While red blood cell transfusion rates have declined in most Australian medical specialties, obstetric transfusion rates have instead been increasing. Obstetric transfusions are mostly linked to postpartum haemorrhage, the rates of which have also increased over time. This study used two methodological approaches to investigate recent trends in obstetric transfusion in New South Wales (NSW) and the extent to which this was influenced by changing maternal and pregnancy characteristics.Linked birth and hospital records were used to examine rates of red blood cell transfusion in the postpartum period for mothers giving birth in NSW hospitals from 2005 to 2015. Logistic regression models were run to examine the contribution of maternal and pregnancy risk factors to changing rates of transfusion. Risk factors were divided into “pre-pregnancy” and “pregnancy related”. Crude and adjusted estimates of the effect of year of birth on obstetric transfusion rates were compared to assess the effect of risk factors on rates over time using two approaches. The first compared actual and predicted odds ratios of transfusion for each year. The second compared the observed increase in transfusion rate with that predicted after controlling for the risk factors.Among 935,659 births, the rate of obstetric transfusion rose from 13 per 1000 births in 2005 to 17 in 2011, and remained stable until 2015. From 2005 to 2015, postpartum haemorrhage increased from 74 to 114 per 1000 births. Compared with the rate in 2005, the available maternal and pregnancy characteristics only partially explained the change in rate of transfusion by 2015 ; adjusted odds ratio 1.29 ). After adjustment for maternal and pregnancy characteristics, obstetric transfusion incidence was predicted to increase by 10.3%, but a 38.7% increase was observed (Method 2).Rates of obstetric transfusion have stabilised after a period of increase. The trend could not be fully explained by measured maternal and pregnancy characteristics with either of the two approaches. Further investigation of rates and maternal and clinical risk factors will help to inform and improve obstetric blood product use.The online version of this article (10.1186/s12874-018-0595-6) contains supplementary material, which is available to authorized users. There has been a global movement to reduce the usage of red blood cell transfusions and focus on patient blood management to prevent avoidable blood loss . In AustIn 2015, the National Blood Authority of Australia released the Patient Blood Management Guidelines module for Obstetrics and Maternity .The use of red blood cells in the obstetric setting is influenced by patient indications as well as clinical practice . There aThis study aimed to assess the recent trend in red blood cell transfusion rates for mothers giving birth in hospitals in NSW, Australia, and, using two methodological approaches, the extent to which this trend can be explained by available maternal, pregnancy and birth characteristics.The study population comprised women delivering live or stillborn infants of at least 20 weeks gestation in New South Wales (NSW) hospitals from July 2005 to June 2015. NSW is the most populous state in Australia with a population of 7.6 million residents in 2015 and accounts for approximately one third of all Australian births .Data on maternal and birth characteristics were from the Perinatal Data Collection (‘birth data’), a record of all births occurring in NSW, reported by the attending midwife or doctor. The Admitted Patient Data Collection  provided hospital inpatient admission records including diagnoses and procedures coded with the 10th revision of the International Classification of Diseases, Australian Modification (ICD10-AM) and the Australian Classification of Health Interventions (ACHI), respectively. These two datasets underwent probabilistic linkage by the NSW Centre for Health Record Linkage, with an estimated false positive and false negative linkage rate of less than 5 per 1000 records [The outcome of interest was the administration of a red blood cell transfusion during the birth admission and in postnatal hospital admissions up to six weeks after the birth , referred to herein as an ‘obstetric transfusion’. This would have included a small number of transfusions that were administered in the birth admission but prior to delivery.We identified potential maternal and pregnancy characteristics known to contribute to the risk of an obstetric transfusion through literature review and clinical experience , 11–16. Maternal demographics, and pregnancy, labour and birth characteristics were obtained from the birth data. Acute and chronic conditions were ascertained from the hospital data, by searching diagnosis codes of the antenatal, birth and postpartum admissions. Anaemia diagnoses were identified from antenatal records only. In vitro fertilisation and intracytoplasmic sperm injection (‘assisted reproductive technology’) were identified if the mother was admitted to hospital with these diagnosis or procedure codes in the twelve months prior to the birth. As hospital data were only available from July 2001, previous postpartum haemorrhage and obstetric transfusion was derived from a four-year look-back period in the linked data prior to the birth. A previous validation study, which compared medical records to hospital discharge data, found that red blood cell transfusion  and PPH  are well reported in hospital data, though there is some under-ascertainment . The useMaternal socioeconomic status (SES) was derived from each mother’s area of residence using the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) from the Socioeconomic Indexes for Areas package produced by the Australian Bureau of Statistics . Each arDescriptive analyses of the outcome and risk factors were conducted by plotting rates of each by year. We used logistic regression to estimate the crude effects on the outcome of each of the risk factors as well as year of birth. Cochran-Armitage tests were also performed to assess the trend in rates of obstetric transfusions, PPH and each of the covariates, by year, over the study period.We used two approaches to assess the extent to which maternal, pregnancy and birth factors could explain the temporal trends in obstetric transfusion rate. The first method assessed the trend in transfusions over time that is not explained by risk factors, and the second demonstrated the expected trend given the risk factors. Both methods used predictive logistic regression models with obstetric transfusion as the outcome while controlling for risk factors. Using these models, with maternal and pregnancy risk factors as predictors, we predicted the rates of red blood cell transfusion over the study period. If changes in maternal and pregnancy risk factors were sufficient to explain the increasing transfusion rate, this would be reflected in the close fit of the models.In the first approach, crude odds ratios for year of birth were compared with adjusted odds ratios for year of birth from models: (a) adjusted for pre-pregnancy risk factors, and (b) adjusted for all pre-pregnancy, pregnancy and birth risk factors, which also include pregnancy complications. Pre-pregnancy factors include maternal demographics, reproductive history and existing comorbidities. The full model adjusted for all of the available pre-pregnancy, current pregnancy and birth factors. The degree to which the adjusted odds ratios moved closer to 1 compared with the crude odds ratios indicated how much of the temporal trend was explained by the risk factors.The second method compared the change in observed rate of obstetric transfusion by year with the predicted rate of transfusion by year from a model with (a) only pre-pregnancy risk factors, and (b) all pre-pregnancy, pregnancy and birth risk factors. These models did not include year of birth as a covariate and included data from all years of the study. The relative increase in the observed rate by year compared with 2005 was calculated by dividing the observed rate in each year by the rate in 2005, thus indicating the proportional change in obstetric transfusions over time. Similarly, the predicted rate-ratios by year showed the relative expected change in rate of transfusion due to the changing distribution of risk factors over time. Both approaches assumed a consistent relationship between each of the risk factors and the outcome over the study period.Covariates were excluded if they could not be consistently ascertained over the study period. We also examined the trends in PPH, but because it is on the causal pathway between many of the risk factors and the outcome PPH was not included as a risk factor in the analyses. Statistical analysis was performed using SAS, version 9.3 .p < 0.001), but then remained mostly stable until 2015, remaining at 17 per 1000 births for each year apart from a drop to 16 per 1000 births in 2012 . Of mothers receiving obstetric transfusions, 76.7% were found to have had PPH (Table p < 0.0001)  births were excluded due to missing values for one or more risk factors. Among the remaining 935,659 births included in the study, mothers