Access to emergency obstetric care, including assisted vaginal birth and caesarean birth, is crucial for improving maternal and childbirth outcomes. However, although the proportion of births by caesarean section has increased during the last few decades, the use of assisted vaginal birth has declined. This is particularly the case in low- and middle-income countries, despite an assisted vaginal birth often being less risky than caesarean birth. We therefore conducted a three-step process to identify a research agenda necessary to increase the use of, or reintroduce, assisted vaginal birth: after conducting an evidence synthesis, which informed a consultation with technical experts who proposed an initial research agenda, we sought and incorporated the views of women’s representatives of this agenda. This process has allowed us to identify a comprehensive research agenda, with topics categorized as: (i) the need to understand women’s perceptions of assisted vaginal birth, and provide appropriate and reliable information; (ii) the importance of training health-care providers in clinical skills but also in respectful care, effective communication, shared decision-making and informed consent; and (iii) the barriers to and facilitators of implementation and sustainability. From women’s feedback, we learned of the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if necessary. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth.  However, compared with a pre-labour or first-stage caesarean birth (i.e. when the cervix is not fully dilated), a caesarean delivery performed during the second stage of labour presents additional risks, including major haemorrhage, infection, extension of the uterine incision and trauma to the baby’s head.The cost-effectiveness of these interventions has not been extensively studied. However, in the United States of America, a cost-effectiveness model analysis of neonatal and maternal outcomes of assisted vaginal birth versus caesarean birth was conducted.–,–,,,Despite current evidence reporting the greater risks and higher costs of caesarean birth compared with assisted vaginal birth, the number of caesarean births has increased while the practice of assisted vaginal birth has declined, particularly in low- and middle-income countries.,,––,,–,Multiple factors contribute to the underuse of assisted vaginal birth globally: the practice requires clinical judgement, expertise and skills, but there exists a lack of adequately trained health-care providers, not only to conduct the procedure but also to identify which labouring women could benefit.WHO recognizes the crucial role of assisted vaginal birth in improving maternal and perinatal outcomes, but also acknowledges the need to conduct research to identify and address barriers to its implementation. WHO therefore led a three-step process to foster thinking and catalyse research on how to optimize the use of assisted vaginal birth, especially in low- and middle-income countries: (i) evidence syntheses; (ii) technical consultation with experts; and (iii) gathering of feedback and views from women’s representatives. We combined the results and outcomes from all three steps to identify the areas in which research, political engagement and support, and resources are urgently required. First, we conducted one quantitative and two mixed-methods systematic reviews of the global literature describing research on barriers to, and factors facilitating the use of, assisted vaginal birth. Our quantitative review synthesized evidence from 16 studies (10 based in low- and middle-income countries) that implemented interventions to increase or reintroduce the use of assisted vaginal births, including didactic sessions, simulation, hands-on training, guideline production and audit/feedback.This synthesis of evidence informed a consultation with 37 technical experts, including health- care providers, researchers, policy-makers and public health experts selected for their wide range of experience, perspectives and geographical locations. A research agenda required for the safe reintroduction of, or increased access to and use of, assisted vaginal birth, especially in low- and middle-income countries, was tentatively identified by participants of the consultation. Following the experts’ initial identification of a research agenda, we ascertained the perceived importance and relevance of this agenda at four workshops to which representatives of women’s and advocacy groups from 27 different countries were invited. To accommodate the range of languages spoken and geographical locations, the workshops were conducted online (each lasting 1.5–2 hours) in English (two), French (one) and Spanish (one) during April–May 2022. Each workshop was conducted by two independent professional facilitators contracted to WHO. Around a week before each workshop, participants were sent the tentatively identified research agenda so that they could begin to consider and construct their views on each research topic. The facilitators led discussions during the workshops and noted the opinions expressed; the facilitators then prepared reports detailing the women’s views on the importance and relevance of the topics on the identified research agenda.Earlier in 2023, WHO published a technical brief describing the results of this process; please see this technical brief for a tabulated form of the following.Accessing reliable information and debunking misconceptions about assisted vaginal birth may be a challenge in contemporary societies. Although most women have basic information about a caesarean birth, many are less familiar with assisted vaginal birth. The views of those who are aware of the practice may have been affected by catastrophic but rare outcomes, undermining evidence-based information and reliable statistics. WHO therefore emphasizes the need for research to understand how assisted vaginal birth is perceived by women and communities, and also how to provide appropriate, reliable and unbiased information about the practice. Determining the most effective ways to communicate information to women and their communities across different settings  is crucial. The provision of decision-making tools for women as well as the role of various communication channels  should both be explored.Women emphasized the importance of recognizing childbirth as a physiological process, as opposed to an illness. Recurrent concerns about assisted vaginal birth reported at the workshops were the safety of the practice, and the consequences of adverse events on both the newborn and mother. Women were greatly troubled by an apparent lack of follow-up and support  in the case of complications. Finally, the misuse of informed consent and its consequences  was identified as a source of distress for women. The importance of well-trained, skilled, knowledgeable and competent health-care providers cannot be overemphasized. Research is needed to identify the most effective ways to educate and train health-care providers to not only perform assisted vaginal birth, but also to recognize the indications and conditions for its safe use, the contraindications and how to manage any complications. The latter is particularly crucial since fear of complications is a documented deterrent for health-care providers considering offering assisted vaginal birth. In addition to improving the clinical skills of providers, training should include other skills such as effective communication, situation awareness, shared decision-making, informed consent, and how to respectfully guide women and their birth companions and/or family through the birth experience. Subsequently, it is essential to develop comprehensive guidelines and training packages that can be used and adapted at country level. As country-level opinion leaders, national professional associations must play an active role in preparing, updating and endorsing management guidelines for labour, childbirth and assisted vaginal birth that are both evidence-based and comprehensive. Professional associations must also support effective training and regulation that is conducive to high-quality assisted vaginal birth as an integral part of obstetric care.,,To be able to address recurrent concerns about the safety of the practice, studies comparing the effect of assisted vaginal birth with second-stage caesarean birth on both the short- and long-term maternal (e.g. the effect on the pelvic floor) and newborn outcomes are needed. In terms of clinical practice, research is needed on the optimal analgesia methods for assisted vaginal birth across different settings, and on the safety, feasibility and effectiveness of new technologies to perform the practice such as the OdonAssist device.The labour and birth environment  has the potential to represent either an insurmountable barrier or an important ally in access to high-quality care for pregnant women. It is therefore important to investigate (i) the factors that incentivize caesarean births and foster inequalities in access to assisted vaginal birth; and (ii) the changes required in the culture of obstetric health-care institutions and systems to prevent disrespect, abuse or overmedicalization.To implement and sustain the practice of assisted vaginal birth, particularly in settings where second-stage caesarean birth may be a riskier option, research is needed to assess maternity organizational models for effective access. Because midwives are the main providers of health care in rural and remote areas of many low- and middle-income countries, assessing the safety, feasibility and effectiveness of midwife-led models of care; exploring the role of midwives, as well as investigating how to train and empower them to undertake assisted vaginal birth safely and effectively, is fundamental. Regardless of the organizational model, ensuring timely access to emergency caesarean section if assisted vaginal birth fails is also crucial. Health-care providers need a supportive work environment, including relevant training, mentoring by more experienced colleagues, and close supervision until an appropriate level of confidence and competence is reached.Other questions that need to be answered include how to manage political and financial barriers, including the structure of the insurance system. Change will be difficult as long as a caesarean birth is more profitable for the system.,In current obstetrics, the challenge of increasing the use of assisted vaginal birth is complex because of the interconnected multiple players ; accepted cultural norms; the dynamic health-care environment; and the numerous behavioural factors  that influence decision-making for mode of birth.Access to assisted vaginal birth is an integral part of emergency obstetric care; we have therefore identified a research agenda to counter the significant decline in its use. Women’s representatives generally agreed with the research agenda initially identified by the technical experts, but also stressed the importance of engaging women and health-care professionals at all stages of this research. Women also emphasized the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if and when needed. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth. Shared and informed decision-making and constructive communication are considered crucial for reducing apprehension and building trust between women and health-care providers.


