe PCHL.Birth during periods with universal newborn hearing screening (UNHS) is associated with benefits to language and reading abilities.The societal costs of prelingual PCHL at 7–9 years increase with its severity and are inversely related to language abilities.>40 dB are, on average, 2.7 fold higher than in those with normal hearing.Total annual costs in adolescents with bilateral PCHL PCHL plus specified additional medical conditions is associated with a doubling of annual cost in adolescence compared to that of PCHL alone.In adolescents with PCHL, superior language skills are associated with significantly lower societal costs in adolescence but birth in periods with UNHS is not.Permanent childhood hearing loss (PCHL) is the most common sensory impairment. It is affecting more than 112 per 100 000 children at birth1 6–8UNHS adds to financial costs in the first year of life, both because of the cost of administering a UNHS programme, estimated in 1998 as £13 881 per annum for a district with 1000 births,Prior to 2000, attempts to model the long-term costs and outcomes of PCHL were limited by lack of dataWe have previously reported that the economic costs of bilateral PCHL in the preceding year of life among participants in the present study when they were aged 5–10 years were £14 092 for children with PCHL compared with £4207 for normally hearing children. Furthermore, each unit increase in the z score for receptive language among children with PCHL was associated with a statistically significant £2553 reduction in cost in the preceding year. Compared with birth during periods without UNHS, birth during periods with UNHS was associated with a smaller cost reduction of £2213, which fell short of statistical significance.The study sample was drawn from 157 000 children born in two birth cohorts in eight districts of Southern England between 1992 and 1997. The Wessex cohort was born over a 36-month period in four districts that formed the population for the Wessex Trial; a quasiexperimental trial in which UNHS was or was not undertaken in alternating 4–6 month periods in two pairs of hospitals, with UNHS equipment and personnel moving back and forth between the paired hospitals. UNHS increased the rate of early identification for infants with PCHL.The language, reading, behaviour and resource use in children with PCHL in these two birth cohorts, and in a normally hearing comparison group (HCG) was assessed in 183 children (120 with PCHL and 63 in the HCG) at a mean age of 7.9 years.Written informed consent was obtained from principal caregivers and the teenage participants.>40–70 decibels (dB) hearing level), severe (71–95 dB) or profound (>95 dB). Intellectual disability , genetic syndrome, visual loss and cerebral palsy were recorded as additional medical conditions (AMC). Methods of assessing participants’ reading comprehension, receptive language ability, non-verbal ability and other outcomes have been reported previously.30Severity of PCHL was classified according to average pure tone thresholds across four frequencies of sound in the better ear as moderate (vide infra) obtained by the four study research assistants at interviews of parents in their homes using instruments previously developed for our 2001–2004 study of the same families.Resource use was considered from the healthcare provider, National Health Service (NHS), Personal Social Services (PSS) and societal perspective, including costs borne by the family. It was estimated by retrospective examination of each child’s audiology records coupled with data on resource use in seven domains  to detect a 0.67 SD effect size of UNHS on reading comprehension, the prespecified primary outcome measure in the HOT study, in participants with PCHL. Sample size was determined by the above power calculation rather than any separate power calculation relating to power to detect group differences in costs, the secondary outcome reported here.Among participants with PCHL, the effect on costs was assessed in four regression models, each with one independent variable of interest: birth during periods with UNHS; ‘early’ confirmation of PCHL; receptive language ability z-score; and reading comprehension z-score. These effects are presented unadjusted and adjusted in two regression models. The first model adjusted for cochlear implantation and the presence of AMCs and the second model added severity of PCHI into that regression model.As violation of normality was confirmed (Shapiro-Wilk P<0.05), mean differences between groups are presented with 95% CIs estimated by bootstrapping (1000 replications). In addition to conventional ordinary least squares (OLS) regression analysis, generalised linear models (GLM) using non-normal distributions, and the alternative model specifications were examined for robustness to deviations from normality and equality of variance in costs.35–37Four of 114 participants in the HOT study did not return the completed economic questionnaire and resource use is therefore reported in 110 participants in this economic study. The mean (SD) age of the participants was 16.9 (1.4) years. Of the participants with PCHL, 32 (44%), 18 (25%) and 23 (32%) had moderate, severe and profound PCHL, respectively . For the10.1136/bmjpo-2017-000228.supp1Supplementary file 1The mean (SD) cost estimates for the teenagers with PCHL and the HCG were £15 914 (14 168) and £5883 (2076), respectively (mean difference (95% CI) £10 031 (£6459 to £13 603), P<0.001) . Both edModerate, severe and profound PCHL were associated with mean costs of £11 799, £12 489 and £24 320, respectively . The meaOf those participants with AMC, 56%, 19% and 25% had moderate, severe, and profound PCHL, respectively. Overall, the presence of a medical condition additional to PCHL was associated with higher mean costs (95% CI) by £15 385 (£8533 to £22 238). This cost difference was £21 876 (£13 024 to £30 728) for loss of vision, £14 200 (£5620 to £22 780) for genetic syndromes, £11 728 (£5456 to £18 000) for intellectual disability and £1642 (−£8013 to £11 296) for cerebral palsy. For the moderate, severe and profound groups, the mean costs by severity for the PCHL group with and without AMC (n=1657) were £22 436, £36 318, £33 990 and £7637, £7723, £22 285, respectively.In children with PCHL, the total mean annual costs associated with birth in periods with and without UNHS were £14 043 and £17 637, respectively  . The cosEarly confirmation of PCHL, like birth in periods with UNHS, was not associated with a significant difference in cost  . The cosEach unit increase in receptive language ability z-score was associated with significantly lower annual costs by £1616 (95% CI £842 to £2389) (P<0.001). Similarly, each unit increase in reading ability z-score was associated with marginally significantly lower annual costs by £1887  . Both of>40 dB at ages 13–20 years was associated with 2.7-fold higher costs in the preceding 12-month period and the presence of prespecified medical conditions in addition to PCHL increased costs almost twofold. No statistically significant association was found between either birth in periods with UNHS or early confirmation of PCHL and costs in adolescence.Compared with participants of similar age with normal hearing, the presence of bilateral PCHL In participants with PCHL, superior language skills were associated with lower costs and this remained marginally significant (0.05<P<0.1) after adjustment for the presence of a cochlear implant or an AMC but not after adjustment for severity of PCHL. Superior receptive language scores were associated with significantly lower costs in the same birth cohort when assessed 9 years earlier at ages 5–10 years.The 7-year range of age at time of assessment is consequent on the study design, that is, an evaluation of a 5-year birth cohort conducted over a 3-year study period. This is both a limitation, in that it makes the estimate for any 1 year of age less precise, and a strength, in that it makes the findings more generalisable to teenagers in general.The two principal limitations of the study were the modest study size with 120 participants at the outset and further reduction in its power to look at subgroups  by slow but steady loss of participants over the 17 years of follow-up, although without apparent attrition bias.The receptive language skills, which we found to be superior in children with PCHL born in periods with UNHS in our study population,Reports of societal costs in more recent and larger birth cohorts exposed to UNHS, such as those reported in the NetherlandsThe messages for policymakers of the associations observed, both at 5–10 years and in adolescence, in the birth cohort reported here include confirmation of the association between PCHL and significantly increased cost to society and the suggestion that interventions that improve language skills may bring benefit to the individual with PCHL and may be seen as a financial investment that should bring longer term cost savings through reductions in educational spending. These findings need confirmation in other larger birth cohorts.