were found to have received an obstetric red blood cell transfusion in 14,275 (15 per 1000 births) births. This rate increased by 38.7% from 13 per 1000 births in 2005 to a peak of 17 per 1000 births in 2011  or giving birth to multiples compared with those who did not have a transfusion Table . Those wFrom the models which included year, if the risk factors could account for the change in rates of transfusion over time, then the odds ratios for each year in the adjusted model would be closer to 1 than the crude odds ratios. Controlling for pre-pregnancy characteristics did not change the effect estimates for year of birth meaningfully when compared with the crude estimates from 2006 to 2010, but slightly larger changes were seen in later years; crude odds ratio (OR) 1.35  1.22, 1.49) to adjusted OR 1.30  in 2014 and crude OR 1.39  to adjusted OR 1.34  in 2015  of obstetric transfusions in the study period were found to coincide with a PPH diagnosis, the rate of which increased throughout the study period, from 74 to 114 per 1000 births.The increase in PPH and transfusion rates observed up to 2011 is consistent with previous studies in NSW , 8. In tThis is the first study to report a largely stable rate of obstetric transfusions in NSW since 2011. Given that transfusion is often used as a marker of severity of haemorrhage, the stable transfusion rate in the context of increasing PPH is an encouraging sign. However, the obstetric transfusion rate in NSW is still higher than observed in the United States of America where there were 7 transfusions per 1000 births between 1998 and 2011 .We found that pre-pregnancy characteristics, while being important risk factors for transfusion, did not contribute greatly to the change in obstetric transfusion rates over time. Accounting for all the pre-pregnancy, and pregnancy and birth factors that were ascertained, explained a larger degree of the change in transfusion rate but still only predicted a quarter of the increase observed from 2005 to 2015. Interestingly, the largest predicted increases in transfusion, with each model, were seen between 2010 and 2015 when the observed rate remained stable. This means that the rate of obstetric transfusion did not increase during this period despite an overall increase in maternal risk factors for obstetric transfusion. Our findings indicate that changes in rates of obstetric transfusion are largely influenced by other unmeasured factors which may include clinical decision making, policy changes, and the unpredictable nature of PPH as it is understood that many women who experience PPH do not possess any identifiable risk factors . The diaWhile the new Patient Blood Management guidelines for Obstetrics and Maternity were only released in 2015 . This isAlongside new guidelines, other treatments for PPH and anaemia have been approved by the Australian Therapeutic Goods Authority (ATGA) and came into clinical practice during the study period, which may have contributed to the stable obstetric transfusion rate. These include tranexamic acid, recombinant activated Factor VII and ferric carboxymaltose (Ferinject). Intravenous tranexamic acid, an antifibrinolytic agent, was approved by ATGA in 2010 to reduce blood loss in cardiac and orthopaedic surgical patients . HoweverThe main strengths of our study were the size and completeness of the dataset as well as the high-quality linked data from both the perinatal and hospital data. All births in NSW hospitals were included in the study with only 0.4% being excluded from the analysis due to missing data. This allowed us to investigate rare risk factors and treatments. While PPH and transfusion codes have been found to be reliable, changes in ascertainment may play a small part in changes in reported rates. This study also used two approaches to answer the study question which provided similar results, strengthening the conclusions. There were, however, some key covariates that are not well reported in either dataset, including body mass index, a change in which over time may have contributed to the changing rate of transfusions. The hospital data did not include laboratory results such as haemoglobin, which may have helped indicate the appropriateness of red blood cell transfusion. We were also limited by our inability to include prior obstetric history of mothers before the availability of linked data in July 2001.While we have taken into account risk factors related to transfusion, particularly in the predicted versus observed analysis, we have assumed the relationship between these factors and risk of transfusion has not changed over time. However, induction of labour (for example) may be more or less likely to result in PPH and transfusion at the beginning compared to the end of our study period.The rate of obstetric transfusion among NSW hospital-based births increased over the period of 2005 to 2011 but has since stabilised through to 2015. Meanwhile, the rate of postpartum haemorrhage continued to rise from 2005 through to 2015. The changes in rate of transfusion could only be partly explained by changes in maternal and pregnancy risk factors using each of the methods employed in this study. Further monitoring and investigation, especially following the implementation of specific patient blood management guidelines for obstetrics in 2015, will give deeper insight into these trends to assist policy makers and clinicians to improve best-practice administration of blood products in an obstetric setting.Additional file 1:Table S1. Maternal and pregnancy risk factors for obstetric transfusion and sources. (DOCX 18 kb)


Adolescent motherhood has been repeatedly linked to poor child outcomes in high income countries and urban areas in low- and middle-income countries. We examine the structural, personal, and caretaking challenges of adolescent mothers and their children in rural South Africa compared to adult mothers over the first 24 months post-birth.n = 470/493) in the rural OR Tambo District was recruited and reassessed at 3, 6, 9, 12, and at 24 months post-birth, with a retention rate above 84% at all timepoints. Maternal and child outcomes were examined over time using multiple linear and logistic regressions.A cohort of sequential births (n = 76/458). Adolescent mothers were more likely to have water in their households, but less likely to live with a partner and to be seropositive for HIV than adult mothers. Risks posed by mental health symptoms, alcohol, and partner violence were similar. Adolescents exclusively breastfed for shorter time and it took longer for them to secure a child grant compared to adult mothers. Although obtaining immunizations was similar, growth was significantly slower for infants of adolescent mothers compared to adult mothers over time.Adolescent mothers reflect 17% of births (In rural South Africa, almost one in five pregnant women is an adolescent. Caretaking tasks influencing child growth, especially breastfeeding and securing the child grant appear as the greatest problems for adolescent compared to adult mothers. Childbirth is the leading cause of death among young adolescent women aged 15–19 years old globally . AdolescAdolescent mothers often have less structural resources: they are often less educated and lack financial independence than adult mothers in both high (HIC) and low- and middle-income countries (LMIC) . In SA, Pregnant adolescents are likely to be those who have personal histories of risk – mental health or to make poor choices in their partners. Adolescent motherhood has been linked to mental health problems in HIC –7. HowevResearch suggests that poverty linked with young age contributes to insufficient perinatal care which can place the mother and child at risk for many health and developmental problems –15. ManyThis study was conducted with approval of the Health Research Ethics Committee of Stellenbosch University (N12/08/046) and the Institutional Review Board at the University of California, Los Angeles (IRB#16–001362).Zithulele Hospital in the King Sabata Dalindyebo sub-district of the OR Tambo District of the Eastern Cape of SA. It is a 146-bed district hospital and has a catchment area with a population of approximately 130,000 people. It is situated in one of the two poorest municipalities in SA , in the Between January to April 2013, a cohort of consecutive of mothers giving birth at Zithulele Hospital and in the area covered by its 10 closest clinics were approached to participate in the study. This included mothers who delivered at home (10%) or on the way to a health facility (3%), and who sought follow-up clinic care for their child. Mothers who travelled to the hospital from outside this catchment area to give birth at the hospital were excluded from the sample. Voluntary informed consent was obtained , and, in the case where the mother was less than 18 years old, consent was also obtained from the parents/guardians of the adolescent mother. Mothers were approached while still in the hospital and typically interviewed in the first few days following birth. Women giving birth at clinics were assessed within the first 2 weeks of birth; those giving birth at home were