Preterm birth is defined as any delivery occurring before 37 + 0 weeks of gestation, and is multifactorial in its origin. Unfortunately, it is still insufficiently understood and explored when considering etiologies , and placental pathophysiology. While prematurity is the leading cause of mortality for children under the age of five worldwide, both the occurrence and burden are disproportionately experienced in low and middle income countries with rates varying from the lowest in well-resourced settings 8-11%) to the highest in low resourced settings (11-20%), like Malawi , intra-uterine or placenta related conditions  or endocrine pathways have been described. However, associations have not been sufficiently strong to adequately predict and identify pregnant women at (high) risk for spontaneous preterm birth, so that currently interventions to prevent or avoid preterm birth remain ineffective. At present, the most robust evidence relates to tocolytic interventions aimed at delaying preterm birth and create a time window 48 h) to administer corticosteroids. This allows acceleration of fetal (lung) maturation and protection against cerebral damage with magnesium sulfate 8 h to ad.The lack of understanding and insight into the pathophysiology of molecular mediators alternately rendering risk of preterm birth or protection to term birth results in real-life consequences for daily clinical practice. First, we primarily only have access to a very few and generally ineffective tocolytic interventions, instead of mechanism-driven therapies. Second, the limited capability to accurately or sensitively predict or identify women at risk for preterm birth leads to about 50% of pregnancies diagnosed as high risk pregnancies, deliver out of the expected time window, resulting in maternal, and more importantly fetal overexposure to antenatal corticosteroids. Prenatal overtreatment with steroids is a relevant concern, as there are animal experimental data  and human epidemiological data on an increase in neurobehavioral disorders during the life course in unnecessary former exposed cases that subsequently delivered at term equivalent age , 7.Chen et al. reflected on this potential new approach on amnion regeneration. Another approach focuses on the potential role of immunomodulation to delay preterm contractions in the setting of preterm delivery. The impact of co-exposure to anti-inflammatory prostaglandins  on inflammatory responses (interleukine-1β expression) in an in vitro cell model  has been quantified. The authors hereby concluded that the effects were cell-type dependent, with increased cell death for cells of vaginal or amniotic epithelial origin. Based on these results, Rasheed et al. concluded that this intervention is unlikely a useful approach. This re-illustrates the earlier described current setting of limited preventive measures, related to insufficient mechanistic understanding.While rupture of membranes often temporally accompanies spontaneous preterm birth, it is not universally true. However, preterm pre-labor rupture of membranes (PPROM) are a common issue associated with preterm delivery , with 25Jansen et al. reported on the risk of iatrogenic preterm birth for placenta previa or low-lying placenta, and how this might be mitigated by preventive interventions. Based on 34 studies retained in a systematic review and meta-analysis, the risks for preterm birth , or very preterm birth (<32 weeks of gestation) were 46% versus 30%, and 17% versus 10% when placenta previa or low-lying placenta respectively were documented. While the risk has been quantified, data on beneficial value of cervical cerclage, pessary and intramuscular progesterone are lacking and inconsistent. Finally, and besides preventive strategies, we also need to better understand when preterm birth will, or will not, result in significant neonatal morbidity with impairments along the entire life course.An additional area of clinical imprecision resulting in preterm birth surrounds placental pathophysiology. Su et al. reported on an increased risk for respiratory complications in extremely preterm male infants. Using a propensity score matching approach, male extreme preterms as compared to gestational aged matched females had a significantly higher risk to develop bronchopulmonary dysplasia . This at least suggest that sex-related endocrinological differences should be further explored, and that neonatal outcome should be reported according to fetal sex].Related to this, As reflected in the diversity of subjects discussed in this special topic, preterm birth is a research field still in search for better mechanistic understanding, to identify potential targets for prevention or treatment related interventions. This should improve the pregnancy and neonatal outcome. Therefore, it is also important to appreciate the sex, racial and social disparities in relation to risk of preterm birth and the accompanying morbidity and mortality.To achieve this, a broad and multidisciplinary collaboration is necessary, and we hope that this Research Topic has contributed to this urgently needed approach.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Seasonal patterns of preterm birth were identified in previous studies, but the effect of conception season on preterm birth has not been extensively studied. Based on the notion that the etiological roots of preterm birth lie in the beginning of pregnancy, we did a population-based retrospective cohort study in Southwest China to examine the effects of season of conception and month of conception on preterm birth.We did a population-based retrospective cohort study in women (aged 18–49) who participated in the NFPHEP from 2010 to 2018, and had a singleton livebirth in southwest China. According to the time of the last menstruation reported by the participants, month of conception and season of conception were then ascertained. We used multivariate log-binomial model to adjust the potential risk factors for preterm birth and obtained adjusted risk ratio (aRR) and 95% confidence intervals (95%CI) for conception season, conception month and preterm birth.Among 194 028 participants, 15 034 women had preterm birth. Compared with pregnancies that were conceived in the summer, pregnancies that were conceived in the spring, autumn and winter had the higher risk of preterm birth  and also had a higher risk of early preterm birth . Pregnancies in December, and January had a higher risk of preterm birth and early preterm birth than pregnancies that were conceived in July.Our study found that preterm birth was significantly related to season of conception. Preterm and early preterm birth rates were the highest among pregnancies that were conceived in winter, and the lowest among pregnancies in summer. Preterm birth is a global public health problem . ApproxiSeasonal patterns of preterm birth have been found in previous studies . An earlCurrently, the effect of conception season on preterm birth has not been extensively studied. As maternal diet, exposure to infectious agents, and ambient temperature vary throughout the year, season of conception can serve as a proxy for these factors. Geographical, cultural and socio-economic differences in different countries or regions may affect the association between season of conception and preterm birth.China is the country with the second largest number of preterm births in the world , so addrWe conducted a population-based retrospective cohort study involving women aged 18–49 years who participated in the National Free Preconception Health Examination Project (NFPHEP) from Jan 1, 2010, to Dec 31, 2018, and had delivered a singleton livebirth in 129 counties in southwest China. NFPHEP was a project initiated by the Chinese National Health and Family Planning Commission in 2010, and integrated into China’s National Basic Public Health Service Program in 2019. It aims to provide free health examinations and other services before conception for couples who planned to become pregnant in the next 6 months, provide pre-pregnancy check-up, early pregnancy follow-up and post-delivery follow-up to women of childbearing age. This study was approved by the Institutional Review Board of the Chinese Association of Maternal and Child Health Studies (AMCHS-2014-6). All participants provided written informed consent before enrolment [After a survey of the fertility desire of women of childbearing age by local health workers, all women who wish to be pregnant in the next 6 months were recruited and given free medical examinations. A standardized questionnaire was used to collect baseline information from women by trained qualified local health workers, including demographic characteristics and reproductive characteristics. The height, weight and body mass index (BMI) of the participants were obtained from physical examination data. Hemoglobin concentrations and hepatitis B serological markers were obtained from laboratory tests. In this study, the diagnostic criteria for anemia referred to the diagnostic threshold recommended by World Health Organization (anemia was defined as lower than 120 g/L for non-pregnant women) and adjusted according to altitude .In the first trimester of the participants, the maternal and child health workers interviewed participants face-to-face or by telephone and investigated whether participants ate meat and eggs, ate vegetables, smoked, consumed alcohol, and took folic acid during pregnancy.All participants were followed up by maternal and child health workers for 1 month after delivery to collect information including pregnancy outcome , delivery date, gestational weeks, and newborn information (singleton or multiple births). The study was terminated when participants had preterm birth or other pregnancy outcomes, or when the study reached the end of the observation period .In this study, women of childbearing age 18–49 years who participated in NFPHEP from January 1, 2010 to December 31, 2018 in 129 counties in Southwest China and had childbirth outcomes were selected as the research subjects. The selection process of the subjects was shown in Fig. Women of childbearing age who voluntarily participated in NFPHEP with informed consent between January 1, 2010 and December 31, 2018;Aged 18–49 years old;Had the outcome of childbirth.Inclusion criteria:Exclusion criteria:Missing the time record of last menstrual period;Missing the gestational week of childbirth;Miscarriage, stillbirth and labor induction after pregnancy;Post-term or multiple births.With the vast Asian continent to the north and the vast Indian Ocean and Pacific Ocean to the south, southwest China is located in subtropical northern latitude. Most of the territory has a typical temperate climate characteristic. In spring (March 21 to June 20), the average monthly temperature is mostly below 20 ℃, with little rain and a large temperature difference between day and night. In summer (June 21 to September 20), the average monthly temperature in most regions is about 22 ℃ and the precipitation is large, accounting for more than 60% of the year. In autumn (September 21 to December 20), the temperature in most areas is about 2 ℃ lower than the spring and the weather is dry with precipitation less than half of the summer precipitation. In winter (December 21 to March 20), the average monthly temperature is 6–8 ℃, sometimes with frost or snow and the precipitation is small, accounting for only 3–5% of the whole year.In this study, according to the time of the last menstruation reported by the participants during the first trimester follow-up, month of conception was then ascertained. We used astronomical birth season in our study, based on solstices and equinoxes as the bounds of the season categories. Four astronomical birth seasons were created following the standard definition of spring (March 21 to June 20), summer (June 21 to September 20), autumn (September 21 to December 20), and winter (December 21 to March 20).The primary outcome was preterm birth which was defined as a delivery from 28 weeks to less than 37 weeks of gestation. Early preterm birth was defined as a delivery from 28 weeks to less than 34 weeks of gestation. Preterm birth rate and early preterm birth rate were the proportion of preterm births and early preterm births in the total number of all singleton livebirths, respectively.2, 18.5–23.9 kg/m2, 24.0–27.9 kg/m2 or ≥ 28.0 kg/m2), HBsAg (positive or negative), and anemia (yes or no). Living habits