Epigenetics and mitochondrial function in fetal tissues might be molecular signatures responsive to in utero tobacco smoke exposure.Maternal smoking during pregnancy results in an increased risk of low birth weight through perturbations in the ONAGE birth cohort, we investigated the effect of self-reported tobacco smoke exposure during pregnancy on birth weight and the relation with placental tissue markers such as, (1) relative mitochondrial DNA (mtDNA) content as determined by real-time quantitative PCR, (2) DNA methylation of specific loci of mtDNA (D-loop and MT-RNR1), and (3) DNA methylation of the biotransformation gene CYP1A1 (the last two determined by bisulfite-pyrosequencing). The total pregnant mother sample included 255 non-smokers, 65 former-smokers who had quit smoking before pregnancy, and 62 smokers who continued smoking during pregnancy.In the framework of the ENVIRp = 0.0002] than mothers who did not smoke during pregnancy. In the smoker group, the relative mtDNA content was lower  than in the non-smoker group; whereas, absolute mtDNA methylation levels of MT-RNR1 were higher . Lower CpG-specific methylation of CYP1A1 in placental tissue  were observed in smokers compared with non-smokers. Nevertheless, no mediation of CYP1A1 methylation nor any other investigated molecular signature was observed for the association between tobacco smoke exposure and birth weight.Smokers delivered newborns with a birth weight on average 208 g lower [95% confidence interval (CI) −318 to −99, CYP1A1 methylation in placental tissue may serve as molecular signatures for the association between gestational tobacco smoke exposure and low birth weight.mtDNA content, methylation of specific loci of mtDNA, and The online version of this article (doi:10.1186/s12967-016-1113-4) contains supplementary material, which is available to authorized users. A growing area of research interest with major public health implications are the consequence of insults during fetal life for the health status in child- and adulthood. It is well known that maternal smoking during pregnancy increases the risk of low birth weight , 2 and pCYP1A1  via the aryl hyrdrocarbon receptor (Ahr) signaling pathway resulting in an oxidative imbalance of the cells. Mitochondrial DNA (mtDNA), which resides as multiple double stranded circular copies in mitochondria, is extremely vulnerable and responsive to tobacco-induced oxidative stress [CYP1A1) [Tobacco smoke consists of particulate and gaseous phases containing more than 7000 chemicals of which at least 70 substances are known to cause cancer . Constite stress . As a ree stress . The inte stress , 12. DNAe stress , 14. Gloe stress –18 and g[CYP1A1) –26 DNA m[CYP1A1) , 24, 27.CYP1A1 methylation, we integrated these biological endpoints in our investigation of placental tissue collected in the framework of the ENVIRONAGE birth cohort study [While several studies described separately the effect of maternal smoking during pregnancy on birth weight, mitochondrial DNA, and rt study . We hypoONAGE birth cohort in Belgium . All procedures were approved by the Ethical Committee of Hasselt University and East-Limburg Hospital. The study design and procedures were previously described in detail [n = 62), whether they smoked before pregnancy and stopped when pregnant , or whether they never smoked in their life . Mothers who had ever smoked filled out the number of smoking years and the number of cigarettes smoked per day before and during pregnancy. We also asked the mothers how long (months) they continued smoking before becoming aware of being pregnant. Furthermore, we have data on passive smoke exposure (due to indoor smoking by somebody else).In the present study, 382 mother-newborn pairs were enrolled in the ENVIRn detail . Briefly3) at a fixed location from the fetal side of the placenta, approximately 1–1.5 cm below the chorio-amniotic membrane, and preserved the biopsies at −80 °C [Placentas were deep-frozen within 10 min after delivery. Specimens of placental tissue were taken on minimally thawed placentas for DNA extraction. We took villous tissue , the D-loop region , and MT-RNR1 .We performed DNA methylation analysis by highly quantitative bisulfite polymerase chain reaction (PCR) pyrosequencing as previously described in detail . BisulfiMTF3212/R3319 and MT-ND1) to two single-copy nuclear control genes (RPLP0 and ACTB) using a quantitative real-time PCR (qPCR) assay as previously described [® Green I dye 2x (5 µl/reaction), forward and reverse primer (each 0.3 µl/reaction), and RNase free water (1.9 µl/reaction) for a final volume of 10 µl per well. Primer sequences  for each CpG site of CYP1A1 (four CpGs), MT-RNR1 (two CpGs) and the D-loop region (three CpGs). Correlations between adjacent CpG sites within one gene or region were tested with Pearson correlation coefficients. With mixed-effects models, we took into account each CpG dinucleotide position and tested the association between gene-specific DNA methylation and maternal smoking status. We applied Dunnett’s test for multiple comparisons of smokers and past-smokers with the reference group (non-smokers). Maternal alcohol consumption, medication use, physical activity, maternal education, ethnicity, maternal age, pre-pregnancy BMI, parity, gestational age, and newborn’s sex were considered as possible confounders, but only those associated with maternal smoking (p ≤ 0.05) and which potentially could influence birth weight and length, mtDNA content or DNA methylation were considered for entry in the models. However, newborn’s sex, maternal age, gestational age, ethnicity, parity, and pre-pregnancy BMI were forced into the model regardless of the p value, in addition to maternal education, and alcohol consumption. Q–Q plots of the residuals were used to test the linearity assumption of the models.We used SAS software  for database management and statistical analysis. Relative mtDNA content (unitless) was logIn a sensitivity analysis, Pearson correlation coefficients were calculated between birth weight or length and measures of smoking . Furthermore, we used mediation analysis to investigate whether the examined molecular signatures underlie the association between gestational tobacco smoke exposure and birth weight .n = 332) of the newborns were Europeans of Caucasian ethnicity. Mean maternal age was 29.0 years (range 18–42 years). Most women  never smoked cigarettes and 65 women (17.0%) stopped smoking before pregnancy; whereas, 62 mothers (16.2%) reported to have smoked during pregnancy [on average 7.8 cigarettes per day  occasionally consumed alcohol during their pregnancy.Demographic characteristics and perinatal factors of 382 mother-newborn pairs are reported in Table p = 0.008), comprised less women with higher education , and delivered newborns of lower birth weight and length. Alcohol consumption was higher in the past-smoker group than in the non-smoker group .Compared to the non-smokers, the group of smoking mothers were younger  and a shorter birth length  in newborns delivered by women who continued smoking during pregnancy compared to non-smoking mothers. Mothers who