approached at the first post-natal clinic visit.Women visit clinics as soon as possible after giving birth where they secure a government Road to Health Card (RtHC). Not only is the RtHC a type of health passport and, therefore, an important health record, it also serves as proof of birth and is used to apply for a birth certificate, which is then used to apply for a child support grants (R250 per month in 2013) from the South African Social Security Agency (SASSA). We are therefore confident that that most mothers giving birth at home in our area were recruited.Women were reassessed at five points in the next 24 months with high follow-up rates: 84.8% at 3, 92.1% at 6, 88.3% at 9, 91.3% at 12, and 88.0% at 24 months post-birth.https://www.mobenzi.com/). The quality of the data entered into the Mobenzi Researcher Platform was checked on a weekly basis.Local, isiXhosa-speaking women were recruited and trained as field workers over a 6-week period focusing on interview techniques, the ethics of research, confidentiality and the use of mobile phones as a data collection tool. Field workers collected data on mobile phones, which were pre-programmed with assessment questions by the Mobenzi mobile phone team , electricity, and the number of people living in the household.Maternal depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) [Mothers self-reported whether they were primipara and how many antenatal visits they attended. This information was verified on the mothers’ antenatal cards when possible. HIV status was self-reported by mothers at each assessment. Maternal serostatus was confirmed using their maternity delivery record  and/or on the child’s government-issued Road to Heath Cards (RtHC) . e (EPDS) , 19. We e (EPDS) .Intimate partner violence (IPV) was self-reported at the baseline interview and the 12-month assessment with four items adapted from Jewkes and colleagues [lleagues , 22. MotWhether or not the mother was receiving the South African CSG was recorded at each assessment post-birth.Mothers self-reported what they had fed their children in the past 24 h and the past week. Breastfeeding habits were specifically enquired about.Number of up-to-date immunizations were recorded at each assessment based on the child’s RtHC and coded as complete (1) or incomplete (0).Low birth weight was recorded for those infants < 2500 g (1) or ≥ 2500 g (0).Growth was measured by field workers certified in using electronic scales and measuring mats. Children’s weight and height measures were then converted to z-scores based on the World Health Organization’s (WHO) age-adjusted norms (http://www.who.int/childgrowth/standards/en/) for: height-for-age (HAZ), weight-for-age (WAZ), and weight-for-length/height (WHZ). A Z-score below -2SD was considered a serious health deficit: as being stunted (<-2SD for HAZ), underweight for age (<− 2 for WAZ) or acute malnutrition (<− 2 for WHZ) [for WHZ) .The gross motor developmental milestones of the WHO for children at 6 (WHO1), 9 (WHO3), 12 (WHO1–5) and 24 months (WHO1–6) were administered . These iThe primary analysis compared adolescent (< 18 years old) and adult mothers using mixed effects regression models, with adult mothers as the reference group. Logistic regression models were used for binary outcomes. Ten of the 470 mothers gave birth to twins, these mothers and their children were excluded in the current analysis. Two HIV-positive children were omitted from the analyses due to death and a coding error. All models were adjusted for repeated measures, where appropriate, and a random participant effect to control for the longitudinal nature of the assessments was used. The regression models were carried out using IBM SPSS Statistics .Table On average, all mothers received an eighth-grade education. More adult mothers lived with the father of their child or with their in-laws, compared to adolescent mothers (38% vs. 8%). About half of all households had monthly incomes under ZAR 2000 (about 144 USD). Only about 16% of households had a water tank on the premises; however, adolescent mothers were significantly more likely to have water on their household’s premises compared to adult mothers (25% vs. 15%). Only about 16% of households had any electricity in their households, with each household having eight members on average.Almost all adolescent mothers were primaparous (95%); three adolescent mothers were pregnant for the second time and one was on her third pregnancy. On average, half of adolescent and adult mothers had the recommended minimum of four or more antenatal visits. Adolescents were significantly less likely to be HIV infected than adult mothers (6% vs. 33%). About 41% of mothers over 24 years of age were HIV seropositive; a rate almost double that of 18- to 23-year olds (24%) and more than five times that of adolescents (6%).M = 7.33, SD = 5.19; 11%) and adult mothers . Compared to depression reported at birth, both adolescent and adult mothers reported fewer depressive symptoms over time. Depression was significantly lower at 3 months , 6 months , 9 months , 12 months , and 24 months post-birth .Depressive symptoms and the rate of depressed mood (EPDS > 13) were also similar at the time of birth between adolescent , B = −.24, Std. Error = .48, p < .001. By 24 months of age, children were similarly receiving the child grant whether they had an adolescent or an adult mother. Adolescent mothers were less likely to exclusively breastfeed for 3 or 6 months when compared to adult mothers, B = − 0.72, Std. Error = .34, p = .04. Complete and up-to-date immunizations were similar over time for adolescent and adult mothers. Adolescent mothers were more likely to have returned to school by 6 months post-birth than adult mothers (17% vs. 2%).Table Estimate = −.26, Std. Error = 0.11, p = .02; Estimate = −.32, Std. Error = 0.12, p = .01, respectively. WAZ and WHZ increased significantly for children of adolescent and adult mothers from birth to 3  6  9  12  and 24  months post-birth. However, HAZ increased significantly for children of adolescent and adult mothers from birth to only 3  and 6  months post-birth. HAZ did not change significantly from birth to 6, 8, 12, or 24 months post-birth p > .05 . However, children of adolescent mothers tended to be significantly shorter and weighed less than children of adult mothers across their first 24 months of life, 0%. HowevIn rural SA, almost one in five pregnant women is an adolescent. With about half of adolescent and adult mothers living in households with reported incomes under ZAR 2000 and limited support from their partners, obtaining the child grant becomes even more important to support mothers and their children. Adolescent mothers experience significant lags in securing child grants compared to adult mothers. However, the reason for the delays in obtaining these child grants is unclear. This puts an already at-risk group in socio-economic jeopardy. Delays in obtaining these funds may be particularly difficult for adolescent mothers who have limited means of income, potentially resulting in elevated risks for malnutrition and stunting for their children.Breastfeeding serves as a protective factor for both adolescent and adult mothers. Overall, the rate of exclusively breastfeeding during the first 6 months of life is higher than the national rate of 8%; however, adolescent mothers are significantly less likely to exclusively breastfeed than adult mothers . This caAs predicted, adolescent mothers face increased difficulties in caretaking. Although the percentage of low birth weight infants and stunted children are similar for adolescent and adult mothers, children of adolescent mothers are significantly shorter and weighed less on average than those of adult mothers over time. Lags in early physical growth are associated with negative health, social, and cognitive outcomes across the lifespan . The redAcquiring HIV, IPV, and, depression are also a significant risk factor for young women who fall pregnant in SA. The pathways to HIV infection among adolescents include unprotected and intergeneration sex , as wellAlthough children’s growth and developmental milestones are measured by the trained interviewers at each assessment, most of the maternal measures are based on maternal self-reports. The HIV status of most mothers is self-reported at each assessment and on their maternity delivery record and their children’s RtHC, which are used to confirm their serostatus. However, no laboratory tests are available to confirm maternal HIV status or to test children’s immune systems.In conclusion, there is a high rate of adolescent pregnancies in the rural Eastern Cape of SA. The impact on adolescent mothers in terms of their caretaking is significant and their babies are also shorter and weigh less on average, than babies of adult mothers. This situation underlines the importance of supporting adolescent mothers, especially those reporting difficulties in acquiring the CSG. Also, ensuring that local officials support all mothers 16 years and over to apply for the CSG immediately may assist in providing essential economic support for adolescent mothers and their children.


