Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children.We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK’s Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases.In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g [95% CI g] less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g [95% CI g] heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6–8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4–7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children.ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted.The online version of this article (10.1186/s12916-018-1203-7) contains supplementary material, which is available to authorized users. The lStudies in both human populations  and animPostnatal infant and child growth is arguably an even more important indicator of long-term disease risk; in particular, catch-up growth from LBW increases the risk of obesity and CMD , 11. OwiThe UK pioneered ART 40 years ago with the first successful birth in Oldham in July 1978 and thus is home to the first cohort of children now approaching middle age. However, the UK has been among the slowest countries to conduct long-term ART follow-up studies, because the original Human Fertilisation and Embryology Act (1990) did not envisage this. In line with shifts in public opinion, the Act was changed in 2010 and under the principle of presumed consent, the UK now possesses the world’s oldest and largest database of ART available for research, with approximately 110,000 children from 1991 to 2009. However, so far, this has only been exploited for a single cancer follow-up study . There hA cohort of ART data from the Human Fertilisation and Embryology Authority (HFEA) register was linked to a series of routinely collected birth and child health records held by the NHS National Services Scotland (NHS NSS) Fig. .Fig. 1DaThe UK has a uniquely comprehensive record of all women who have had ART since August 1991, when it has been compulsory for every UK fertility clinic to report details of all treatments to the HFEA. Up to October 2009, data on 289,000 women and 110,000 children born after treatment has been collected. Data on treatment cycles after October 1, 2009, was not included as, from this time, those undergoing ART were asked to give “consent to disclosure” of identifying information, enabling their records to be used for research. The data relating to children born prior to April 1997 was not included in the study, as they were over the age of 16 at the time of data release and we took a cautious approach as to whether consent had been provided. The HFEA register does not contain a single unique patient identifier, but does contain names and dates of birth.The SMR02 is primarily a source of data on obstetric outcomes, collated from hospital administration records following a woman’s episode of care in an obstetric facility . Birth weight, gestational age, Apgar score, occipital-frontal circumference (OFC), length, weight and admission to a neonatal intensive care unit (NICU) have been recorded consistently over time. There is also data on maternal lifestyle with self-reported smoking being consistently recorded. The child’s Community Health Index (CHI) number allows linkage to child data in other datasets.Data on child growth is available from a number of routine screening programmes. The data consistently collected at 6–8 weeks and on entry to school  comprise height (length and OFC at 6–8 weeks), weight, body mass index (BMI) and read-coded health concerns.In the absence of a unique identifier, HFEA and SMR02 data were linked using probabilistic matching based on maternal names and maternal/child dates-of-birth as described in Additional file Deprivation was assessed from quintiles of the 2012 Scottish Index of Multiple Deprivation . MaternaBirth weight was adjusted for gestational age, gender and (when available) parity (1st baby vs. > 1st baby) using the GROW formula .Growth velocities were defined as the average change in weight per week (between birth and 6–8 week measurements) or month (between 6 and 8 weeks and school entry).Numerical outcomes were modelled using linear regression while NICU admission and sex ratio  were modelled using logistic regression. Bootstrapped standard errors (using 1000 replications) are presented. Details of all the models considered are given in Additional file For analyses comparing ART and naturally conceived infants, the primary covariates were deprivation, smoking status, maternal age (fitted as a quadratic function) and an indicator of whether the embryos were from fresh or frozen transfer cycles, plus the matching variables, year and month of delivery and gender. For within ART analyses, we additionally included paternal age (as a quadratic function), use of ICSI, number of previous ART cycles and infertility causes  plus treatment centre and year of treatment. As data relating to embryo culture time and number of embryos created were only available on a subset of cases , these were not included in the primary analyses, but a secondary analysis including these was conducted. For the analysis of child health programme (CHP) outcomes, we additionally controlled for age at the time of measurement and feed type  at 10 days post-birth.In the analysis of NICU admission, the primary analysis was unadjusted for birth weight and gestational age. A secondary analysis was also conducted in which both raw birth weight and gestational age were controlled for.z-scores.Using tables of age- and gender-specific L, M and S values , we tranAll analyses were conducted using STATA (version 14), within the National Safe Haven of Scotland, managed by NHS NSS.The linkage process and derivation of the analysis datasets is summarised in Fig. The resultant dataset comprised 4127 singleton births following fresh ART and 1091 singleton births from FET cycles, along with 20,879 matched NC children. See Additional file At 6–8 weeks, data was available for 3224 fresh ART births (78%), 812 births following FET (74%) and 15,900 naturally conceived births (76%). The corresponding numbers at school entry were 2095 (51%), 519 (48%) and 10,507 (50%).The proportions and characteristics of the infants contributing