stopped smoking before pregnancy delivered newborns whose birth weight (p = 0.55) or length (p = 0.87) did not differ from that of never-smokers.Birth weight and length were respectively 225 g and 1 cm lower for newborns from the smoker mothers compared to the non-smokers (Table p = 0.01) lower in smoking mothers, but not in past-smokers (p = 0.72), in comparison with non-smokers  and marginally higher in mothers who stopped smoking prior to pregnancy  compared with non-smokers , and the methylation levels at the D-loop region did not differ between the groups (p = 0.85).After adjustment for the aforementioned covariates, the relative mtDNA content in placental tissue was 21.6%  . Placental methylation levels at CpG3 were significantly lower in mothers who continued smoking during pregnancy compared to non-smoking mothers   Table . No signCYP1A1 methylation levels with placental mtDNA content , and a negative association with placental mtDNA methylation  .As anticipated, we observed a clear dose-effect relation between birth weight or length and measures of smoking status . In comparison with non-smokers, no significant difference was observed in birth weight or length of newborns from mothers who stopped smoking for a longer period of time before pregnancy or mothers who stopped just prior to pregnancy. We observed a positive association of 02) Fig. . FurtherCYP1A1 in placental tissue.The present investigation showed that women who smoked during pregnancy had neonates with lower birth weight and length, lower mtDNA content, higher mtDNA methylation at specific loci, and lower CpG-specific methylation levels of CYP1A1 in placental tissue, which could be indicative of a relationship between mitochondrial dysfunction and the epigenetic landscape of the nuclear genome [Despite a limited number of (epi)genomic studies in placental tissue and cord blood, we are improving our understanding of the molecular pathways underlying the association between gestational tobacco smoke exposure and low birth weight. Combining gene expression and epigenome-wide methylation arrays Suter et al.  showed tr genome . Whetherloci in a number of individuals and also to assess whether any of these CpG loci are associated with a trait or an environmental pollutant [AHRR and CYP1A1) in cord blood of newborns exposed to tobacco smoke during pregnancy. This finding was confirmed in another population of infants by analyzing whole blood obtained by a heel prick [CYP1A1 in cord blood [CYP1A1 gene in placental tissue which is in contrast with the findings in cord blood [CYP1A1 in our study, Suter et al. [CYP1A1 in placental tissue. Moreover, other studies demonstrated increased CYP1A1 mRNA [An expanding body of evidence suggests that the epigenome of placental tissue and cord blood is sensitive to environmental exposures . Epigenoollutant . A 450 Kollutant  demonstrel prick . Maternard blood . Conversrd blood  observedrd blood  in cord rd blood  in placerd blood . Althougr et al.  previous1A1 mRNA  and prot1A1 mRNA  expressi1A1 mRNA .Fig. 4CpA limitation of our study is the chance of exposure misclassification. Information about maternal smoking during pregnancy was based on self-report and is not verifiable. A possibility to overcome this limitation is the determination of the cotinine concentration in plasma or urine of the mother. Nevertheless, previous studies demonstrated that this would not be superior to self-reported smoking habit in pregnant women . We acknOur findings are of clinical relevance because responses of mitochondrial DNA and changes in the fetal methylome are plausible alterations that may underlie the adverse effect of tobacco smoke exposure on birth weight. They increase our knowledge on the mechanisms of perturbations in the fetoplacental exchange that might lie at basis of low birth weight and, hence, may be used in the broader sense of clinical context.ONAGE birth cohort.This study provides epidemiological evidence of molecular changes in placental tissue that can serve as molecular signatures of exposure to tobacco smoke during pregnancy. Whether the molecular signatures described in our study may be related to early developmental changes in Belgian children will be investigated in the ongoing follow-up study of the ENVIR


Streptococcus , and infants born by C-section (n = 7). Molecular profiles  of the 16 S rRNA genes indicate that there is a delay in the expansion of Bifidobacterium, which was the dominate infant gut colonizer, over the first 12 weeks and a persistence of Escherichia when IAP for GBS exposure is present during vaginal labour. Longer duration of IAP exposure increased the magnitude of the effect on Bifidobacterium populations, suggesting a longer delay in microbial community maturation. As with prior studies, we found altered gut colonisation following C-section that included a notable lack of Bacteroidetes. This study found that exposure of infants to IAP for GBS during vaginal birth affected aspects of gut microbial ecology that, although dramatic at early time points, disappeared by 12 weeks of age in most infants.Early life microbial colonization and succession is critically important to healthy development with impacts on metabolic and immunologic processes throughout life. A longitudinal prospective cohort was recruited from midwifery practices to include infants born at full term gestation to women with uncomplicated pregnancies. Here we compare bacterial community succession in infants born vaginally, with no exposure to antibiotics (n = 53), with infants who were exposed to intrapartum antibiotic prophylaxis (IAP) for Group B  In the first hours and days following birth there is a rapid evolution of microbial communities3 becoming adult-like before 3 years of age5. When initial exposure to the maternal microbiota is altered, for instance due to birth by Caesarean section (C-section), colonisation of the infant gut has been shown to differ in both the type and distribution of organisms10. It is possible that an atypical microbiota established early in life disrupts the initiation of metabolic and immunologic processes and contributes to lifelong changes in the host but details about microbial succession during this formative period are limited. The microbiome has been associated with chronic diseases in adulthood, such as obesity12, allergy and atopy13, inflammatory bowel disease14, and the development of colon cancer15, however causal effects in either direction have not been shown. It is, therefore, essential to understand infant gut microbial community succession, in the absence of medical interventions, and to study the impacts of early life exposures on the processes involved.The intestinal microbiota is essential for metabolic, nutritional, physiological and immunologic processes and influences a broad range of health outcomes16 and management of Group B Streptococcus (GBS)17. Although treatment with IAP is considered safe, the impact on gut microbiome development in the infant is uncertain. IAP may affect non-target bacterial populations within the mother and reduce the transmission of susceptible bacterial groups to the