during pregnancy include eating meat and eggs (yes or no), no eating vegetables (yes or no), smoking (yes or no), drinking alcohol (yes or no) and taking folic acid (yes or no).Covariates related to preterm birth and season of conception were adjusted, including demographic characteristics, reproductive characteristics, health status, and lifestyle habits during pregnancy. Demographic characteristics included age , ethnicity , education  and occupation . Reproductive characteristics included first gestation (yes or no), primipara (yes or no), history of preterm birth (yes or no), history of spontaneous abortion (yes or no), history of induced abortion (yes or no) and history of stillbirth (yes or no). Health status includes BMI  and 95% confidence intervals (95% CI) for conception season, conception month and preterm birth. To test the robustness of the results, we adjusted different covariates in stages. In model A, we adjusted for demographic characteristics of participants. In model B, in addition to those factors included in model A, the reproductive characteristics were also adjusted. In model C, in addition to those factors included in model B, we also adjusted for health status of participants. In model D, we additionally adjusted for living habits during pregnancy. All of the analyses were done with SPSS 21 and R 3.6.0 software. Two-sided p values of less than 0.05 was considered statistically significant.Participants were not involved in setting the research question or the outcome measures, nor were they involved in the design or implementation of the study. No participants were asked to advise on interpretation or writing up of the manuscript.Based on inclusion and exclusion criteria, a total of 209 513 women aged 18–49 years who participated in NFPHEP and had a childbirth outcome from January 1, 2010 to December 31, 2018 were involved in this study. We excluded 8916 with missing information on the last menstrual period; 1633 with missing information on the gestational period; 1756 who had a miscarriage, induced labor or stillbirth and 3126 who had post-term or multiple births. Finally, 194,082 women were included in the study.Of the 194 082 women of childbearing age, 53 334 (27.5%) were pregnant in spring, 46 400 (23.9%) in summer, 40 246 (20.7%) in autumn, and 54 102 (27.9%) in winter , reproductive characteristics , health status  and living habits during pregnancy  were all concentrated in spring and winter Table .The average gestational week of 194082 women was 39.37 ± 2.23 weeks, of which 15034 women had preterm birth, accounting for 7.7% of the total participants, and 5287 women showed early preterm birth, accounting for 2.7% of the total participants. The preterm birth rates of pregnancies in spring, summer, autumn and winter were 7.5%, 6.9%, 7.8%, and 8.6%, respectively, and the early preterm birth rates were 2.7%, 2.5%, 2.7%, and 2.9%, respectively . Compared with pregnancies that were conceived in the summer, pregnancies that were conceived in the spring, autumn and winter had the higher risk of preterm birth  and also had a higher risk of early preterm birth . Multivariate log-binomial model showed that after adjusting for covariates, compared with pregnancies that were conceived in summer, pregnancies in spring, autumn and winter were at increased risk of preterm birth by 10%, 15%, and 28%, respectively, and at increased risk of early preterm birth by 9%, 10%, and 18%, respectively. The adjustment of different covariables did not affect the results, and the results of the four models were robust , 1.41 (95% CI: 1.30 to 1.54), and 1.31 (95% CI: 1.20 to 1.42), respectively; pregnancies in October, December, and January had a higher risk of early preterm birth, with aRR values of 1.16 (95% CI: 1.00 to 1.35)、1.25 (95% CI: 1.09 to 1.44) and 1.16(95% CI: 1.01 to 1.33), respectively  and early preterm birth rate (2.5%) of pregnancies conceived in July were the lowest, and the preterm birth rate (9.1%) and the early preterm birth rate (3.1%) of pregnancies conceived in December were the highest; this finding is consistent with seasonal f preterm birth.Studies examining the association of the season of conception and the risk of preterm birth are limited. Previous studies conducted in the United Kingdom ; Greece In their retrospective cohort conducted in the United States, Bodnar et al.  observed3 increase in PM2.5  and PM10  during the first trimester. Regarding preterm birth, mechanisms that implicate toxic fine particulates include maternal hematologic transport of inhaled noxious chemicals, the triggering of systemic inflammation, or alterations in function of the autonomic nervous system [Conflicting or slightly varying results between countries were most likely related to geographical, cultural and socio-economic differences between the study populations. Globally, the preterm birth rate showed different seasonal trends in different regions. For example, in high-latitude countries such as the United Kingdom and Sweden, the rate of preterm birth was higher in winter, , 28, whis system . Ultravis system . A revies system . Vitamins system . Previous system . Some res system –35, whicNutritional status during pregnancy may also affect the preterm birth rate . PreviouPrevious studies had found that season of conception was also associated with other adverse pregnancy outcomes. A study by Benavides et al.  in TexasFrom a biological perspective, there is a critical period spanning the weeks around conception when gametes mature, fertilization occurs and the developing embryo forms. These are the events most sensitive to environmental factors such as the availability of macro- and micronutrients or exposure to smoking, alcohol, drugs or other teratogens . TherefoOur study has several strengths. First, this study was a large population-based retrospective cohort study that recruited all women who participated in the NFPHEP and had a singleton livebirth from 129 counties of Southwest China between 2010 and 2018, which may have less selection bias. Second, our study adjusted the demographic characteristics, reproductive characteristics, health status and living habits during pregnancy which were related to preterm birth in stages, especially the HBsAg positive  and foliOur study has some limitations. The NFPHEP did not collect information on pregnancy complications such as gestational hypertension, gestational diabetes, and therefore may influence the interpretation of the results to some extent. Although we have found the seasonal characteristics of preterm birth, we cannot determine the mechanism of the conception season’s influence on preterm birth. Further research is still needed for in-depth exploration.Preterm birth exhibited a seasonal variation, and preterm and early preterm birth were significantly related to season of conception. Preterm and early preterm birth rates were the highest among pregnancies conceived in winter, and preterm and early preterm birth rates were the lowest among pregnancies conceived in summer. This trend should raise concern since prematurity places a huge toll emotionally, physically and financially on families, medical systems and regional or national economies. Improved identification of the causes for rising rates of preterm birth in China and appropriate management to minimize untimely birth remains a challenge.


Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min−1 kg−1) to 1.91 ± 0.25 mg min−1 kg−1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.Sodium–glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction ( Sodium–glucose cotransporter 2 (SGLT2) inhibitors were developed to treat diabetes mellitus (DM), but they are now recognized as a new class of drugs to treat heart failure , 2. The +/K+ ATPase activity. Hence, glucose reabsorption is energy consuming. The ATP level in the renal proximal tubules decreases shortly after renal ischemia :2\d:2\d20]:2The baroreflex equilibrium diagram was obtained by plotting the neural and peripheral arcs on a pressure versus SNA plane , 32. The10(·) is the common logarithm; G and x0 denote the gain and x-intercept, respectively.The AP–nUF relationship during a stepwise CSP input approximated a straight line in our previous studies , 29, 33.An arterial blood sample was obtained once at the end of the experiment. The plasma sample was frozen at −80 °C after centrifugation. Urine samples obtained during BL, T1, T2, and T3 periods were also frozen at −80 °C. Later, the glucose, sodium, and creatinine concentrations were measured by outsourcing .cr) was calculated as the value per kidney by halving the average nUF for compatibility with our previous reports [The urinary glucose and sodium excretions were calculated from the product of the average nUF and the urinary glucose and sodium concentrations, respectively. Creatinine clearance  values. Time-dependent changes in the baroreflex static characteristic parameters, urinary excretion-related data, and AP–nUF relationship parameters were analyzed using one-way repeated-measures analysis of variance (ANOVA) with the Greenhouse–Geisser correction, followed by Dunnett’s test . A nonparametric Mann–Whiney test  comparedn = 5, age: 17.5 ± 0.7 weeks, P = 0.606; heart weight: 0.903 ± 0.018 g, P = 0.004; normalized heart weight: 2.251 ± 0.043 g/kg, P < 0.001 by Mann–Whitney test). Further, Table n = 9, 0.39 ± 0.02 pg/mL, P < 0.001 by Mann–Whitney test) or that in Goto–Kakizaki rats [n = 7, 0.33 ± 0.05 pg/mL, P = 0.002 by Mann–Whitney test).Table aki rats   during BL and markedly increased after empagliflozin , 0.931 ± 0.025 (P = 0.004), 0.940 ± 0.022 (P = 0.027), and 0.949 ± 0.020 (P = 0.027), respectively, where the P values were calculated between the linear and logarithmic estimations using Wilcoxon signed-rank test.Figure sis Fig. b, the gaThe acute effects of an intravenous administration of empagliflozin on baroreflex function and urinary excretion were examined in post-MI rats. The baroreflex neural arc, which describes the baroreflex-mediated SNA response over a wide CSP range, remained unchanged while the effect of empagliflozin on urinary glucose excretion was confirmed during the entire observation period. There was a transient increase in the intercept of the peripheral arc after the empagliflozin administration. During the last observation period, AP did not change relative to BL despite the increased UF.Renal energy status can affect systemic SNA via renal afferent signaling . For insThe lower asymptote of the total arc increased during T1 Fig. a, with aThe upward peripheral arc displacement may have increased the cardiac afterload and is disadvantageous for the failing heart. However, hemodynamics were not acutely deteriorated after empagliflozin administration in the present study. Recently, a direct cardiac effect of empagliflozin to improve cardiac energy status is suggested despite the lack of SGLT2 expression in cardiac tissues . Such anAP increases with SNA in the present experimental settings Fig. d, and APWe only examined the acute effects of empagliflozin under anesthetized conditions while MI was induced chronically. Hence, the results cannot directly be extrapolated to an interpretation of the long-term effect of empagliflozin in a conscious state. As we did not test empagliflozin on sham-operated rats, it remains uncertain whether the observed results were specific to chronic MI rats. Second, the surrounding structures, including the renal nerves, could be damaged to some extent during the flow probe attachment to the left renal artery. Hence, the results of RBF and RVR need to be carefully interpreted. Third, cardiac function was not assessed in the present study. A continuous, stable recording of left ventricular pressure is challenging in the present experimental setting because the large change in the cardiac loading condition can induce ectopic beats possibly through contact of a catheter tip with the ventricular wall. The measurements of cardiac output and left atrial pressure in addition to CVP  may allow us to estimate changes in stressed blood volume . FurtherThe effect of empagliflozin on open-loop baroreflex function was examined in post-MI rats. The sympathoinhibitory effect of empagliflozin was not detected within the observation period. AP, at a given SNA, was well maintained despite a significant increase in urine excretion. Empagliflozin would take more time to manifest a significant hemodynamic effect in this rat model of chronic MI.