to each of the assessments did not vary between conception groups ], but significantly higher from FET  with an increased incidence of macrosomia (> 4000 g) ] and FET   for fresh and OR = 1.00; 95% CI  for FET]. However, this effect did not remain when we adjusted for gestation and birth weight ; ART fresh transfers slope 2.59 g/year; 95% CI ; FET slope 0.80 g/year; 95% CI .Within the ART cohort, we examined the effect of ART treatment factors on birth outcomes (Table The difference in (adjusted) birth weight between babies from FET, compared to fresh transfer, was estimated as 127.4 g [95% CI ]. Both OFC  and crown-heel length  were significantly larger in babies born following FET. There were no significant differences in gestational age, sex ratio or NICU admission ], OFC  and length , but those from FET show no differences , but this is not seen in just the smaller babies (lower 3 deciles). Significantly, less catch-down growth is seen in the fresh ART cohort  and this is also seen when considering only the largest babies . FET babies generally show more similar rates of catch-up and catch-down growth to NC babies than to fresh ART babies.Of particular interest is the proportion of infants who show accelerated (‘catch-up’) or decelerated (‘catch-down’) growth (weight) from birth to school entry. In Table Birth weight and early child growth are important predictors of long-term CMD risk . AlthougThe major strength of this study is the registry-based national cohort design. The loss to follow-up is a concern, although we believe most of this loss is administrative and we could detect no strong biases in those with and without data. The data on NC infants did not include parity and, therefore, we were not able to include this in the birth weight adjustment. It is likely that more NC babies were born to parous women than ART-conceived babies, which would lead to a small, but unquantifiable, over-estimation of birth weight in this group, in turn reducing the effect in ART-Fresh cycles while increasing the effect in FET cycles. Within-ART comparisons were parity-adjusted. Postnatal growth estimates for both ART-conceived and NC children are based on changes and are therefore largely unaffected by parity.Newborn infants conceived by fresh embryo transfer were smaller than NC infants, with significant differences in birth weight, length and OFC. Some infants were small because they were born early, at gestational ages of < 37 or < 32 weeks, and there were more admissions to the NICU, probably due to conditions associated with prematurity. Other infants were small for gestational age (SGA), which may be due to a slowing down of intrauterine growth, implicating a reduction in placental transfer of nutrients. FET infants by comparison had a higher birth weight, length and OFC than NC infants. The birth weight findings are consistent with previous studies , 22, andAt 6 to 8 weeks of age, the weight, length and OFC of the FET infants and NC infants were similar, while weight, length and OFC in the fresh ART-conceived infants remained smaller. At school entry, weight, length and BMI in the three study groups were similar, showing that low birth weight fresh ART infants, when free from the constraints on intrauterine growth, resume their growth trajectory postnatally and attempt to achieve their genetic potential by catch-up growth. OFC measurements were not available; however, brain growth and somatic growth are likely to be in harmony. The BMI values at school entry were consistent with those reported previously at a similar age.Previous studies of ART child growth have been small (≤ 500 children) and unable to adequately control for confounding factors, and show conflicting results . In threIt is currently unknown what alters fetal and child growth trajectories for children conceived through ART; however, it is noteworthy that the magnitude of impact of ART on birth weight is nearly as great as that of maternal smoking in pregnancy. Catch-up or catch-down growth (centile crossing) after birth are both significant predictors of long-term disease risk. Most LBW children show catch-up growth in the first few months, with accelerated growth associated with increased risk of obesity and CMD risk , 31, 32.Our major finding that children born from FET cycles differ significantly in birth weight and child growth from their fresh ART counterparts, strongly implicates some aspect of the ART treatment process itself rather than parental subfertility, as does the animal literature showing that adverse outcomes can be phenocopied in fertile mice subjected to ART . HoweverOther than the effects of embryo cryopreservation/FET, we failed to detect any significant associations between newborn or child weight, length and OFC and other ART patient or treatment factors available. However, the HFEA database lacks information on factors such as the type of culture medium embryos were grown in, an important omission in light of recent evidence that culture medium is associated with altered embryo gene expression , epigeneThese longitudinal growth data from a national cohort of more than 5000 ART children identify an increased risk profile for non-communicable disease in later life. ART treatments are constantly evolving, and these studies will need to be replicated in more recent cohorts to capture changes in technology and practice. There is clearly a need to further the research agenda in this area and to take steps to reduce risks from treatment. We call for more detailed studies of the impact of modifiable aspects of IVF on early child growth to reduce risk to the next generation of ART children.Additional file 1:Supplementary Descriptive Text and Tables. (DOCX 124 kb)