infant during delivery. In addition, establishment of the gut microbiome may be altered as a result of IAP passed into the fetal/neonatal bloodstream through the placenta.In North America, as many as 50% of all low risk, full term infants are exposed to intrapartum antibiotic prophylaxis (IAP) for indications such as prevention of maternal infection associated with C-section birth18, infant feeding practices18 and administration of oral antibiotics to infants19. Here we describe early findings of the Baby & Mi pilot study20, a prospective birth cohort designed to specifically determine the effects of intrapartum antibiotic administration on the development of infant gut microbiome among a low-risk population in Ontario, Canada. This longitudinal study describes the very early gut microbiome development at four time points over the first 12 weeks of life.While many studies have addressed the gut microbiome in adults, research on the developing infant microbiome has focused mainly on the impact of C-section birth20 enrolled 83 mother-infant pairs. Five participants were excluded as follows: ineligibility for continued follow up due to a high risk complication prior to birth (n = 1), withdrawal prior to birth (n = 1), lost to follow up (n = 2) and not providing any samples up to the 12 week time point (n = 1). As our intent was to focus on the influence of IAP for GBS on the developing gut microbiome, we also excluded 4 participants from this analysis due to exposure to IAP for GBS and C-section (n = 3) or exposure to antibiotics for treatment of a suspected infection (n = 1). An analysis of the effect of IAP for GBS on the infant gut microbiome that also accounts for delivery mode will be undertaken in the full study, should the number of participants be sufficient to overcome the inter-individual variability in the type and abundance of shared microbial signatures. Thus, the analysed cohort was comprised of 74 mother-infant pairs. Table th CI: 11, 831 minutes), with longer exposures in the vaginal IAP for GBS group than in those receiving IAP for a C-section. Furthermore, 63% of the vaginal IAP group were exposed to antibiotics for >4 hours prior to delivery compare to none in the C-section group. All of the C-section deliveries occurred after the onset of active labour; none were electively scheduled. All babies were breastfed at least partially. Infant exposure to antibiotics was low in the first 12 weeks of life with only 2 (3%) receiving antibiotics.The Baby & Mi pilot cohortirth n = , withdraOverall, the gut microbiome of infants born vaginally without exposure to IAP differed significantly from that of infants born vaginally but exposed to IAP for GBS or born by C-section . The bacterial community in fecal microbiota from infants exposed to IAP for GBS prior to vaginal birth, differed from that of unexposed infants at 10 days and 6 weeks of age (p < 0.05) but no differences were seen by 12 weeks Table . The relThe gut microbiome of infants born by C-section was different from the microbiome in vaginally born infants, without IAP exposure, at each time point except 6 weeks  at early time points but, reached levels similar to communities in unexposed infants by 12 weeks of age Fig. . Trends Bifidobacterium (p < 0.01), a positive effect on the abundance of Escherichia (p < 0.05), at 12 weeks of age  and positive effect on the abundance of Clostridium (p < 0.05) over time  on the pattern of microbiome development, we made several novel observations. We identified a distinct influence of IAP for GBS on the fecal microbiota of infants born vaginally and noted that the length of intrapartum exposure to the antibiotics influenced this impact.Succession of bacterial populations during early infancy has an important influence on early immunological and metabolic programming that can affect long-term healthBifidobacterium, Escherichia and Bacteroides23, we found that amongst healthy, full-term, vaginally born infants not exposed to IAP, an abundance of Bifidobacterium came to dominate the bacterial communities in many infants by 12 weeks, with a corresponding decrease of other members of the communities that were most dominant at 3 days and 10 days, notably Escherichia and Streptococcus.Similar to previous studies that found the infant gut microbiome of newborns were colonized mainly by 24, C- section19 and formula feeding25 have been shown to alter patterns of succession. However, prior studies have not accounted for IAP for GBS during vaginal delivery, which may have influenced these results. We have demonstrated a clear effect of IAP for GBS on the infant gut microbiome amongst vaginally born infants. The fecal microbiota of IAP exposed infants had significantly lower alpha diversity and there was a delay in the colonization patterns in these infants compared with unexposed infants. Bacterial genera most impacted by IAP for GBS during vaginal birth included Bifidobacterium, Escherichia and Parabacteroides. By 12 weeks of age, community diversity and structure of the bacterial communities of vaginally born infants exposed to IAP for GBS was similar to that of unexposed infants. However, for every hour of IAP administration, there was a decrease of 7% in the abundance of Bifidobacterium at 12 weeks suggesting that infants with longer IAP exposures experienced a more persistent impact. Previous studies on the effect of IAP6 (or GBS26) on the early infant gut microbiome have overlooked its impact on populations of Bifidobacterium. Whether this is due to underestimation of Bifidobacteria in these previous studies or a genuine difference in bacterial profiles within participants is unknown.Early life events such as preterm birth28. Consistent with previous studies, we observed an effect of C-section delivery on the infant microbiome. Though the number of infants born by C-section was low, it is important to note that none of these babies was a planned C-section, meaning that all of the mothers had entered labour. Results from previous studies on the effect of C-section10 matched what we observed, namely an absence of Bacteroidetes for up to 12 weeks and a reduction in Actinobacteria. The reduction in the abundance of Bacteroidetes was more pronounced after C-section delivery  than it was after vaginal birth with IAP for GBS when compared with infants born vaginally and not exposed to IAP. This suggests that IAP exposure acts independently of mode of delivery in influencing the gut microbiota over the first 12 weeks of life. It is important to consider that the antibiotics utilized for GBS are different from those used to prevent maternal infection associated with C-section.Birth by C-section has been associated with negative health outcomes in childhood and later life such as allergy, asthma and obesity20 that will determine the long-term consequences of IAP for GBS on both microbial community succession and on host health and disease risk and provide the power necessary to explore in more depth the influence of maternal and infant covariates on the infant gut microbiome.The first 12 weeks of life is a period marked by few outside exposures, compared to later