ObjectiveThe aim of this study was to determine the rate and severity of intermittent hypoxic episodes in premature infants who underwent overnight pulse oximetry prior to discharge.MethodsPreterm infants with a birth weight of 1500 grams or less and who underwent overnight pulse oximetry prior to discharge were included. Maternal and neonatal demographic data and complications of prematurity were recorded. All infants underwent overnight pulse oximetry prior to discharge and the McGill score was used to categorize the degree of desaturations .ResultsFifty infants underwent the overnight pulse oximetry The McGill score showed that 2% had no hypoxia, 50% had mild hypoxia, 20% had moderate hypoxia, and 28% had severe hypoxia. The frequency of desaturations (62.5%) was found more in infants with a birth weight of 1000 grams or less. The results showed that the O2 requirement at discharge was significant (p = 0.0341), and increased values of O2 at discharge were associated with more severe hypoxia. As a result of these findings, 40% of infants were discharged home on oxygen and 26% were discharged on caffeine. Fifty-two percent of infants were initially diagnosed to have stages 1 & 2 retinopathy of prematurity (ROP), 14% had stage 3, and 2% had stage 4 ROP. Eight percent of infants required surgical intervention for ROP.ConclusionsClinically inapparent significant episodes of intermittent hypoxia (IH) are frequent in preterm infants in the early postnatal age, and they may persist post-discharge. Knowledge of the association between IH and morbidity among all neonatal intensive care unit (NICU) caregivers would be of great benefit. Indications for screening preterm infants at risk of severe IH should be reconsidered. Intermittent hypoxic (IH) episodes are due to immature respiratory control and are triggered by the cessation of respiratory neural output. Furthermore, their significance is commonly undervalued by clinically used pulse oximeters. A considerable problem has been reported regarding the inability to determine the incidence and magnitude of apneic events utilizing the standard pulse oximetry technique because it cannot document the obstructed inspiratory efforts that commonly prolong central respiratory pauses . In extrThese intermittent hypoxic episodes can be unapparent and easily missed by neonatal intensive care unit (NICU) caregivers, particularly prior to discharge. Hunt et al. showed in longitudinal home recordings of oxygen saturation utilizing pulse oximetry during unperturbed sleep in preterm and term infants that clinically unapparent IH occurs in epochs unperturbed by and temporally unrelated to apnea or bradycardia events, especially in preterm infants at 36 to 44 weeks postmenstrual age (PMA) .In animal models, intermittent hypoxia occurring during a period of critical brain development evokes behavioral and neurochemical alterations that are long-lasting and consistent with disorders of minimal brain dysfunction .The irregular respiratory pattern of premature infants becomes more regular as gestational age increases. The persistent apnea of extremely low birth weight infants contributes to their prolonged hospitalization. Some premature Infants continued to exhibit apnea and intermittent hypoxia beyond 37 weeks postmenstrual age. A prospective randomized clinical trial showed that substantial IH persists after the termination of caffeine treatment and progressively decreases with increasing PMA. Moreover, extended caffeine treatment decreases IH in premature .In this descriptive study, we aimed to determine the rate and severity of intermittent hypoxic episodes in premature infants who underwent overnight pulse oximetry prior to discharge.This is a retrospective descriptive study that included preterm infants with a birth weight of 1500 grams or less, and who had overnight pulse oximetry prior to discharge between January 2014 and December 2017. Infants with major congenital anomalies were excluded from the study. Maternal medical records were reviewed to obtain the following data: maternal age, antenatal care, antenatal steroids, use of magnesium sulfate, evidence of chorioamnionitis, evidence of hypertension during pregnancy, mode of delivery, and multiple gestations. Neonatal medical records were reviewed to obtain the following data: demographic data , initial steps of resuscitation performed on infants, types of respiratory support used during the early hospital course, neonatal medications used for various indications , and indomethacin), sepsis, length of hospital stay and complications of prematurity that included: respiratory distress syndrome (RDS), BPD at 36 weeks' postmenstrual age, patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL). In our NICU, all infants with a birth weight of 1500 grams or less should be started on a loading dose of 20 mg/kg caffeine citrate, followed by 5-8 mg/kg/day once daily. Caffeine therapy is usually stopped when infants reach 35 weeks corrected age and are discharged home when they are apnea-free for five days .The pulse oximeter used in this study was a Criticare 504DX, from Criticare Systems Inc., Waukesha, Wisconsin. The recorded O2 saturation and heart rate data were stored in the oximeter and subsequently connected to the serial port of a PC. The application installed in the computer is able to transfer, store, analyze, and quantify the oximeter data.The results of the pulse oximetry study were reviewed by a pediatric pulmonologist to confirm its significance. The McGill score was used to categorize the degree of desaturations  -12. The The definitions used in this study for BPD , NEC 1414, IVH , ROP 1616, and PStatistical methods and analysisDescriptive analyses were conducted on all obtained variables, utilizing Stata version 17.0 . These analyses involved the calculation of measures of centrality and variation for continuously scaled variables and the calculation of counts and percentages for categorically scaled variables. Graphically, box-and-whisker and stem-and-leaf plots illustrated the distributions of each of the variables. Where possible , pairwise Spearman correlation coefficients were calculated between all pairs of variables.Fifty premature infants who had overnight pulse oximetry were identified and enrolled in the analysis. All infants had overnight pulse oximetry because they experienced short episodes of desaturation during feeding or sleeping except six infants with a median birth weight of 633.5 grams (540-1060) who had the study merely because they were born less than 27 weeks gestation.The maternal characteristics showed that maternal age (Mean ± SD) was 30.3 ± 5.34, 98% of mothers had prenatal care, 82% received antenatal steroids, 30% had antenatal magnesium sulfate, 12% had hypertension, 12% had evidence of chorioamnionitis, and 35% had a cesarean section to delivery these infants. Clinical characteristics of infants  days.The results of this study show several findings regarding IH in infants born prematurely. Brief episodes of oxygen desaturation may appear clinically insignificant to the NICU caregivers; however, in this study, we found that 48% of the studied infants had moderate and severe hypoxia. Twenty-six percent (26%) of the studied infants were discharged home on caffeine. We also found that decreased birth weight was significantly associated with moderate/severe hypoxia (p = 0.0157). These hypoxic episodes are usually due to immature respiratory control that results in apnea and respiratory pauses. Nevertheless, these episodes of IH were typically not apparent clinically and continuous physiologic recording was required to detect and confirm their significance. Intermittent hypoxia should be taken seriously because it might have adverse effects on neonatal outcomes. Studies show continuing exposure to IH during early postnatal life disrupts expression patterns of proteins involved with dopamine signaling  and causThe effect of IH on the neurodevelopment of these infants has been studied. In a multicenter Canadian Oxygen Trial (COT) using continuous recordings of oxygen saturation in a large cohort study, authors found a significant correlation between prolonged hypoxemic episodes during the first two to three months after birth and adverse 18-month outcomes, including late death or disability, cognitive language delay, and motor impairment . Their rWe discharged 26% of infants home on caffeine because they had significant hypoxic episodes during the overnight pulse oximetry study. Caffeine intake in preterm infants may have a neuroprotective effect by blocking adenosine action, increasing myelination, promoting oligodendroglial maturation, and process arborization in hypoxia-exposed white matter . A prospIn conclusion, clinically inapparent significant episodes of IH are frequent in preterm infants in early postnatal ages and they may persist to post-discharge. Knowledge of the association between IH and morbidity among all NICU caregivers would be of great benefit. Screening high-risk premature infants with continuous recordings of oxygen prior to discharge will help identify those who have severe episodes of IH to determine the appropriate treatment to be used.The limitations of this study are the small sample size, being single-armed, and the lack of a control group. There was no long-term follow-up to assess neurodevelopmental outcomes.Clinically inapparent significant episodes of IH are frequent in preterm infants in early postnatal age and they may persist to post-discharge. Knowledge of the association between IH and morbidity among all NICU caregivers would be of great benefit. Screening high-risk premature infants with continuous recordings of oxygen prior to discharge will help identify those who have severe episodes of IH to determine the appropriate treatment to be used.