Maternal hemodynamics in pregnancy is associated with fetal growth and birth weight, which in turn are associated with offspring cardiovascular disease later in life. The aim of this study was to quantify the extent to which birth weight is associated with cardiac structure and function in adolescence.n = 1964; 55% female) of the Avon Longitudinal Study of Parents and Children were examined with echocardiography at a mean age of 17.7  years. The associations of birth‐weight Z‐score for sex and gestational age with cardiac structure  and left atrial diameter index), systolic function  and diastolic function  and early mitral inflow velocity/mitral annular early diastolic velocity (E/e′)) were evaluated. Linear regression models were adjusted for several potential confounders, including maternal prepregnancy body mass index, age, level of education and smoking during pregnancy.A subset of offspring  and E/e′  and higher LVMI . There was no or inconsistent evidence of associations of birth‐weight Z‐score with relative wall thickness, left atrial diameter and measurements of systolic function. Further analyses suggested that the association between birth‐weight Z‐score and LVMI was driven mainly by an association observed in participants born small‐for‐gestational age and it did not persist when risk factors in adolescence were accounted for.Higher birth‐weight Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.Higher birth weight adjusted for sex and gestational age was associated with differences in measures of diastolic function in adolescence, but the observed associations were small. It remains to be determined the extent to which these associations translate into increased susceptibility to cardiovascular disease later in life. © 2018 The Authors.  Those with a successful examination, defined in this study as having an estimable ejection fraction, were included in the study sample . Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.This study includes a subset of offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population‐based birth cohort. Pregnant women resident in the Bristol area of South West England, UK, with expected dates of delivery between 1 April 1991 and 31 December 1992, were eligible for recruitment. Of 14 541 women originally recruited, there were 13 617 singleton offspring alive at > 1 year of age. In total, 4770 of these participated in a clinic assessment at 17 years of age and a random subsample was examined with echocardiography Data collection in ALSPAC has been described in detail for mothers2.7 (LVMI)The echocardiography examination protocol has been described previouslyZ‐score as a continuous variable was appropriate compared with different categorizations of birth‐weight Z‐score that would allow for a non‐linear association across birth‐weight distribution. To do so, model‐fit statistics of a model with continuous birth‐weight Z‐score were compared with models including birth‐weight Z‐score categorized in various ways for each echocardiography outcome (Appendix We first tested the extent to which modeling birth‐weight Appendix .a priori as variables that are plausible shared antecedent causes of the exposure (birth‐weight Z‐score) and the cardiac outcomes. In Model III, we adjusted further for participant factors in adolescence, including BMI, systolic blood pressure (SBP) and heart rate, all of which are potential mediators of the association between birth weight and cardiac outcome. Consequently, the results of this model might be interpreted as indicating the effect of birth weight once the effects of birth weight acting through these mediators is accounted for; however, mediation models have considerable potential to introduce other biases and the resulting model should be interpreted with caution and in the context of the assumptions madeIn Model I, we adjusted for sex and offspring age at the clinical assessment. In the main confounder‐adjusted model (Model II), we adjusted further for maternal height, maternal education and pregnancy‐related factors including maternal age, parity, maternal prepregnancy body mass index (BMI), maternal diabetes mellitus/glycosuria during pregnancy, preterm birth, hypertensive disorders of pregnancy and maternal smoking during pregnancy. These confounders were chosen n = 1592). To test the extent to which any observed association was also present in those with normal birth‐weight Z‐score, the analyses were repeated but restricting the sample to those with birth‐weight Z‐score between the 10th and 90th percentiles . To investigate the extent to which the indexing strategy influenced our results for LVMI and LADI, we performed complementary analyses in which we used different strategies to account for participant height  included participants had missing data for birth weight or other covariables. To increase power and minimize bias, we used multiple imputation to impute missing values of birth weight and covariables for all participants. All imputed variables had < 10% missing data. Twenty imputed datasets were generated and analyzed by implementing the ‘mi impute’ and ‘mi estimate’ commands in Stata 13.1  kg. Characteristics of the study sample and of other singleton participants in ALSPAC attending the visit at 17 years of age are shown in Table Appendix .Z‐score and measures of cardiac structure and function in adolescence. In the main model adjusted for maternal and pregnancy factors as well as offspring sex and age (Model II), higher birth‐weight Z‐score was associated with larger LVMI and differences in diastolic function as assessed by E/A and E/e′. Additional adjustment for factors in adolescence  substantially attenuated the association between birth‐weight Z‐score and LVMI, and evidence of an inverse association with LADI emerged. There was no evidence of associations with RWT or ejection fraction.Table Z‐score and echocardiography outcome in participants with normal birth‐weight Z‐score (between the 10th and 90th percentiles). Among these participants, there was no evidence of an association between birth‐weight Z‐score and LVMI. However, the estimates of inverse associations with diastolic function (E/A and E/e′) were similar to those observed in the main analysis. To explore these findings further, we generated linear splines with knots at the 10th and 90th percentiles of birth‐weight Z‐score  that was restricted to participants with low birth weight (Z‐score < 10th percentile). Restricting analyses to participants with no missing data provided similar results compared to the main analyses . In the complementary analyses accounting for height, the results for LVMI remained similar, while the associations for left atrial size appeared somewhat strengthened in Model II , predicts cardiac events among patients with hypertensionZ‐score, SBP and BMI were similar. In addition, there were no data on placental dysfunction; hence, our ability to distinguish reduced fetal growth from non‐pathological low birth weight was limited. Furthermore, it should be noted that there are inherent limitations with utilizing estimates of cardiac volumes from two‐dimensional imaging data. For example, it has been reported previously that FGR is associated with left ventricular shapeWhen compared with previous studies, the novelty and methodological strengths of this study are the combination of well‐defined maternal pregnancy data that allow for better control of confounding, the prospective longitudinal cohort study approach, the duration of follow‐up until adolescence and the use of multiple imputation to address missing data. However, the study also has some relevant limitations. Only a subset of the original birth cohort was examined with echocardiography at a typical age of 17, though a pseudorandom sample was chosen among adolescents attending follow‐up at the time and the birth‐weight Z‐score across its entire range was associated with minor alterations in diastolic function in adolescence, as measured by echocardiographic indicators. In contrast, the positive association between birth‐weight Z‐score and LVMI was driven by those born SGA. All observed effect estimates were small but should be considered in the perspective of life‐course trajectories. Whether and, if so, the extent to which these associations are explained by causal effects mediated through birth weight, pleiotropic genes or suboptimal maternal cardiovascular adaptation to pregnancyIn conclusion, higher birth‐weight Appendix S1 Methods for data collection and echocardiography examinations in ALSPAC and statistical analyses in current studyClick here for additional data file.Appendix S2 Results of model‐fit statistics and analyses performed including only participants with complete data and when accounting for heightTables S1 and S2 Association between birth weight and cardiac structure and function in participants without missing birth‐weight or covariable data (Table S1) or with normal birth weight without missing covariable data (Table S2)Table S3 Influence of height on association between birth weight and left ventricular mass or left atrial diameter in adolescenceClick here for additional data file.


Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed.We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth , defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15–30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 760 participants (380 per group) will detect a reduction in adverse neonatal outcome from 11.95% to 6% . A cost-effectiveness analysis will be performed from a societal perspective.This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC’s in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results.Nederlands Trial Register . The primary outcome is perinatal mortality and neonatal morbidity, not prolongation of pregnancy.This is the largest randomised trial comparing atosiban to placebo for women with threatened preterm birth.Over 40 hospitals in Europe will participate.Tocolysis is incorporated in daily routine as it has been the recommendation in many guidelines.It will prove to be a challenge in counselling patients to participate in a placebo controlled trial, especially in an acute setting.Preterm birth, defined as birth before 37 weeks’ gestation, is a major contributor to perinatal mortality and morbidity, complicating over 15 million pregnancies worldwide.6Maternal administration of corticosteroids to accelerate fetal lung maturation is an effective treatment for women with threatened preterm birth.The two most commonly used tocolytic drugs, atosiban and nifedipine, showed comparable perinatal outcome in the APOSTEL 3 study.The oxytocin receptor antagonist atosiban has fewer maternal side effects in head to head comparison with alternative drugs,14One explanation might be that since spontaneous preterm birth is associated in 40%–70% of cases with chorioamnionitis,Perinatal outcome has also markedly improved over the last few decades, in part due to postnatal interventions such as exogenous surfactant treatment which reduces mortality and respiratory morbidity in preterm infants.Worldwide, practice varies widely. Several large institutions in countries like Canada, Scotland and Ireland, rarely use tocolytics, while in the USA, COX (indomethacin) and calcium channel blockers (nifedipine) are popular. In Europe, nifedipine and the oxytocin antagonist, atosiban, are both widely used.In conclusion, current widespread use of tocolytic drugs for this indication is not supported by the available evidence. The primary goal of tocolysis should not be prolongation of pregnancy, but improvement of neonatal outcome. This view is supported by the WHO, as they state in their 2015 guidelines on preterm birth that the effectiveness of tocolytics is not proven, and that placebo-controlled studies are urgently needed.To test the hypothesis that tocolysis with atosiban in late preterm birth (30–34 weeks) reduces neonatal mortality and morbidity and is cost-effective compared with placebo.We will conduct an international, multicentre, double-blind, randomised, placebo-controlled clinical trial, performed in The Netherlands, UK and Ireland.