in infancy, and is a critical period for development of the infant gastrointestinal microbiome. This study found that IAP for GBS affected all aspects of gut microbial ecology including species richness, diversity, community structure, and the abundance of colonizing bacterial genera. We found that although dramatic at early time points, effects of IAP for GBS on the microbiome during vaginal birth largely disappeared by 12 weeks of age in most infants. The impact of IAP for GBS on the gut community in infants was also impacted by the duration of IAP administration. This study recapitulated previously published observations examining the influence of C-section delivery, and suggests that IAP may act independently of mode of delivery to impact the bacterial populations that colonize the infant gut. A larger study is underway29 with no pregnancy complications now or in the past, no significant maternal medical disease, no prior perinatal morbidity or mortality, with adequate fetal growth and they needed to be planning a vaginal birth. Further, they needed to be able to communicate in English. Women were excluded if they had a multiple pregnancy or a preterm birth (before 37 completed weeks gestation).A cohort of mother-infant pairs was formed by enrolling eligible women from midwifery practices in Hamilton and Burlington, Ontario, Canada between July 1st 2012 and December 31st 2013. Women were eligible to participate in the study if they were under the care of a midwife which necessitates that they have a healthy pregnancy with low predictable risk (i.e. low risk) defined according to the Ontario Antenatal recordBirth data and obstetrical history, including maternal age, place of birth, mode of birth, IAP exposure  and gender were collected from antenatal and birth records and mother and infant charts by the midwives. Infant stool samples and data about infant diet and infant antibiotic use were collected from the mothers as closely as possible to 3 days, 10 days, 6 weeks and 12 weeks postpartum. Diapers containing stool were transferred to a plastic storage bag, stored frozen in a household freezer and delivered to the laboratory by the women when they attended study visits with their infants at weeks 6 and 12 at McMaster University Medical Centre. Methods were carried out in accordance with the Research Ethics Boards at all participating healthcare organisations , St. Joseph’s Healthcare Hamilton (Project number: 12-3721) and Joseph Brant Hospital (Study number: 000-022-14)) and all participants, or their legal guardians, provided written informed consent. All experiment protocols were approved by McMaster University Biosafety Office (BUP-128).30. The bacterial 16 S ribosomal ribonucleic acid (rRNA) gene v3 region (150 bp) was amplified as in31 and libraries were sequenced in the McMaster Genomics Facility in the forward and reverse direction on the Illumina MiSeq instrument as described previously30. The completed run was de-multiplexed with Illumina’s Casava software.DNA was extracted from 100–200 mg of stool with a custom DNA extraction protocol involving mechanical and enzymatic lysis followed by a phenol:chloroform extraction and purification, as previously described39. Briefly, after sequence trimming, alignment and filtering to remove sequences with length <100 bp, operational taxonomic units (OTU) were picked using AbundantOTU+ 33 with a clustering threshold of 97%. Taxonomy for each OTU’s representative sequence was assigned using the Ribosomal Database Project classifier34 with a minimum confidence cut-off of 0.8 against the Greengenes (2013 release) reference database. All OTUs classified as “Root:Other”, indicating that they were not of bacterial origin, were excluded.Illumina sequences were processed as described35 formulation for calculating the expected species richness in random subsamples from the community, calculated with a depth of 11,231 sequences. Shannon diversity was calculated with the diversity function, within the vegan package in R36. For principal coordinate analysis (PCoA) beta diversity was calculated with the Bray-Curtis dissimilarity measure36 on relative OTU abundances. For comparative analyses  beta diversity was also calculated with the Bray-Curtis dissimilarity measure but on genus level abundances, since OTU level analysis (excluding singletons) did not indicate an effect of IAP for GBS . This was likely due to inter-individual variability in OTU carriage since many OTUs provided only a minor contribution to the variability in the microbiome due to IAP for GBS exposure, whereas only a small number of genera contributed greatly to the IAP for GBS effect  were reported in a separate table. For the comparative analysis, samples were first stratified by collection time point, then by mode of birth. Amongst vaginally born infants with IAP for GBS exposure, the effect of IAP (binary variable) and duration of IAP administration (continuous variable) were analysed. Finally, the effect of mode of birth on the microbiome was compared among Caesarean born and vaginally born infants who were not exposed to IAP for GBS.Beta diversity was explored with PCoA ordination of Bray-Curtis dissimilarities calculated from relative OTU abundances. Next, a comparative analysis was done with permutational multivariate analysis of variance using Bray-Curtis dissimilarity matrices calculated from genus level taxonomic assignments with the adonis function within the vegan package in R37 significance was determined with the lmerTest package in R38. The effect of IAP for GBS on alpha diversity estimates was modeled within vaginal births only by adding IAP to the model as a fixed effect. Abundance of each of the top 10 bacterial genera was modeled over time within infants born vaginally and either exposure to IAP for GBS or duration of IAP exposure for GBS included as a fixed effect. The effect of delivery method was similarly modeled, however, first excluding all vaginal births with IAP for GBS then including Caesarean delivery as a fixed effect. Multiple testing correction was not applied, due to the exploratory nature of this study, whose purpose was for the generation of hypotheses and not for definitive inference.There was a distribution of ages at each collection point Figure , therefoThe datasets generated and analysed during the current study are available through NCBI SRA under accession  PRJNA403824.Ethics approval was obtained from the Research Ethics Boards at all participating healthcare organisations , St. Joseph’s Healthcare Hamilton (Project number: 12-3721) and Joseph Brant Hospital (Study number: 000-022-14)) and all participants provided written informed consent.Supplementary material