Lumbar ligamentum flavum cyst is a rare spinal condition that can cause significant morbidity and neurological deficits. Traditional surgical treatment involves open surgery, which can be associated with prolonged recovery time and significant morbidity. In recent years, endoscopic treatment of lumbar ligamentum flavum cyst has emerged as a minimally invasive and effective alternative to open surgery, but only a few cases have been reported in the literature. This paper describes our experience with endoscopic resection of an L4/5 ligamentum flavum cyst through an interlaminar approach and reviews the literature on the treatment of lumbar ligamentum flavum cyst.An 87-year-old man presented with lameness in the left leg, and magnetic resonance imaging (MRI) showed nerve compression by a ligamentum flavum cyst at the L4/5 intervertebral plane. The patient underwent endoscopic resection of the ligamentum flavum cyst through a left interlaminar approach with the facet joint preserved. The present study was approved by the Ethics Committee of our hospital. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Text regarding patient consent is not applicable for this case.Postoperative clinical results improved significantly, and postoperative MRI showed complete cyst resection.Total endoscopic resection via an interlaminar approach provides a new minimally invasive approach for the surgical treatment of lumbar ligamentum flavum cyst, which can be used as a reference by clinicians. Spinal ligamentum flavum cyst is a rare degenerative disease of the intraspinal canal, first reported by Moiel in 1967 . In NoveAn 87-year-old male was admitted to our hospital in November 2020, presenting with pain in the lower back and left lower limb for one year. In 2018, the patient received T12-L4 internal fixation in another hospital due to lumbar spinal stenosis (LSS) and degenerative scoliosis and recovered well after the operation. One year ago, the symptoms of low back pain with left lower limb pain were slightly relieved after local physiotherapy such as acupuncture, without special treatment. However, the symptoms gradually worsened, and now the standing and walking were limited, but conservative treatment was not improving. The visual analog scale (VAS) score for the lower limb was 8. Positive signs included L4/5 interspinous and left paraspinal tenderness, L4/5 left paraspinous percussion that could induce radiation pain in the left lower limb, and a Lasegue sign of 45°( +) in the left leg. The strength of the left thumb dorsal extensor was grade III. On November 17, 2020, MRI in our hospital suggested that short T1 and long T2 signals and high lipid pressure signal could be seen on the left side of L4/5 spinal canal. The admission diagnosis was lumbar ligamentum flavum cyst (L4/5)  Accurate preoperative positioning is required, with the puncture path planned in advance, and the target point punctured to avoid puncturing or sawing the cyst wall. (2) While both the foraminal and interlaminar approaches are acceptable, we recommend the interlaminar approach because the foraminal approach requires foraminoplasty, which increases operation time and may cause joint destruction and instability. (3) Due to the limitations of channels and instruments, it is difficult to completely remove the cyst under endoscopy, and the cyst wall may need to be destroyed. After the contents flow out, the cyst wall should be removed and sent for pathological examination.In conclusion, endoscopic surgery for lumbar ligamentum flavum cyst through the interlaminar approach has the advantage of less trauma, less bleeding, and minimal impact on spine stability. It can achieve the same effect as open surgery, providing a new minimally invasive option for lumbar ligamentum flavum cysts that can be considered by clinicians.


Objective To evaluate the continuation rates of the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) during the first 5 years of use, reasons for its discontinuation, bleeding patterns, and new contraceptive choice after the 5thyear, in adolescents and young women.Methods The present study was a 5-year prospective cohort conducted in a Family Planning Service of a tertiary hospital in Brazil. We selected 100 healthy women between 15 and 24 years old who used 52-mg LNG-IUS for contraception. The clinical follow-up of these women took place from June 2017 to December 2022. The study evaluated the continuation rates of the method, reasons for its discontinuation, bleeding patterns, and new contraceptive choice after the 5thyear. Continuous data were reported as mean ± standard deviation (SD) and range (minimum-maximum). Categorical variables were described as percentages.Results The continuation rates of LNG-IUS were 89.1% (82/92), 82.9% (72/87), 75.3% (64/85), 70.5% (60/85), and 64.2% (54/84) in the 1st, 2nd, 3rd, 4th, and 5thyears of use, respectively. The main reason for discontinuation was acne (11/30). Amenorrhea rates were 50, 54.1, 39, 35.7, and 51.8% at 12, 24, 36, 48, and 60 months, respectively. All patients who completed the study and needed contraception after the 5thyear opted for long-acting contraceptive methods (LARC).Conclusion The LNG-IUS showed high continuation rates in adolescents and young women in the first 5 years of use. Most patients who completed the study chose a LARC method after the 5thyear. Teenage pregnancy is a severe global health problem, especially in low- and middle-income countries.The use of long-acting contraceptive methods (LARC) in adolescents could lead to the prevention of pregnancies at an early age and the spacing between them, avoiding unintended pregnancies and abortions.Several studies have demonstrated high continuity rates for using the 52-mg levonorgestrel-releasing system (LNG-IUS) among young women.Regarding the side effects of LNG-IUS, some studies demonstrated that participants aged between 16 and 35 years old at enrollment were significantly more likely to report new or worsening acne, dyspareunia, pelvic pain, and dysmenorrhea.Barriers to using LARC by adolescents include patients' lack of familiarity with or understanding of the methods, potentially high cost of initiation, lack of access, low parental acceptance, and obstetrician-gynecologists' and other health care providers' misconceptions about the safety of LARC use in adolescents.thyear of use of the 52-mg LNG-IUS in adolescents and young women.The present study aimed to evaluate continuation rates, bleeding patterns, reasons for its continuation, and new contraceptive choices in the 5The present study was a 5-year prospective cohort conducted at the Family Planning Service, Department of Obstetrics and Gynecology, Hospital das Clínicas of the Universidade Federal de Minas Gerais , Belo Horizonte, state of Minas Gerais, Brazil, from June 2017 to December 2022. The project was approved by the Research Ethics Committee of UFMG (protocol 65138816.8.0000.5149). Participants were women who sought the Family Planning service for 52-mg LNG-IUS insertion for contraception or treatment of gynecological conditions. All women who agreed voluntarily to participate in the study signed an Informed Consent Form (ICF). Participants < 18 years old provided informed assent, while their parents provided the ICF. The present study is the continuation of a previously published paper with a 5-year follow-up.The study was conducted with nulliparous or parous women aged between 15 and 24 years old who were eligible for the use of LNG-IUS, according to the World Health Organization (WHO) medical eligibility criteria for contraceptive use. The exclusion criteria were: uterine sounding < 5 cm; cervical cytological abnormalities in the last 18 months; uterine cavity distortion ; current breast cancer, endometrial cancer, or cervical cancer (awaiting treatment); recent history of pelvic inflammatory disease or untreated genitourinary tract infection; abnormal uterine bleeding of unknown cause; < 6 weeks postpartum or postabortion.Women were applying for the use of LNG-IUS for planning counseling. They accepted the LNG-IUS as a contraceptive method after an explanation of all contraceptive methods available. They answered a questionnaire containing information on education level, parity, previous menstrual pattern, and previous use of contraception. A gynecologist performed a clinical examination. It was not necessary to perform a gynecological ultrasound prior to the insertion of the devices.thday of the menstrual cycle by an obstetric gynecologist and/or a trained resident physician. A urinary or blood pregnancy test was used to exclude pregnancy if the woman was not using an effective contraceptive method. For patients using any effective method of contraception, the LNG-IUS was inserted at any time of the menstrual cycle. According to the service's routine protocol, a transvaginal ultrasound was performed to verify the LNG-IUS positioning 30 days after insertion. The LNG-IUS was considered malpositioned when described as partially expelled, rotated, embedded in the myometrium, or located in the lower uterine segment or cervix.The insertion of the 52-mg LNG-IUS was performed up to the 7thyear of follow-up, patients were contacted by telephone to choose a new contraceptive method since, in Brazil, extended use of the 52-mg LNG-IUS has not yet been approved by the National Health Surveillance Agency (ANVISA).Follow-up visits occurred every year up to 5 years of use. The continuation rates of the method, reasons for its discontinuation, and bleeding patterns were evaluated. The menstrual pattern was self-reported and classified according to the following definitions. Menstrual cycles within 24-32 days, with bleeding lasting no more than 5 days, were considered regular cycles. Amenorrhea is the absence of uterine bleeding for at least 3 months. Spotting was considered occasional and unpredictable bleeding in small amounts. When it was impossible to return to face-to-face consultations, the women were contacted and questioned via telephone or social networks. At the end of the 5Continuous data were reported as mean ± standard deviation (SD) and range (minimum-maximum). Categorical variables were described as percentages.We performed 52-mg LNG-IUS insertion in 100 adolescents and young women. The characteristics of the participants are presented inThe only complication observed during the insertion of LNG-IUS was vasa-vagal responses  in 7% of women. Major complications, such as uterine perforation or infection, did not occur. Five insertions were guided by ultrasound. Ninety-two LNG-IUS were well positioned, 6 were poorly positioned, and 2 patients did not return for reassessment after insertion. Patients with poorly positioned IUS had their IUS repositioned, or a new device was inserted. Participants' follow-up over the first 5 years of the present trial is presented in the Participants Flowchart .st, 2nd, 3rd, 4th, and 5thyears of use, respectively.As shown inthyear had amenorrhea in the 5thyear, and patients with amenorrhea were less likely to discontinue SIU-LNG use in the last year.Menstrual patterns through the 5 years of observation are presented inPercentage of different bleeding patterns presented by adolescents and young women using 52-mg LNG-IUS during 12, 24, 36, 48, and 60 months of follow-up. In total, 30 participants stopped using LNG-IUS either because of adverse events or a desire to become pregnant. The reasons for the discontinuation of 52-mg LNG-IUS and the time at which they occurred are presented inthyear, 23 patients chose extended use of 52-mg LNG-IUS, 24 chose to insert a new 52-mg LNG-IUS, three