+0 and 33+6 weeks are eligible. Threatened preterm birth is defined as uterine contractions withWomen, aged ≥18 years, with threatened preterm birth and a gestational age between 30A cervical length of <15 mm orA cervical length of 15–30 mm and a positive fibronectin test orIn centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) orRuptured membranes.These inclusion criteria are based on the results and conclusions of the APOSTEL 1 studyThis study was designed in a pragmatic fashion, in order for the results to be applicable in the current clinical practice. As most national guidelines and local protocols propose treatment for threatened preterm birth in both singleton and multiple pregnancies, as well as women with ruptured membranes, all these categories of patients are eligible for the study.Women with a contraindication for tocolysis, signs of fetal distress, clinical signs of intrauterine infection, previous treatment for threatened preterm birth with corticosteroids in the current pregnancy and known fetal chromosomal or severe structural abnormalities are not eligible.Potential participants will be identified by the local research co-ordinators and/or the staff of participating hospitals. Women eligible for the trial will be counselled by doctors, midwifes or research nurses trained in ‘good clinical practice’, and will be given a patient information form to read. Those who wish to participate, will be asked to give for written informed consent and are registered within the central trial database. Randomisation will be performed by using sequentially numbered medication packs available in each centre. Only the independent data manager has access to the computer-generated randomisation list in which the medication numbers are linked with atosiban or placebo. Treatment allocation is blinded to investigators, participants, clinicians and research coordinators. Randomisation will be balanced with varying block sizes of 2 and 4, and stratified by centre.At study entry, baseline demographic, prior obstetric and medical history will be recorded into the web-based case report form accessible through a secure central website .4 for neuroprotection and antibiotics if needed.Participants are allocated to atosiban or matching placebo  for 48 hours. The medication will be administered by a bolus injection of 6.75 mg/0.9 mL in 1 min followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for the remaining 45 hours. Participating women will otherwise be treated according to local protocol based on national guidelines, including corticosteroids MgSOwww.crown-initiative.org).22Outcome parameters are in line with the core outcome set for studies on prevention of preterm birth defined by members of GONet and the Core Outcomes in Women’s health (CROWN) initiative , periventricular leucomalacia (PVL) >grade 1, intraventricular haemorrhage >grade 2, necrotising enterocolitis (NEC) ≥stage 2, retinopathy of prematurity >grade 2 or needing laser therapy, and culture proven sepsis.et alet al.et al.The diagnosis of BPD will be made according to the international consensus guideline as described by Jobe and Bancalari.Secondary infant outcomes will be birth within 48 hours, time to birth, gestational age at birth, birth weight, number of days on invasive mechanical ventilation, length of neonatal intensive care unit (NICU) stay, convulsions, asphyxia, meningitis, pneumothorax until hospital discharge.Maternal outcomes will be mortality, infection of inflammation and harm to mother from interventions (side effects). Side effects are defined as admission to intensive care, anaphylactic shock, dyspnoea, hypotension , liver test abnormalities (elevated aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT)), general side effects , postpartum haemorrhage defined as >500 mL blood loss and maternal mortality.We will ask informed consent to approach the parents for long-term follow-up of the children. We intend, subject to funding, to use standardised questionnaires at 2 and 5 years of age.Maternal quality of life will be assessed at randomisation and at 3 months baby corrected age using the EuroQol (EQ-5D-5L) questionnaire. This consists of five dimensions  that are rated using five levels .Societal costs will be assessed using adapted versions of the iMTA Medical and Productivity Cost Questionnaires at 3 months corrected baby age. Cost data include costs of the intervention, other healthcare utilisation, patient and family costs and costs of productivity losses.Participants can cease study treatment at any time for any reason if they wish to do so. Unless they refuse to allow further data collection, such participants will continue to be followed-up and will be analysed in the group to which they were originally allocated. Participants who decline follow-up will have no further trial data collected. Any results collected up to the point at which they decline follow-up will be analysed. Study medication will be discontinued in patients with signs of intrauterine infections or signs of fetal distress . Data of such participants will continue to be analysed. Further management will be left to the expertise of the responsible clinician. The responsible clinician can contact a perinatologist from the project group in case of suspected side effects or other medical problems. If necessary, treatment will be discontinued.An independent data safety monitoring board (DSMB) will focus on both effectiveness and safety. Serious adverse events (SAEs) will be collected from the first study-related procedure until 3 months after delivery. All SAEs will be reported to the DSMB within 7 days. Whenever there is proof of effectiveness  or safety issues (increased (serious) adverse events in one of the two treatment arms) the DSMB will advise whether the trial should be stopped or continued. The DSMB will be blinded when first analysing the data, but unblinded before reaching a decision.The advice(s) of the DSMB will only be sent to the sponsor of the study. Should the sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the advice to the reviewing Medical Ethics Committee, including a note to substantiate why (part of) the advice of the DSMB will not be followed.A formal interim analysis is planned after data collection of 500 women. At these interim analyses, the Haybittle-Peto alpha spending function will be used, which means that an effect at interim with a p value <0.001 is considered statistically significant.Based on the APOSTEL 3 data, the proportion of adverse perinatal outcome in women randomised between 30 and 34 weeks gestation and treated with atosiban was 6%.Data analysis will be performed according to the intention-to-treat principle. In the baseline table, categorical variables will be expressed as a number with the percentage of the total allocation arm. Continuous variables will be presented as mean with SD, as geometric mean with 95% CI or as median with IQR, whichever appropriate.The main outcome ‘adverse neonatal outcome’ will be assessed on the infant level, using a log-binomial generalised estimating equations model to take into account the correlation of outcomes in multiples, resulting in an RR with accompanying 95% CI. To account for stratified randomisation by centre, we will also take centre into the model if the model converges.30The other secondary outcome measures on the child level will be analysed similar to the primary outcome measure. Outcomes on the maternal level will be assessed by using a binomial regression model with log-link function. When a statistically significant difference in primary outcome is found between both groups, we will calculate the number needed to treat. Time to delivery will be evaluated by Kaplan-Meier estimates and Cox proportional hazard analysis, taking into account the different durations of gestation at study entry, and will be tested with the log rank test. A p value of <0.05 will be considered to indicate statistical significance.The following subgroup analyses are planned:Singleton versus multiple pregnancy.Cervical length <15 mm versus cervical length 15–30 mm and a positive fibronectin test .Ruptured or unruptured membranes at entry.Previous preterm birth.A sensitivity analysis will be performed excluding multiple pregnancies and pregnancies complicated by preterm premature rupture of membranes.To assess whether a subgroup effect is present, we will add an interaction term between the subgrouping variables and the treatment allocation to the regression model. When an interaction term is statistically significant (p<0.05), we will estimate the treatment effect within strata of the subgrouping variable.Details of the statistical analysis will be describes in separate statistical analysis plan that will be completed before data lock.The cost-effectiveness analysis will be done according to the intention-to-treat principle. Missing cost and effect data will be imputed using multiple imputation according to the Multivariate Imputation by Chained Equations (MICE) algorithm developed by Buuren.The preterm birth research line of the Dutch consortium is in close collaboration with two Dutch patient associations, the Vereniging van Ouders van Couveusekinderen  and the Nederlandse Vereniging van Ouders van Meerlingen (freely translated to Dutch society of parents of multiples). They are involved in the design of new studies, updated on progress of running trials and informed of study results. Project members are invited speakers at yearly conferences of these societies to present on the progress of our preterm birth research line. At these conferences, surveys are being performed on patient preferences on study ideas. Tocolysis was deemed an important research issue. Both associations have written support letters to the funding agency ZonMw  for the APOSTEL 8 study.A project panel of parents who experienced a spontaneous preterm birth consisting of six couples was involved in the design of our study. A survey was performed during the design of the study among members of the closed Facebook group of the VOC, to address questions on whether they would be interested in participation in the APOSTEL 8 study.The Dutch consortium has a website where it publishes all results of completed studies, and publishes the protocols of currently recruiting studies.Presentations will be held at yearly conferences at patient organisations and updates on research are being published in the journal of the VOC.The Research Ethics Committee (REC) at the Amsterdam University Medical Centres, location AMC, approved this study. Additional regional approval was obtained for the remaining participating hospitals in The Netherlands. Furthermore, the study was approved by the REC of the National Maternity Hospital in Dublin, Ireland, and the REC of East Midlands—Derby in the UK. Protocol amendments will be communicated to a relevant parties. This trial is registered with the Nederlands Trial Register.A manuscript with the results of the primary study will be published in a peer-reviewed journal. A separate manuscript will be written on the cost-effectiveness analysis. The results of this clinical trial will be presented at conferences and disseminated through publication in a peer-reviewed journal.