In line with the wider application of non-contact voltage transducers in the engineering field, transducers are required to have better performance for different measuring environments. In the present study, the D-dot voltage transducer is further improved based on previous research in order to meet the requirements for long-distance measurement of electric transmission lines. When measuring three-phase electric transmission lines, problems such as synchronous data collection and composite electric field need to be resolved. A decomposition method is proposed with respect to the superimposed electric field generated between neighboring phases. The charge simulation method is utilized to deduce the decomposition equation of the composite electric field and the validity of the proposed method is verified by simulation calculation software. With the deduced equation as the algorithm foundation, this paper improves hardware circuits, establishes a measuring system and constructs an experimental platform for examination. Under experimental conditions, a 10 kV electric transmission line was tested for steady-state errors, and the measuring results of the transducer and the high-voltage detection head were compared. Ansoft Maxwell Stimulation Software was adopted to obtain the electric field intensity in different positions under transmission lines; its values and the measuring values of the transducer were also compared. Experimental results show that the three-phase transducer is characterized by a relatively good synchronization for data measurement, measuring results with high precision, and an error ratio within a prescribed limit. Therefore, the proposed three-phase transducer can be broadly applied and popularized in the engineering field. The operational status and health level of alternating-current transmission lines could be directly reflected by the amplitude and phase position of three-phase voltage, offering direct data references for the operation and maintenance of an electric system . The conCurrently, a large amount of research work has been carried out to improve the performance of field-type transducers. The authors of  proposedThus, charge simulation method is used to deduce a composite electric field equation at any point of a three-phase transmission line. This paper establishes a mathematical model for horizontally arranged lines, to decompose the composite electric field, calculate the electric field component and obtain a derived inversion equation of the electric field component. Simulation calculation software has been adopted to determine the voltage of three-phase lines by measuring the data of a three-phase transducer, and an experimental platform has been constructed to verify the performance of the studied measuring system and validate values of theoretical studies and actual systematic projects.The working principle of a D-dot transducer can be summarized as follows: performing non-contact indirect measurements of the voltage by measuring the rate of change for electric displacement vector .t) as the electric field intensity of the measured point, r as the distance of the measured point to the wire center, and r0 as the radius of the electric cable.Specific measurement principles can be found in references ,15. For Furthermore, the resistance drop has a positive relationship with the rate of change related to the electric field in the electrode , which ceqA is represented as the equivalent area of the voltage transducer, whereas R is the load resistance value.In the equation, Based on the uniqueness theorem of the electric field, Charge Simulation Method is to replace electric charges distributed continuously in the surface of energized conductor by a set of discrete charges in the conductor , and all the charges are simulative ones ,17. SimuFor the convenience of engineering calculations, the simplified treatment is conducted for the model of three-phase transmission lines: the ground is an infinitely great conductor plane with an electric potential of 0; charges have no electric field distortion. In the computational domain, the electric three-phase conductor shall only be considered and surrounding conductors can be neglected , such asj  that are set in the interior of the transmission conductor with three phases, namely, A, B and C. In addition, a rectangular coordinate system is established in a two-dimensional computational domain with given potential boundary conditions, and  is regarded as its coordinate. Q = P−1According to the superposition theorem, electric potential expression obtained , which ijth simulative charge generated in ith point; P electric potential coefficient matrix, the ijP solution equation based on image theory is:In Equation (4), ih is the height of the conductor to the ground; Rn is the radius of the conductor; i conductor and its mirror image to j conductor.In Equation (5), xE and yE respectively in the horizontal and vertical directions for any point  in the computational domain can be obtained:Based on superposition theorem, the values of the electric field intensity The transducer is installed under the transmission conductor. Given that the electric field intensity in the x direction is quite small, only the y direction shall be considered, namely, the electrical field intensity in the vertical direction. According to Equation (6), the composite electric field intensity of any position near the conductor can be calculated . In orde2, the distance between phases is L = 1.38 m, and the vertical height from the ground is 1.8 m. Three D-dot voltage transducers are respectively installed right under the three phases of the conductor, namely, Sensor A, Sensor B and Sensor C, h = 0.15 m, as shown in Taking the horizontally arranged 10 kV overhead transmission line as the case, its composite electric field detected by a three-phase transducer is decomposed for simulation calculation. Based on LGJ-500-45 regulations, the sectional area of the conductor radius is 35 mmAZE is the electric field component of the transducer arranged vertically under an A-phase conductor; C1E is represented as the electric field component of the C-phase conductor to Transducer A; and B1E is the electric field component of the B-phase to Transducer A. Meanwhile, the electric field components of all phases in Transducers B and C are as shown by the marks of the figure and the distances of the three transducers to the conductor are all equal to h. From In a 10 kV transmission line, a three phase transmission line is arranged horizontally, as shown in From Equation (7), the electric field intensity of Transducer A is composed of three electric field components: A-phase conductor component and the disturbance variables of the B and C conductors. Similarly, the electric field intensity measured by Transducers B and C is respectively constituted by the electric field component of the respective conductors and disturbance variables of neighboring two-phase conductors. Equation (6) shall be substituted into Equation (7):AzE, BzE and CzE. The line voltage of the three-phase transmission line can be calculated by Equations (1)–(3). When the voltage phase is 0[deg] and contrasts with the reverse generation results of the actual voltage of transmission line, the relative amplitude errors are as shown in the following table:After the measurement, the above results in Based on the data from The data further show that the voltage amplitude has slight errors, which are caused by errors of the device module, and data conversion errors, among others, in a simulation environment. The