chose to change to 19-mg LNG-IUS, and 2 chose to insert a copper intrauterine device. Two patients chose not to use any contraceptive methods because they were without a male partner , 82.8% (72/87), 75.3% (64/85), 70.5% (60/85), and 64.2% (54/84) in the 1The main reason for the discontinuation of LNG-IUS in this group was acne, which contrasts with previous studies.thyear had amenorrhea in the 5thyear, and patients who had amenorrhea were less likely to discontinue SIU-LNG use in the last year. This menstrual pattern coincides with descriptions in the literature.The discontinuation rate due to irregular bleeding was extremely low (only 1 patient), and most patients had favorable bleeding patterns during the 5-year follow-up. Amenorrhea was the predominant bleeding pattern throughout the 5 years. Amenorrhea rates were 50, 54.1, 39, 35.7, and 51.8% at 12, 24, 36, 48, and 60 months after insertion. The increase in the amenorrhea rate is justified by the fact that some patients who reported spotting in the 4The expulsion rate in our study was 2.2% at 12 months and 3.6% after an overage follow-up of 60 months. This is consistent with other studies supporting that younger women are less likely to experience expulsion than older women.thyear opted to maintain a LARC method. Because of the high risk of unintentional pregnancy, adolescents need highly effective contraceptive methods.It is important to observe that all women who needed contraception after the 5A criticism of the methodology used in the present study is the subjective evaluation of blood loss, so we cannot assure that the menstrual pattern was correctly described. Another problem is that we did not question acne presence before SIU-LNG insertion.Teenagers and young women are more likely to request premature discontinuation of their IUDs for contraception.The strengths of our study include data collection by a single investigator throughout the five-year follow-up period, as well as lower loss (16%) to follow-up during this period. All patients had a contact telephone number for the main researcher during the entire follow-up period of the research, which may have positively interfered with the low loss of follow-up.The data from the present study contribute to reaffirming the safety of LNG-IUS in young patients, as well as the high continuation rate during 5-year use. Special attention should be given to counseling and treatment of adverse effects, especially acne.thyear.The LNG-IUS should be routinely offered to young women as a safe and effective contraceptive option. The LNG-IUS showed high continuation rates in adolescents and young women in the first 5 years of use. Most patients had a favorable menstrual pattern with the use of 52-mg LNG-IUS. Young patients should be counseled about side effects, especially acne. Most patients who completed the study chose a LARC method after the 5


Evidence comparing double‐balloon vs single‐balloon catheter for induction of labor is divided. We aim to compare the efficacy and safety of double‐vs single‐balloon catheters using individual participant data.clinicaltrials.gov was conducted for randomized controlled trials published from March 2019 until April 13, 2021. Earlier trials were identified from the Cochrane Review on Mechanical Methods for Induction of Labour. Randomized controlled trials that compared double‐balloon with single‐balloon catheters for induction of labor in singleton gestations were eligible. Participant‐level data were sought from trial investigators and an individual participant data meta‐analysis was performed. The primary outcomes were rates of vaginal birth achieved, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. We used a two‐stage random‐effects model. Data were analyzed from the intention‐to‐treat perspective.A search of Ovid MEDLINE, Embase, Ovid Emcare, CINAHL Plus, Scopus, and p = 0.050; I2 0%; moderate‐certainty evidence). Both perinatal outcomes  and maternal composite outcomes  were not significantly different between the two groups.Of the eight eligible randomized controlled trials, three shared individual‐level data with a total of 689 participants, 344 women in the double‐balloon catheter group and 345 women in the single‐balloon catheter group. The difference in the rate of vaginal birth between double‐balloon catheter and single‐balloon catheter was not statistically significant (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86–1.00, Single‐balloon catheter is at least comparable to double‐balloon catheter in terms of vaginal birth rate and maternal and perinatal safety outcomes. Single‐balloon catheter is at least comparable to double‐balloon catheter in terms of vaginal birth rate. Maternal and perinatal safety outcomes are comparable between the two types of balloon catheters. AD‐MAaggregated‐data meta‐analysesIPD‐MAindividual participant data meta‐analysisRCTrandomized controlled trialSingle‐balloon catheter is at least comparable to double‐balloon catheter in terms of vaginal birth rate. Maternal and perinatal safety outcomes are comparable between the two types of balloon catheters.1Labor induction rates have been increasing globally. In Australia alone, there has been a 20% surge in labor induction rates among selected first‐time mothers from 26% in 2010 to 46% in 2020.Mechanical methods mainly include double‐ and single‐balloon catheters. Balloon catheters place pressure on and stretch the cervix, causing a release of local prostaglandins that hasten the cervical ripening process.A multitude of randomized controlled trials (RCTs) have compared double‐balloon with single‐balloon catheters for induction of labor regarding efficacy at achieving vaginal birth and maternal and perinatal safety outcomes, but their findings are divided.These issues could potentially be solved by performing an individual participant data meta‐analysis (IPD‐MA). IPD‐MA can reanalyze data using the same statistical measure,We performed this IPD‐MA to compare double‐balloon catheters with single‐balloon catheters for labor induction in relation to efficacy and safety to assist in providing greater clinical clarity.22.1This IPD‐MA was prospectively registered in PROSPERO (registration number CRD42021226744) and was reported in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analyses of Individual Participant Data (PRISMA‐IPD) guidelines. Ethical approval was gained from Monash University Human Research Ethics Committee (Project ID 27401).2.2clinicaltrials.gov was conducted to identify trials published since the Cochrane Review search and was completed on April 13, 2021.Eligible trials for inclusion were identified from their inclusion in the Cochrane Review on Mechanical Methods for Induction of LabourThe search strategy keywords included “single balloon”, “foley”, “double balloon”, “atad” and “cook” were combined with MeSH terms and Boolean operators to identify RCTs comparing double‐balloon catheter and single‐balloon catheter for labor induction  autonomously reviewed titles and abstracts, and full texts for inclusion following the inclusion and exclusion criteria using the online platform Covidence.2.4Corresponding or primary authors were invited to share raw data via email correspondence. If there was no response, co‐authors were invited to participate via email. If also unresponsive, the institutions associated with the authors including hospitals and universities, co‐authors on more recent publications with the author of interest, colleagues from our network in the same country as the author of interest, and finally the journal where the eligible RCT was published were all contacted. A maximum of 12 rounds of emails were sent and corresponding or primary authors were contacted in every round of email.A data‐sharing agreement between our institution and the corresponding institution was completed before data sharing. Data were transferred via email in password‐protected worksheets and all data shared were deidentified. All data were checked for discrepancies and all discrepancies were clarified with the author of the data set. Data checking also included assessing for missing or excluded data, checking for errors, checking for the presence of randomization, checking internal consistency, and replicating the baseline outcomes and results from the published trial with the trial's raw data.2.5Primary outcomes include vaginal birth rate, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. Maternal composite outcomes comprised maternal admission to the intensive care unit, maternal infection , postpartum hemorrhage >1000 mL, maternal death, and uterine rupture. Perinatal composite outcomes include stillbirth , neonatal death (defined as death of a neonate less than 28 days after birth), neonatal seizures, neonatal intensive care unit admission for longer than 48 hours, severe neonatal respiratory compromise , and meconium aspiration syndrome.Secondary outcomes were selected to further assess the efficacy and safety profiles of the two methods for both the mother and the neonate. They included unassisted vaginal birth rate, assisted vaginal birth rate, emergency and scheduled cesarean section rate, indication for cesarean section and instrumental vaginal birth, time from commencement of cervical ripening to birth, use of oxytocin augmentation, maternal use of analgesia during labor , uterine hyperstimulation , failed induction , neonatal Apgar score <7 at 5 min, meconium‐stained liquor, and increase in modified Bishop score .2.6Two investigators (MP and DC) independently conducted risk‐of‐bias assessments on participating RCTs using the Cochrane Risk of Bias 2 Tool and certainty of evidence assessments using the GRADE approach.2.7I2.A two‐stage random‐effects model was used to perform evidence synthesis. All analysis was conducted on an intention‐to‐treat basis. Stage one analysis involved calculating the primary and secondary binary outcomes using relative risks (RR) with 95% confidence intervals (CI) for each trial. To calculate the secondary outcome, change in modified Bishop score, means and standard errors were calculated for each trial. Time‐to‐event analysis for induction to vaginal birth time was calculated using a subdistribution hazard competing risks model. Subdistribution hazard ratios and 95% CI were estimated. Stage two analysis involved combining the summary estimates from stage one analysis using a random‐effects model with the Der Simonian Lair method. Statistical heterogeneity was quantified using Treatment–covariate interaction analysis was performed for the primary outcome vaginal birth rate. Initial subgroups of interest for interaction analysis included gestational age, parity, premature rupture of membranes, and indication for induction. However, there were insufficient data on premature rupture of membranes and indication for induction. We then added body mass index, maternal age, and initial modified Bishop score as explorative covariates. Interaction analysis was performed using generalized linear methods with Poisson regression (robust error estimate) between treatment and covariates for each study. RRs for the interaction terms were then pooled with a random‐effects model, in the same way as the primary analysis. A post hoc subgroup analysis was performed for indication of labor induction and Bishop score (≤3 and ≥4).To assess for data unavailability bias, AD‐MA was performed for the primary outcome vaginal birth rate for all eligible trials. All analysis was conducted with the Stata version 16.1 . All results are presented as double‐balloon catheter compared with single‐balloon catheter (i.e. reference