Mucinous nonneoplastic cyst of the pancreas is a rare disease defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts. Mucinous nonneoplastic cyst of the pancreas has no malignant potential and does not require surgical resection or surveillance. However, its preoperative differentiation from other cystic lesions of the pancreas is difficult because of several overlapping clinical, radiological, and biochemical features. We report a rare case of large mucinous nonneoplastic cyst of the pancreas in which surgery was required due to infection and the possibility of malignancy.A 75-year-old Japanese man was found to have a pancreatic cyst in 2006 while undergoing postoperative evaluation for colon cancer. In 2015, the cyst ruptured, and it was treated conservatively. In 2017, he fell down on a road with a fever of 40 °C and was transported emergently to a nearby hospital. Enhanced computed tomography revealed a cystic lesion in the body of the pancreas measuring 119 mm × 100 mm and an adjacent left renal cyst measuring 63 mm in diameter. The wall of the pancreatic cyst was thickened. Magnetic resonance imaging demonstrated a liquid surface in the pancreatic cyst. Pancreatic cyst infection was diagnosed as the source of infection. However, identification of the organism was difficult. Furthermore, due to the increase in the size and wall thickness of the cyst, it was unclear whether the cystic mass was neoplastic with malignant potential. For these reasons, the patient underwent distal pancreatectomy and splenectomy with deroofing of the left renal cyst. Intraoperatively, the pancreatic cyst adhered to the descending colon, and partial resection of the colon was added. Pathologic analysis of the resected cyst demonstrated a simple cyst lined by mucinous epithelium. There was no underlying stromal condensation or epithelial dysplasia, and communication with the native pancreatic ducts was not observed. Based on the operative and histological findings, a final diagnosis of mucinous nonneoplastic cyst of the pancreas with colonic communication was made. The colonic fistula was presumed to be the source of infection.Mucinous nonneoplastic cyst of the pancreas is generally benign and requires little follow-up, but large cysts may penetrate other organs and cause severe complications. Asymptomatic pancreatic cysts are being detected with increasing frequency due to widespread use of sensitive abdominal imaging tests such as multidetector computed tomography and magnetic resonance imaging (MRI). The classification of cystic pancreatic neoplasms is generally based on differentiating mucinous from nonmucinous cysts and benign from malignant cysts –3.Mucinous nonneoplastic cyst of the pancreas (MNNC) is defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts . MNNC haA 75-year-old Japanese man was found to have a pancreatic cyst in 2006 while undergoing postoperative evaluation for colorectal cancer. The pancreatic cyst increased in size, and surgery was recommended, but the patient declined Fig. a, b. In The patient was treated with new quinolone-based antibiotics for 3 weeks as a conservative treatment after hospitalization. Bacteria were not detected by blood culture examination at admission. Enhanced computed tomography (CT) revealed a cystic lesion in the body of the pancreas measuring 119 mm × 100 mm and an adjacent left renal cyst measuring 63 mm in diameter. The wall of the pancreatic cyst was thickened. The pancreatic ducts were not dilated Fig. . MagnetiPancreatic cyst infection was diagnosed as the source of infection. However, identification of the organism was difficult. Furthermore, due to the increase in the size and wall thickness of the cyst, it was unclear whether the cystic mass was neoplastic with malignant potential. For these reasons, the patient underwent distal pancreatectomy and splenectomy, with deroofing of the left renal cyst. Intraoperatively, the pancreatic cyst strongly adhered to the descending colon, so partial resection of the colon was added.Bacteroides fragilis and Streptococcus sanguinis were detected as a result of culture examination of the pancreatic cyst contents. On the basis of the operative and histological findings, a final diagnosis of MNNC with colon communication was made (Fig. Pathologic analysis of the resected cyst demonstrated a simple cyst lined by mucinous epithelium Fig. b. There ade Fig. . The smaPostoperatively, the patient was treated for a grade B pancreatic fistula. On postoperative day 12, emergency surgery was performed for thrombotic descending colon perforation. On postoperative day 94, the patient was discharged on foot.et al. [et al. [et al. [We describe a case of a large MNNC that eroded into the colon, leading to cyst infection. MNNC is an increasingly recognized subset of pancreatic cysts. In 2002, Kosmahl et al.  reportedet al. –11. The et al. , 9. MNNC [et al.  studied  [et al.  reported [et al. . MRI enaIn our patient’s case, the cyst was previously identified on the basis of CT in 2006. Surgery was recommended at that time because the cyst was difficult to distinguish from a malignancy, but the patient refused. The cyst later ruptured and then developed a cryptic infection requiring extensive surgery.We are aware of no prior case reports of MNNC and colonic fistula. However, severe acute pancreatitis can lead to localized complications such as the formation of a pseudocyst, necrosis, or an abscess. Acute pancreatitis complications with colonic involvement have a relatively low incidence of approximately 3% . FistulaIn our patient’s case, it was presumed that the increased MNNCs were in communication with the colon, resulting in a small colon fistula through which enteric bacteria could pass, causing a cystic infection. CT revealed increased pancreatic cyst size and wall thickness. MRI suggested a mucinous component of the cyst. It was difficult to evaluate the whole cyst in detail by EUS. For these reasons, we were unable to rule out malignancy and chose to proceed with surgical resection. Surgical intervention allows for complete removal of the cyst and provides tissue for an accurate histological diagnosis.Because the cyst communicated with the descending colon, a partial resection of the colon was also performed. It is possible that ischemic changes caused by the resection led to the subsequent colonic rupture. The colon rupture was unpredictable as a postoperative complication, but it should be considered when similar cases are seen in the future.This was a case of a large MCCN that caused a fistula to the descending colon, through which the cyst became infected. MCCN is generally benign and requires little follow-up, but large cysts may penetrate other organs and cause severe complications.


Nasofrontal fistulas correspond to the persistence of an abnormal communication of embryological origin between the deep layer of the skin and the central nervous system (CNS). They can rarely be associated with a dermoid cyst and be revealed by a locoregional infection, and especially neuromeningeal infections can be serious. The treatment is mainly surgical by performing a total excision of the cyst and the repair of defects. The authors report the case of an 18-month-old infant operated for a dermoid cyst revealed by a nasofrontal fistula. They insist on the characteristics of this pathology in order to establish a diagnosis and an early treatment to avoid the complications that can be heavy in certain cases. They describe the steps of nasofrontal reconstruction by a small flap taken from the outer table of the frontal bone with better esthetic results. The nasofrontal dermoid cyst is a rare abnormality of embryological development and may be revealed by a nasofrontal fistula that corresponds to the absence or incomplete obliteration of the neuroectoderm during the development of the frontonasal region. The progressive enlargement of the dermoid cyst can lead to skeletal deformation, soft tissue, and a locoregional infection, especially a neuromeningeal infection, which can be serious. Early diagnosis and appropriate treatment are important to avoid neuromeningeal and esthetic complications , 2]. We. We2]. WAn 18-month-old infant without specific pathological history presented at 1 month of admission a median frontal swelling facing the nasion associated with a citrin yellow flow of increasing intensity without fever. Clinical examination showed a nasofrontal fistula allowing a flow to the top of a small inflammatory mass slightly sensitive to palpation Figure 1  evolvingDuring the development of the skull base and the nose, the mesenchymal structures are formed by the fusion of several structures that ossify. But before fusion, there are recognized spaces between these structures that include the fonticulus frontalis, the prenasal space, and the foramen caecum, which are normally closed by fusion and ossification , 4]. Du. Du4]. DDifferent approaches are described in the literature ranging from a simple incision with cyst ablation to lateral and transverse rhinotomy. A bicoronal approach in case of an intracranial extension of the cyst is sometimes necessary , 9]. An. An9]. AFinally, it is important to insist on the complete excision of the cyst. Indeed, a partial resection exposes to recurrence in 50 to 70% . FistulaThe knowledge of the embryological development of the nose and the skull base is important because a defect of obliteration and embryological communication between the nasal region and the dura can lead to a nasofrontal fistula, which must be excluded as a diagnose in cases of a nasofrontal discharge especially in infants and small children, and may reveal a dermoid cyst. Imaging helps in diagnosis and choice of treatment. A complete surgical excision is essential as well as bone and dura defect repair to avoid infection.The authors declare that they have no competing interests.