inductance exists in loops with slightly declinational phases. Results show that theoretical values acquired by a non-contact voltage transducer are highly consistent with measured ones.In this paper, Ansoft software is used to implement the simulation of the electric field distribution under the transmission line. The results of the simulation are compared with the results of the subsequent measurement system. The model parameters of the three-phase transmission line to be established are listed in the following A line is drawn under each phase of the transmission line. The voltage value is checked at each point of the three lines, as shown in The voltage measurement system of three-phase D-dot transducer as show in The D-dot electric field transducer is made into the form of a PCB (Printed Circuit Board) in Voltage signals measured by the D-dot voltage transducer are processed for pre-amplification and electrical-level lifting by an analog signal processing module. After the treatment, a single-chip carries out high-speed collection and AD converter for the treated analog signals. Then the acquired digital signals are delivered to a WIFI wireless communication module according to the UART  Communication Protocol. The signals are then transformed to the UDP (User Datagram Protocol) protocol format and transferred to a data acceptance unit in the PC-port software by wireless networks.After the data measured by the transducer is received by the data acceptance unit in a PC-port software part, iterative computations are executed by a digital signal processing unit to restore voltage waveforms of three phases. Moreover, the discrete signal collected by the sensor is converted into a continuous signal through the AD conversion, and the synthetic field decomposition algorithm proposed in the theoretical analysis is utilized. Then, the voltage waveform analysis unit analyzes this voltage signal to obtain information such as its voltage amplitude, frequency and degree of distortion. The waveform record unit performs the waveform storage for follow-up consultation and usage.To test the D-dot transducer and the working performance of its measurement system, the three-phase experimental platform is established to measure the results and analyze the electric field environment of the 10 kV voltage power line transmission line. The measurement spot of the voltage transducer is shown in After the voltage regulator, the three-phase alternating current is loaded to three-phase transmission line after boosting the standard voltage transformer. The transducer is installed right under the transmission line and measuring circuits are connected to the transducer by signal lines. Collected data are then sent to the host computer by wireless module and the upper computer adopts the LabVIEW software for programming. Following the UDP Communication Protocol, data are received and transferred to corresponding iterative calculation module to a finally acquire the three-phase voltage waveform.As shown in The experimental part of the article will be analyzed from two aspects, according to the IEC60044-7 Standard. The results of the two aspect experiment determine whether the performance of the transducer can meet the requirements of the actual application.The steady-state error experiment is implemented in the built experimental platform. According to IEC60044-7 Standard, the value of the three-phase voltage is adjusted during the experiment. The proportion of the rated voltage is 10%, 20%, 40%, 60%, 80%, 100% and 120% respectively, using the high-voltage detection head and the non-contact voltage transformer for measurement. In addition, the high-voltage detection head is connected to a three-phase conductor and the oscilloscope is adopted to synchronously measure voltage. Finally, data in two different voltage measuring points are fit to acquire a comparison of the linearity between the high-voltage detection head and the experimental system and to obtain the error ratio of the voltage.H. Output voltages of the transducer are sent to the computing unit, which exist based on Equations (1)–(8) to acquire measured voltage UM by inverse substitution. Dynamic range and linearity of the transducer are measured and results are shown in The detection results of High-voltage probe are represented by UBased on the obtained detected data, a comparative experiment, the calibration curve and the error curve of the output voltage of the transducer and high-voltage detection head are shown in When the initial phase of three-phase transmission line is 0, we use sensors to measure different positions under the transmission line to obtain their voltage values, and simultaneously extract voltage values from the Ansoft simulation results at the same point. We then contrast the two voltage values. The solid triangle represents the simulation results and the hollow triangle represents the result of the measurement as shown in the figure below. Our comparison and analysis of the results measured by the high-voltage detection head and the transducer, are as follows.(1)As shown in the LabVIEW display from (2)When the three-phase voltage changed within range of 10%–120% of the rated voltage, the specific value error of the electric-field coupling voltage transducer is ε% < 0.5%. The measured voltage in The measured results of the software simulation and transducer are compared and analyzed. In the comparative curve in From the two experiments above, we observe that the measured results have some errors and the error becomes more significant with an increase in the measured distance. This observation is because the boundary conditions adopted in the simulation calculation are ideal, but the conductor length, sag and transducer location all deviated from ideal conditions, thus largely affecting precision.The three-phase D-dot voltage transducer measuring system was constructed and tested. With the aim of addressing the composite electric field problem during the measurement process of a three-phase transmission line, we proposed a decomposition method and verified its feasibility with experiments. The measuring system can realize synchronous acquisition by multipath signals and successfully meet the accuracy class of the 0.5-level voltage transformer used for measurement when the rated voltage is within the range of 10%–120%. Furthermore it has relatively good linearity across all voltage measuring points.The non-contact voltage measuring system of a three-phase field-type transducer further promotes non-contact voltage measuring work in electric power projects. In cases where the measuring precision requirement is not high, the measuring system can achieve a rapid, convenient and safe measurement, which has relatively high engineering value in measuring electric parameters of distribution automation. In current projects, influences of tower sag and locations places of multiple transducers will result in errors of the voltage measurement in an experimental system. Thus, for future studies, the complexity degree and algorithm precision of the model should be improved to gradually resolve this problem.