group).33.1Five trials were identified for participation from the Cochrane Review on Mechanical Methods for Induction of Labour3.2A summary of methodological criteria and inclusion/exclusion criteria of eligible studies is available in Supporting Information Appendix A summary of the characteristics of participating studies is provided in Table 3.3All trials had a low risk of bias for the domain's randomization process, missing outcome data and measurement of outcome. One trial3.4p = 0.050; I2 0%; moderate‐certainty evidence as downgraded because of imprecision)  or perinatal composite outcome  was noted  Figure . No signd Figure .p = 0.007; I2 0%). The risk of assisted vaginal birth rate  was similar for both double‐ and single‐balloon catheters . Outcomes including uterine hyperstimulation and rates of meconium‐stained liquor were only reported in one RCT and no positive cases were recorded in either group.There was no significant difference in the increase in Bishop score from balloon insertion to removal . A cumulative incidence function that compares the two groups alongside time is shown in Supporting Information Appendix On pooling subdistribution hazard ratios, the difference in the chance of vaginal birth that considered the time from induction to birth was not significant  or post‐term pregnancy . Other indications did not have sufficient data for the subgroup analysis. Similarly, vaginal birth rate was not significantly different between the two methods in those with Bishop score ≤3  or Bishop score ≥4 .Covariates including gestational age, parity, body mass index, maternal age, and initial modified Bishop score did not demonstrate statistically significant interactions with treatment for vaginal birth rate. Maternal ethnicity was not analyzed as only one study provided data for this subgroupp = 0.056; I2 45.1%). The rate of vaginal birth was comparable between the two interventions when all trials were pooled together  with significant heterogeneity (I2 59.4%).We also conducted an AD‐MA including all eligible studies for the primary outcome vaginal birth rate and we grouped the results by trials that did and did not share data (Supporting Information Appendix 4In this IPD‐MA, we did not find a statistically significant difference in vaginal birth rate between the double‐balloon catheter and the single‐balloon catheter. Maternal and perinatal safety outcomes were comparable between the two types of balloon catheters.A strength of our study includes the relatively equal number of participants that each participating trial contributed. This ensures that our study is not strongly influenced by one large study. A further strength is that in conducting an IPD‐MA, rather than an AD‐MA, we were able to assess for potential errors and bias within contributing studies to a higher standard, analyze unpublished but collected data from trials, perform treatment–covariate interaction analysis, combine outcomes measured across trials with different statistical measures, and calculate composite outcomes which are not possible without IPD. Also, we followed a predefined and registered protocol for this IPD‐MA.Our study does have some limitations. One of which is data unavailability, which in theory could introduce bias. Eight trials were eligible to participate, contact was made with seven of these trials and three shared data with us. However, these three trials contributed over half of the overall number of eligible participants. This disparity between trials eligible to participate and trials that participated was not isolated to this IPD‐MA alone.We found double‐balloon catheter may be less effective than single balloon catheter with reduced rates of vaginal birth using IPD from three trials, but this difference was not statistically significant. Although there were differences in clinical characteristics between the included trials such as the volume of saline used for inflating the Foley catheter and the maximum time allowed for balloon placement, the heterogeneity for vaginal birth and most other outcomes appears to be small.Four previous AD‐MA on this topic found no significant difference between the two groups for vaginal birth rate.A unique feature of the double‐balloon catheter is that the dilator vector is applied by two balloons inflated on both sides of the cervix when it is held in place, avoiding the need for traction.Both maternal and perinatal composite outcomes were comparable between double‐ and single‐balloon catheters. AD‐MAs for Apgar scores <7 at 5 min found no significant difference between the two groups.Single‐balloon catheter is substantially cheaper than double‐balloon catheter. Also, the cost of an unassisted vaginal birth is lower than the cost of a cesarean section.5Single‐balloon catheter is at least comparable to double‐balloon catheter for both efficacy and safety. In consideration of its lower cost, single‐balloon catheter should be the preferred mechanical method in labor induction.BWM and WL designed the meta‐analysis and were responsible for overseeing all aspects of conduct. MDP, KRP, and WL contributed to various stages of the project including aspects of design, eligibility screening, data extraction, risk of bias assessment, IPD checking, and trial analysis. MDP managed the project and collaborative process, WL carried out data synthesis, KRP and BWM provided clinical oversight, and MDP designed and conducted the literature searches. MDP wrote the manuscript supervised by WL with input from all authors. All authors were involved in the decision to submit the manuscript. All contributing trial investigators had opportunities to comment on the initial scope and the draft protocol. Trial investigators also prepared and supplied data and answered questions about their trials.BWM declared grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, and grants from Merck, outside the submitted work. KRP has received research grant funds from Glaxo Smith Kline and consultancy fees from Janssen Pharmaceuticals for section 3, unrelated to this work. WL has received research grant funds from the Norman Beischer Medical Research Foundation, unrelated to this work. All other authors have stated explicitly that there are no conflicts of interest in connection with this article.Appendix S1‐S4.Click here for additional data file.


High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, the incidence is increasing, and in the United States it disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood ALL.We used data from California birth records (1982-2015) and California Cancer Registry (1988-2015) to identify ALL cases diagnosed <14 years and 50 times as many controls matched by sex, race/ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. Association between ambient temperature and ALL was evaluated per gestational week, restricted to May-September, adjusting for confounders. Bayesian meta-regression was applied to identify critical exposure windows. For sensitivity analyses, we evaluated a 90-day pre-pregnancy period (assuming no direct effect before pregnancy) and constructed an alternatively matched dataset for exposure contrast by seasonality.Our study included 6,258 ALL cases and 307,579 controls. The peak association between ambient temperature and risk of ALL was observed in gestational week 8, where a 5 °C increase was associated with an odds ratio of 1.09  and 1.05  among Latino and non-Latino White children, respectively. The sensitivity analyses supported this.Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood ALL. Further replication and investigation of mechanistic pathways may inform mitigation strategies. ALL is the most common childhood malignancy with more than 50,000 new cases every year worldwide, and the incidence is steadily increasing.10 and environmental exposures occurring during pregnancy such as air pollution have been associated with an increased risk of childhood ALL.13 Exposure during the first trimester is suspected to be the most critical because this is when the most profound developmental alterations in hematopoiesis occur .14 There are multiple reasons to suspect that maternal exposure to high ambient temperature may initiate the pathogenesis of ALL in fetal life. First, pre-leukemic clones may be caused by oxidative stress,9 and high ambient temperature increases oxidative stress.15 Also, inflammatory markers, heat shock proteins, and stress hormones increase in response to heat,16 and stress in pregnancy has been linked to an increased risk of ALL and other childhood cancers.18It is well established that most cases of childhood ALL have a prenatal origin,Using a population-based linkage study derived from the general birth cohort in California (1982-2015), we conducted a nested case-control study to evaluate the potential association between high ambient temperature during pregnancy and risk of ALL in the offspring. In particular, we aimed to identify critical windows of exposure and to evaluate possible differences by racial/ethnic groups. We hypothesized that any harmful effect of high ambient temperature would be the greatest during the first trimester and that Latino children would be impacted more by high temperatures. This is the first study to directly evaluate the association between ambient temperature in pregnancy and the risk of cancer in the offspring.19 Non-cancer controls were selected from the statewide birth records. Information on cancer status was gathered from the California Cancer Registry, and birth records from the Center for Health Statistics and Informatics, both within the California Department of Public Health. This study received approval from the institutional review boards at California Department of Public Health, Yale University, University of California, Berkeley, and University of Southern California.This study leveraged the California Linkage Study of Early-Onset Cancers (CALSEC), which is a population-based, statewide linkage study that included children born in California during 1982-2015 and diagnosed with childhood cancer in California during 1988-2015.rd edition, to identify cases, where codes of 9811-9818, 9826, 9835-9837 were considered consistent with a diagnosis of ALL. An age-limit of <14 years was used to define childhood ALL.7 We initially identified 6,849 cases of childhood ALL. Of these, we excluded children who 1) had missing residential address at the time of birth (n=142); 2) had mothers who resided outside of California (n=7); 3) had missing information on gestational age (n=349), birth weight (n=1), birth order (n=3), mother’s birthplace (n=4), or delivery mode (n=3); or 4) had congenital abnormalities (n=79) or had missing information on this item (n=2). We next selected 50 (or as many available meeting our criteria) non-cancer controls per case matched on sex, race/ethnicity, and date of mother’s last menstrual period (LMP) ±7 days. One case was further excluded due to no available matched controls. A total of 6,258 cases and 307,579 controls were included in the primary analyses of this study.We used the International Classification of Diseases for Oncology, 319 Exposure to ambient temperature was estimated from the Daily Surface Weather Data on a 1-km Grid for North America, Version 4.20 This dataset utilizes a combination of interpolation and extrapolation and multiple inputs from weather stations and provides information on daily minimum and maximum temperature at a spatial resolution of 1 km. The exposure of interest was daily mean temperature which was estimated from daily minimum and maximum temperatures. The smallest unit of exposure used in our