Objective. To analyze the presence of periodontal disease, proinflammatory cytokines, and prostaglandin E2 (PGE2) in pregnant patients at high risk for preterm delivery. Materials and Methods. Pilot study for a case-control study. We included 46 pregnant patients (23 patients at risk of preterm delivery as cases and 23 patients without risk of preterm delivery as controls). We excluded patients who received periodontal treatment, antibiotics, or antimicrobials over the last 3 months as well as those with infections or diseases such as diabetes or hypercholesterolemia. The patients underwent a periodontal assessment, and their levels of cytokines  and prostaglandin E2 (PGE2) were quantified. Results. Patients with periodontal disease showed higher levels of cytokines  and PGE2. Patients at high risk for preterm birth showed higher IL levels compared with patients at low risk for preterm delivery. PGE2 increased with the severity of periodontal disease. PGE2 was higher in patients at low risk for preterm delivery, although this difference was not significant. Conclusion. Periodontal disease can increase the systemic inflammatory response as well as the levels of PGE2 and inflammatory cytokines in pregnant patients.Periodontal disease is an infection that, in pregnant women, can act as a risk factor for preterm delivery by increasing local and systemic inflammatory responses. Pregnancy is a physiological process associated with adverse outcomes such as preterm birth (<37 weeks), low birth weight <2500 grams), or very low birth weight <1500 grams). The global incidence of preterm delivery is 9.6%, which is equivalent to 12.9 million premature infants. Currently, preterm delivery is the second most common cause of death in children younger than 5 years after pneumonia. Each year, 1 million premature infants die. In addition, preterm birth is associated with deterioration in growth, cognitive and visual alterations, and learning disabilities [500 grams500 gramsThe adverse outcomes of pregnancy are associated with elevated systemic inflammatory mediators and intrauterine infections. Current evidence suggests that preterm delivery is primarily due to ascending infections from the vagina or cervix or via hematogenous spread from nongenital sources. F. nucleatum, P. gingivalis, C. rectus, among others) might be related to the adverse results of pregnancy, which might partially explain the biological plausibility of the associations among periodontal disease, periodontopathogenic bacteria, systemic inflammatory mediators, and adverse pregnancy outcomes [Significant evidence supports an association between the spread of pathogenic bacteria associated with moderate/severe periodontitis and infections and extraoral inflammation. The virulence properties assigned to specific oral pathogenic bacteria  1, IL2, and IL-6 as well as inflammatory mediators such as prostaglandin E2 (PGE2) [Maternal periodontitis might represent a nongenital source of microorganisms that, because of their routine entry into the circulation system, have the potential to influence the health of the fetal-maternal pair. Periodontal infection and its pathogens generate virulence factors via the production of lipopolysaccharides (LPSs) and increased cytokines such as tumor necrosis factor- (TNF-) 2 (PGE2) .2 and PGI2).During pregnancy, changes in maternal physiology and metabolism occur; for example, peripheral vascular resistance decreases to compensate for the increases in renin and angiotensin. This effect is attributed to specific prostaglandins  the levels of PGEes birth . Howeveres birth , 10.α and inflammatory mediators such as PGE2 in pregnant patients at risk of preterm delivery and their relationships with periodontal disease.Therefore, the objective of this work was to analyze the cytokines IL-2, IL-6, IL-10, and TNF-To achieve the proposed objective, a pilot case-control study was conducted.Pregnant women with a gestational age greater than 20 weeks were considered for inclusion. Patients who received periodontal treatment, antibiotics, or antimicrobials over the last 3 months or who showed active infections or underlying diseases such as diabetes or hypercholesterolemia were excluded from this study.α as well as inflammation mediators such as PGE2.We analyzed 46 pregnant patients (23 cases and 23 controls). The cases were pregnant patients considered at risk of preterm delivery; the controls were pregnant women not at risk. The evaluated exposure was periodontal disease as a local infection; inflammation and the systemic inflammatory response were analyzed based on the presence of cytokines such as IL-2, IL-6, IL-10, and TNF-The risk diagnosis of preterm delivery was classified as follows: (1) threat of preterm birth ; (2) preterm labor during the initial phase ; and (3) advanced phase preterm labor . This classification was determined based on the Clinical Practice Guidelines of the Obstetrician-Gynecology Service of San Ignacio University Hospital and was performed by a trained gynecologist .The patients in the case group were hospitalized at San Ignacio University Hospital and presented with the risk of preterm delivery in stages 1 and 2 . Pregnant patients were included in the control group if they had received routine gynecological care on an outpatient basis and did not present with the risk of preterm delivery.This research was classified as minimal risk in accordance with the regulations established by Resolution 8430, Ministry of Health of Colombia and CIOMS , 12. The2. The second tube was centrifuged immediately at 10,000 rpm for 10 minutes at room temperature to obtain blood serum and frozen at -20°C until use. IL-2, IL-6, IL-10, and TNF-α were quantified using the BD CYTOMETRIC BEAD ARRAY (CBA) Human Th1/Th2 Cytokine Kit II (reference: 55181) following the manufacturer's instructions. Samples were acquired in the Hospital Universitario San Ignacio, using the FACSCanto II flow cytometer from Beckton Dickinson, and the data were analyzed using FCAP Array software.The patients who entered the study provided a blood sample, and two tubes were obtained: one tube to analyze the cholesterol, triglycerides, HDL, LDL, basal glycemia, and hematocrit levels and a second tube to quantify the levels of cytokines and PGE2 was quantified using the ELISA technique via the Human PGE2 kit reference KHL1701 (Invitrogen) following the manufacturer's instructions. The absorbance levels were recorded using a spectrophotometer at a wavelength of 412 nm, and the values obtained were transposed to the values given by the standard curve that comes with the kit and replaced in the formula suggested by the kit. Thus, the calculated results were given in picogram units per milliliter (pg/ml).PGEAll of the patients underwent a periodontal evaluation after completing the periodontogram, during which a North Carolina periodontal probe was used. Only two people calibrated to perform periodontal examinations conducted this assessment. Periodontal disease was diagnosed based on the 1999 Armitage classification .2 were described using means, medians, ranges, standard deviations, and 95% confidence intervals. A bivariate analysis was performed in which the levels of the cytokines and PGE2 were compared between groups, and the periodontal diagnosis was examined using ANOVA after ensuring the normal distribution of the variable data (α < 0.05).For data analysis, the demographic characteristics, the results of the periodontal evaluation, the cytokines, and the PGEThe sample consisted of 46 patients who were divided into two groups based on the risk of preterm delivery. The case group consisted of 23 patients at risk of preterm delivery or high risk (HR) and the control group consisted of 23 patients not at risk or normal (N). The average age was 25.9 years (SD = 6.4 years), and the average gestational age was 29.4 weeks (SD = 4.3). The following periodontal diagnoses were determined: two patients were healthy (4.3%), 21 had gingivitis (45.7%), and 23 had chronic periodontitis (50%).The mean gestational ages were 31 weeks for women at risk of preterm delivery and 28 weeks for women without risk of preterm delivery (p = 0.466). Both groups had an average age of 26 years.When analyzing the oral clinical variables with regard to the percentage of biofilm, number of teeth, number of teeth with chronic periodontitis, number of teeth with gingivitis, percentage of teeth with chronic periodontitis, and percentage of teeth with gingivitis, no significant group differences were found. The percentage of biofilm (62%) and the number of teeth with gingivitis (21.8) clinically was higher in the group at risk for preterm delivery, but this difference was not significant .The between-group analysis with regard to periodontal diagnosis chronic