A tailgut cyst is a rare developmental lesion and usually is located in the retrorectal or presacral space. Extrahepatic hydatid disease has been reported in several locations including the pelvis and it often poses a diagnostic challenge. There are very few reported cases of primary perineal hydatid cysts. We present the multimodality imaging findings of a tailgut cyst and concurrent perineal hydatid disease in a 32-year-old male patient. A tailgut cyst is a rare congenital lesion. It has a female predilection and is usually asymptomatic and detected during middle age . It is u Echinococcus granulosus and Echinococcus multilocularis are the two main infectious causative agents. Although liver and lung are the most commonly affected organs, hydatid cysts have the potential to affect any part of the human body. Primary extrahepatic hydatid cysts have been reported in different organs and anatomical locations and generally pose a diagnostic challenge [Hydatid disease is a zoonotic parasitic disease.hallenge , 6. Therhallenge –9. We pr18F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scan was performed and showed no abnormal uptake in these lesions; no regional lymphadenopathy or distant metastases were seen  multilocular, hypoattenuating, retrorectal cystic lesion. It displaced the rectum and rectosigmoid anteriorly and had no relation with the prostate, seminal vesicles, or adjacent major vessels. The CT also revealed a collection of smaller contiguous cysts in the left ischioanal fossa and the left perineal subcutaneous fat. This collection of cysts paralleled and was adjacent to the left puborectalis muscle and breached the left levator ani. No other lesion was found in the abdominal cavity. Atrophy of the right hemipelvis and proximal thigh muscles was related to the history of poliomyelitis . An 18F-ere seen .Pelvic magnetic resonance imaging (MRI) was performed. The retrorectal mass showed intermediate signal intensity on both T1 and T2 with multiple internal T1 hypointense foci and T2 hyperintense foci. The left ischioanal fossa collection of cysts showed low T1 and high T2 signal intensity with multiple internal cysts and T2 and T1 hypointense rim. There was thin peripheral enhancement with no enhancing mural solid component. There was no osseous involvement .The patient underwent surgical resection. The histopathologic examination of the resected retrorectal cyst revealed a benign tailgut cyst. The resected left ischioanal and gluteal cystic lesions showed an outer histiocytic reaction to a hydatid cyst.The unique feature of this primary extrahepatic hydatid cyst is its very unusual location in the ischioanal fossa with extension to the left perianal and gluteal areas. While the hydatid cysts had increased signal on T2-weighted images, the tailgut cyst had intermediate signal, denoting proteinaceous or mucinous content. The presence of both a perineal hydatid cyst and tailgut cyst with differing signal characteristics on MRI in a contiguous location in one patient imposed a diagnostic challenge where the added information of MRI proved very useful. In fact, the interpreting radiologist suggested a developmental lesion such as a tailgut cyst and atypical hydatid disease. The differential diagnosis might include a myxoid tumor such as myxoid neurofibroma or aggressive angiomyxoma due to the presence of myxoid, proteinaceous, or mucinous contents. However, the lack of an enhancing solid component makes those diagnoses less likely.A tailgut cyst is a rare developmental lesion that is a remnant of the embryonic tailgut. The tailgut is the most caudal part of the hindgut that normally involutes during embryonic development. Tailgut cysts have a female predilection, are usually asymptomatic, and are often detected in middle age. They can be discovered at any age and may cause symptoms such as abdominal pain or constipation .The imaging findings of tailgut cysts on CT and MRI have been described. Usually, CT shows a presacral, discrete, and well-marginated lesion of fluid or soft tissue attenuation depending on the cyst contents. Cyst wall calcifications may be seen and the rectum may be displaced if the lesion is large –4. On MRBecause of the malignant potential of a tailgut cyst, to distinguish it from the other presacral cysts is essential. Differential diagnoses of a presacral cystic lesion might include rectal duplication cyst, dermoid cyst, epidermoid cyst, cystic lymphangioma, and anterior meningocele. These diagnoses are usually unilocular except for a tailgut cyst and cystic lymphangioma which are usually multicystic , 14. TaiEchinococcus granulosus and Echinococcus multilocularis are the two main infectious causative agents of hydatid disease. Dogs are usually the definitive hosts and sheep are the most common intermediate hosts. Humans are an intermediate host and may become infected after ingestion of food contaminated with Echinococcus eggs. Hydatid cysts have three components, the pericyst, middle laminated membrane, and the inner germinal layer. The pericyst is the surrounding host tissue inflammatory response. The scolex  arises from the inner endocyst [ Echinococcus antibody should be part of the work-up of any detected cystic lesion in an unusual location.endocyst , 6. AlthIn humans, hydatid disease affects the liver, the lung, and other locations in approximately 75%, 15%, and 10% of cases, respectively . When ocHydatid disease has a variable imaging appearance. There is a standardized WHO classification of the hydatid cyst stages based on the Gharbi ultrasound classification , 18. TheStojkovic et al. compared the MR and CT imaging findings with ultrasound and concluded that the hydatid cyst matrix is the main defining feature of cyst stage. Also, the “double line sign” is diagnostic for hydatid stage 1. The cyst wall calcifications play some role in defining cyst stage 5 which may be challenging on MRI. Therefore when compared to ultrasound, MRI performs very well with WHO hydatid cyst stages 1, 2, 3, and 4. T2-weighted MR images provide the best sequence to detect cyst contents, that is, septa (stage 2) and daughter cysts (stage 3b) . Singh aWhile a tailgut cyst is a rare entity, it should be considered when there is a presacral multilocular mass. Hydatid disease may affect any part of the human body and often has nonspecific imaging findings and serological tests are not always positive. The simultaneous contiguous occurrence of both diagnoses is rare. Attention to the unique imaging features of each cystic lesion facilitates the diagnosis. Clinicians and radiologists should entertain hydatid cysts in their differential diagnoses whenever they encounter cystic lesions especially if the patient is from an endemic area.