analyses was the mean weekly ambient temperature, which was estimated based on the average daily mean temperature each week.Maternal residential addresses at the time of her child’s birth were geocoded.st, 2nd, >=3rd), maternal age , paternal age , maternal education , birth weight (grams), and mode of delivery . Maternal residential addresses were linked to 2000 Census block group data to obtain the proportion in the block group living below the 150% federal poverty level (tertiles based on the distribution among controls). Date of the first day of LMP was estimated based on date of birth and registered gestational age at birth.Birth records were used to gather the following information about our study population: Gestational age at birth (in days), date of birth, race/ethnicity , sex, birth order ; and 2) analyses on an alternatively matched dataset matching on residential address and year of LMP instead of date of LMP .This study included a range of analyses that are described in detail below. In brief, the main analysis evaluated the gestational week-specific association between high ambient temperature and risk of ALL after adjusting for key confounders and matching on race/ethnicity, sex and date of LMP. We also evaluated subgroups and conducted non-linear analyses. Finally, we conducted two important sensitivity analyses: 1) The association between high ambient temperature st-September 30th. For any given week of exposure, at least one day of that week had to be in the warm period.We evaluated the association between weekly mean ambient temperature and the risk of childhood ALL, one week at a time before running Bayesian meta-regression analyses (see below). All results are expressed as odds ratio (OR) for ALL per 5 °C increase in mean weekly ambient temperature. Given that we wanted to evaluate the effect of high ambient temperature, we restricted the season of interest to the warm period May 121 As embryonic lymphopoiesis starts around gestational week 8,14 we hypothesized that we would see no association between ambient temperature and ALL in the weeks preceding pregnancy.One of the objectives of our study was to identify whether there were critical windows of exposure. Thus, we considered ambient exposure to temperature in each week of pregnancy from LMP to date of birth in separate models. Additionally, we evaluated the 13 weeks (90 days) preceding LMP as an approximate negative control exposure period.and residential address. Instead, we considered date of LMP to be the more important confounder of the two, which was therefore included in the primary analyses, while adjustment for residential address was achieved in a sensitivity analysis of a secondary matched dataset (see below). Unless stated otherwise, all characteristics and analyses presented were based on the primary matched dataset .In our analyses, we adjusted for the matching variables  and a set of additional potential confounders identified through literature search and construction of directed acyclic graphs: Birth order, maternal and paternal age, maternal education, neighborhood poverty, seasonality and time trend (captured through LMP), and residential address at the time of birth. Given that exposure contrast to ambient temperature is achieved by time and/or space, we could not simultaneously match on date of LMP 15 We did not adjust for mediators.We considered pregnancy complications and birth outcomes to be potential mediators of the association between high ambient temperature in pregnancy and risk of ALL. Similarly, air pollution is generally considered a mediator of the association between high ambient temperature and adverse health outcomes.To identify critical windows of exposure, we analyzed our data in two stages. First, we ran conditional logistic regression models, separately for each week, where the association between mean ambient temperature and ALL risk was estimated, along with a standard error for the estimate. Next, we used a Bayesian meta-regression framework, where the estimates and standard errors from the first stage were used as input for the second analysis stage.et al. to the meta-regression setting.22 The first stage association estimates were assumed to be normally distributed with mean equal to the true but unobserved association of interest, and variance equal to the squared standard error. The true associations were then modeled using the original CWVS methodology, which decomposes the single effect into continuous and binary components and uses a joint Gaussian process with temporal correlation structure to provide “smoothed” parameter estimation while conducting Bayesian variable selection output  method of Warren n output . From th23After identifying the gestational week where the association between ambient temperature and risk of ALL was the greatest , we used this gestational week as basis for two subsequent subgroup analyses. First, we conducted analyses separately for Latino and non-Latino White subjects; the other racial/ethnic groups had too few cases to warrant stratified analyses. The other subgroup analysis was stratified on the age of diagnosis. Subgroup differences were compared by calculating the z-statistic.th, 27.5th, 50th, 72.5th and 95th percentiles). This analysis was adjusted for the same confounders as the main analysis. The non-linear analysis was only carried out in the gestational week with the largest estimated association with ambient temperature exposure that was statistically significant. A log-likelihood ratio test was run to evaluate whether the non-linear model was a better fit than the linear model.We conducted a regression analysis that included mean ambient temperature modeled using a restricted cubic spline with 5 knots  but at different locations, while the secondary matched dataset compared pregnancies occurring in the same location (within 10 km) but at different times during the same year : An increased proportion of cases (compared with controls) conceived in early summer would result in higher mean ambient temperature (compared with controls) in early gestational weeks, while the ambient temperature would be lower among cases (compared with controls) in gestational weeks in late pregnancy as these would to a greater extent (compared with controls) be in the winter months.The two-stage meta-regression analyses used the rjags package (version 4.13) in R (version 4.2.2), and all other analyses were performed with SAS version 9.4 , with a statistical significance level of 0.05.th and 75th percentiles were 19.0 °C and 23.9 °C, respectively, and the minimum and maximum weekly mean temperatures were 0.0 °C and 40.1 °C, respectively.For the warm season in the years 1982-2015, the mean of the weekly mean ambient temperature was 21.5 °C (standard deviation 3.7 °C), the 25A majority of the study population were male, and most were of Latino ethnicity . Sex, raIn our main analysis we observed a significant association between high ambient temperature in early pregnancy and an increased risk of childhood ALL . SpecifiIn subgroup analyses of gestational week 8 stratified by race/ethnicity, we observed a slightly larger effect of high ambient temperature among Latino compared with non-Latino White children , but theStratified by age of diagnosis, there was a comparable and pronounced association between high ambient temperature and increased risk of ALL diagnosed at 0-4 and 5-9 years of age . The apex of the curve of the sensitivity analysis was shifted towards an earlier week as compared with the main analysis. We interpret this shift as reflecting bias from seasonality. Of note, there is seasonal variation in air pollutants, and concentrations of nitrogen dioxide in California, for instance, tend to be the highest during the fall.We observed no effect of high ambient temperatures prior to pregnancy. The length of the lag-time between heat exposure and the initiation of leukemogenesis is not known, but it is reasonable to assume that the farther away from the initiation of lymphopoiesis, the weaker the association between high ambient temperature and ALL will be. The pre-pregnancy period can thus serve as an approximate negative control exposure period, and our findings offer strong support of a robust effect of ambient temperature in the first trimester on risk of ALL.3 When stratified by age of onset, we observed a strong association between high ambient temperature in pregnancy and risk of early-onset childhood ALL, but no association for late-onset childhood ALL. This is in line with research that finds that early-onset childhood ALL may have a stronger link to fetal insults compared with later onset childhood ALL.18There was a tendency of a more pronounced association between high ambient temperature and risk of ALL among Latino than non-Latino White subjects. If replicated, such differences may reflect disparate exposure to heat due to occupation and residence.7 amounting to a maximum of a dozen misclassified controls, which is unlikely to affect our results. Recall bias is not possible because that birth record data are collected prior to the diagnosis of ALL. We used highly accurate ambient temperature data within a 1-km grid, which represents a much finer level of detail than what is most often used in studies of ambient temperature in pregnancy.4 In addition to robust adjustments for confounding, we carried out extensive sensitivity analyses to make sure that our estimates were not due to bias, notably by examining non-sensitive windows before pregnancy and by carrying out an alternative matching strategy to allow for additional confounding adjustment. Lastly, our sample size is large and unprecedented for an epidemiologic study of childhood ALL.Our study has notable strengths. The population-based record-linkage between the California Cancer Registry and birth records allowed us to include close to all children with ALL born in California, minimizing selection bias. The controls were a random sample representative of the birth cohort in California each year. Some controls may in theory have moved out of California and since developed childhood ALL before 14 years of age, thus introducing control misclassification. However, childhood ALL is rare, affecting 40 per million,30 In the present study, we did not have the opportunity to address possible mechanisms of action that are at play in the link between ambient temperature and ALL ; this will be an important topic for future research.There are also inherent limitations that should be highlighted. The individual-level exposure to high ambient temperature may be modified by factors such as access to adequate air conditioning and line of work; we did not have data to evaluate these factors. Also, geocoding was based on maternal residential address at the time of birth, and in situations where subjects had moved prior to birth there would be exposure misclassification. However, residential mobility has little impact when evaluating critical exposure windows in pregnancy, and there is no reason to believe that this exposure misclassification would be differential by case/control-status, so any bias would be towards the null.1 We have for the first time established a robust association between high ambient temperature during pregnancy and risk of childhood ALL. Our study is adding to a growing body of literature that underscores that high ambient temperature not only has immediate health effects, but may be a cause of future chronic diseases.Due to climate change, high ambient temperature is expected to be more common and intense over the coming decades, in the US and worldwide.Supplement 1