periodontitis , gingivitis , and healthy periodontal  revealed that more pregnant women in the group at risk of preterm delivery had more chronic periodontitis, and this group had no healthy periodontal patients.2, an average of 84.4 pg/ml (SD = 23.2) was found, with a minimum of 36.2 pg/ml and a maximum of 157.8 pg/ml. According to the Kolmogorov-Smirnov test, this variable was normally distributed (p = 0.695), which enabled the later evaluations by group differences (with risk versus without risk) and periodontal diagnosis  (With regard to the level of PGEontitis) .2 levels of 79.9 pg/ml (22.3), whereas those without risk showed PGE2 levels of 88.9 pg/ml (SD 23.8); however, this difference was not significant (p = 0.196).The comparison of the averages of the two study groups revealed that women at risk for preterm delivery had PGE2 was evaluated with regard to periodontal diagnosis, the results revealed that the severity of the periodontal disease increased with the levels of PGE2. No significant differences were found with regard to periodontal diagnosis (p = 0.168), which might be due to the sample sizes of the different groups . All 46 women in this study, regardless of group or periodontal disease, had high  values of this marker.Subsequently, the cut-off point for the level of PGEα) than those at low risk; significant differences were observed with regard to IL-2 , IL- 10 , and TNF-α   .The relationship between cytokines and the severity of periodontal disease revealed that, as the latter appears and increases in severity , the levels of the former increase. The highest values were found among patients with chronic periodontitis .2. In human and nonhuman primates, maternal plasma concentrations of PGE2 increase gradually during pregnancy and reach maximum levels at the end of pregnancy. Likewise, COX2 is expressed at low-to-undetectable ranges in the uterus during most of pregnancy, and it is highly regulated by proinflammatory cytokines and PGE2; COX2 catalyzes the production of prostaglandins in the amnion and plays a crucial physiological role in the initiation of labor by functioning as a potent activator of uterine contractions. PGE2 is positively regulated during preterm delivery; in turn, it is induced by an inflammatory response that promotes the contraction of the uterine smooth muscle [α, IL-1, and IL-6) and inflammatory mediators (PGE2) to become a risk factor of preterm delivery.Childbirth is a complex mechanism which has not been fully elucidated. Most, if not all, events that induce labor can be attributed to the action of the PGEh muscle , 14. Perα) also increased, such that the highest values were found in pregnant patients with chronic periodontitis. These findings are consistent with the results of Zadeh 1999 [α as a systemic inflammatory response.The present investigation found that, as periodontal disease appeared and increased in its severity , the levels of cytokines , Deortbudak et al. (2005), and Goepfert et al. (2004) reported contradictory evidence by failing to find evidence that the increase of these mediators in gingival crevicular fluid, serum, or amniotic fluid in patients with periodontitis is associated with pregnancy complications [In addition, investigations such as those by Greig et al. 1997 and Von Minckwitz et al. 2000 , 18 haveications , 19–21.2, the present study showed that, as the severity of periodontal disease increases, the levels of PGE2 increased in pregnant women. These findings are similar to those reported by Konopka et al. (2003), who evaluated the relationships among periodontal disease, preterm birth, and low birth weight as well as the levels of PGE2 and IL-1β in the gingival crevicular fluid (FCG) and those in the blood serum of women with preterm labor and women who gave birth at term. They found that, in the presence of severe and generalized periodontitis, preterm delivery is 3.9 times more likely compared with women with a healthy periodontium. Among women with preterm delivery, significantly higher concentrations of PGE2 and IL-1β were found in the crevicular fluid [When analyzing PGEar fluid .2, IL-1β, IL-6, and TNF-α) in the gingival crevicular fluid and serum samples among women with preterm birth and term delivery and correlate these levels with periodontal parameters. They found that women with preterm delivery exhibited significantly more periodontitis and showed an increase in the levels of IL-6 and PGE2 in the crevicular fluid compared with the term delivery group. Serum levels of PGE2 and TNF-α were positively correlated with probing depth and clinical insertion level (CAL) in women with preterm delivery [Perunovik et al. (2016) evaluated the levels of four factors that trigger labor (PGEdelivery .α) were higher in patients at high risk for preterm delivery, supporting what is stated in the literature regarding the role that inflammatory cytokines play in the mechanisms that initiate labor. Similarly, Arntzen et al. (1998) [α, IL-1, IL-6, and IL-8 in the amniotic fluid of women with preterm and full-term labor and found an association between increases in TNF-α, IL-1, and IL-6 levels and preterm delivery, suggesting that IL-1 plays a dominant role in the presence of chorioamnionitis, whereas IL-6 seems to be more important during preterm idiopathic delivery.The present investigation found that the levels of cytokines   quantifiOur results might contribute to the biological plausibility of the relationship between periodontal infection and the risk of preterm delivery and justify what Amare Teshome et al. (2016) reported in a systematic literature review regarding the effect of periodontal disease on preterm delivery and low birth weight, which noted that periodontal disease increased the risk of preterm birth and low birth weight in 9 of the 10 articles analyzed, with an odds ratio (OR) that ranged from 2.04 to 4.19. Only one article did not report this association .Likewise, Corbella et al. (2016) evaluated periodontal disease as an independent risk factor for the adverse outcomes of pregnancy. To accomplish this goal, they performed a meta-analysis to calculate the relative risk (RR) for each pregnancy outcome. The calculated RR of periodontitis was 1.61 for preterm birth assessed across 16 studies (p<0.001); 1.65 for low birth weight assessed across 10 studies (p<0.001); and 3.44 for low preterm birth weight assessed across four studies. They concluded that an association exists, albeit low, between periodontitis and adverse pregnancy outcomes .Scientific evidence has shown some probable mechanisms of the relationship between periodontal disease and adverse outcomes of pregnancy. Unfortunately, the largest multisite randomized trials have failed to show a reduction in preterm birth even when the gold standard of treatment, deep scaling, and root planning was employed. Different meta-analyses show that the randomized clinical trials investigating the effect of periodontal treatment on adverse outcomes are of low quality because of high risk of bias, mainly due to the lack of blinding and to the heterogeneity of the trials , 28.The results of this investigation could not determine whether the differential change of the patient's baseline in inflammatory cytokines and PGE2 is an absolute risk factor for preterm birth or if there is a real value beyond the risk of preterm delivery. Many women at risk of preterm labor, in fact, carry it to term. It would be interesting to include in future research only women with actual premature births and to compare them with term delivery controls.Given the scientific evidence that increasingly supports the role of the systemic inflammatory response generated by remote infections  regarding preterm delivery, it is worthwhile and justified to continue researching interdisciplinary groups involving both doctors and dentists to expand the sample and control the possible confounds in such a way that it is possible to visualize the true risk that a pregnant woman with a chronic infection such as periodontal disease might carry with regard to her pregnancy. In addition to this, periodontal disease and preterm delivery are two health problems of interest for public health; for this reason, if periodontal disease can be treated, dentists would be contributing to decrease the risk for preterm delivery.2 values increase. We observe that, in patients with chronic periodontitis, both those at high and low risk of preterm delivery had higher levels of PGE2; and patients at high risk for preterm labor and those with periodontitis had higher levels of systemic relevant cytokines that participate in both diseases. For this reason to have periodontal disease can favor the outcome of preterm delivery.In pregnant women as the severity of the periodontal disease increases, PGE