Reducing the incidence of preterm birth is a national priority. Maternal cigarette smoking is strongly and consistently associated with preterm birth. The objective of this study was to examine prenatal exposure based on combined measures of timing (by trimester) and intensity level (the number of cigarettes smoked per day) of maternal smoking to identify a pregnancy period with the highest risk of preterm birth.A sample of 2,485,743 singleton births was drawn from the 2010 National Center of Health Statistics (NCHS) linked birth/infant death file of US residents in 33 states that implemented the revised 2003 birth certificate. Nine mutually exclusive smoking status categories were created to assess prenatal exposure across pregnancy in association with preterm birth. Gestational age was based on the obstetric estimate. Multiple logistic regression analyses were conducted to compare the odds of preterm birth among women who smoked at different intensity levels in the second or third trimester with those who smoked only in the first trimester.Overall, 7.95% of women had a preterm birth; 8.90% of low intensity (less than a pack/day) smokers in the first trimester only, 12.99% of low and 15.38% of high intensity (pack a day or more) smokers in the first two trimesters, and 10.56% of low and 11.35% of high intensity smokers in all three trimesters delivered preterm. First and second trimester high  and low intensity smokers  had higher odds of preterm birth compared to those who smoked less than a pack a day only in the first trimester, but the odds did not increase for all three trimester smokers relative to the first and second trimester smokers. In sensitivity analysis, adjustment for exposure misclassification error corrected data and testing for effect modification by maternal race/ethnicity found no significant interaction.This study documented a biologically plausible vulnerability window for smoking exposure and the increased risk of preterm birth. For women who do not modify their smoking behavior preconception, preterm birth risk of smoking remains low until late in the first trimester. Preterm birth before 37 weeks gestation occurs in about 5 to 18% of all pregnancies and is associated with increased morbidity and mortality in newborns. Smoking during pregnancy is a potentially preventable risk factor for preterm birth, yet nearly one-third of reproductive age women (18–44 years old) are daily smokers and at least half of women continue smoking during pregnancy. Infants whose mothers do not smoke at all have dramatically better outcomes. Although women try to quit smoking upon pregnancy recognition, little is known about when smoking cessation during pregnancy matters most for preterm birth. To date, few studies thoroughly examined variability in patterns of timing and intensity of smoking to capture the extent of prenatal exposure across trimesters of pregnancy. This is the first population-based study to utilize combined measures of timing, intensity and duration of maternal smoking to identify a potential biologically plausible window of enhanced vulnerability to smoking exposure, which is late in the first trimester, to avoid preterm birth.Preterm birth of less than 37 weeks gestation occurs in about 5 to 18% of pregnancies. In the United States, the overall rate of preterm birth rose from 9.63% in 2015 to 9.85% in 2016 and to 9.93% in 2017, and for singleton births only the rate increased from 7.82% in 2015 to 8.02% in 2016 and to 8.13% in 2017.  In the UApproximately one-third of reproductive age women 18–44) in the US are daily cigarette smokers.  Tobacco –44 in thNational reports indicate that smoking in pregnancy is more prevalent among non-Hispanic White women, 20–24 years old, and less educated women.  Among thIt is well documented that infants whose mothers do not smoke at all have dramatically better outcomes, but little is known whether and when during pregnancy smoking cessation matters for preterm birth. Prior studies linking evidence of smoking any time during pregnancy with the increased risk of adverse birth outcomes suggested that quitting early in pregnancy reduced , 17 or rGiven low rates of quitting and high rates of relapse among women who smoke in the first trimester of pregnancy, , 16 we sN = 4,007,105) of all births registered in the 33 states that had implemented the 2003 revised version of the birth certificate, representing 76% of all US births. [As a data source in this study, we used the electronic 2010 National Center for Health Statistics (NCHS) linked birth/infant death dataset , births in states with unrevised certificates , births with missing data on maternal race (n = 2146) and on other maternal demographic characteristics , and on smoking by trimester .This cross-sectional study included the entire population of 2,485,743 singleton live births in the United States in 2010, after excluding multiple births : the first trimester (months 1–3- or 1–13-weeks gestation), the second trimester (months 4–6 or 14–27 weeks gestation), and the third trimester (months 7–9 or 28 weeks to delivery). Preterm birth was defined as delivering a singleton newborn between 20 and less than 37 weeks gestation, based on the best obstetric estimate (OE) of gestation at birth that combines date of maternal last menstrual period (LMP) and ultrasound (US) measurement available in the revised birth certificate.  The OE hA vulnerability window for prenatal smoking exposure was defined as the most sensitive period (trimester) in pregnancy , 29, as The exposure variable was cigarette smoking during pregnancy. On the revised birth certificate the mother reports the average number of cigarettes smoked per day in each trimester of pregnancy and before pregnancy.  In this The outcome variable was preterm birth defined categorically based on gestational age of less than 37 weeks gestation or between 20 0/7 and 36 6/7 weeks gestation.We combined race and ethnicity to form five categories: non-Hispanic White, non-Hispanic Black, Hispanic, non-Hispanic Asian, and American Indian. Maternal age categories were 12–19, 20–34 and 35 years old or older; maternal education was categorized as less than high school, high school graduate, some college or associate degree, and a bachelor’s degree or higher; and marital status was married or unmarried.Prenatal exposure status was examined based on variability in maternal smoking patterns across trimesters. –32 WomenOur study advanced standard methodology by creating nine mutually exclusive smoking intensity status categories combining measures of timing (trimesters in which smoking was reported), intensity (the number of cigarettes smoked per day) and duration (consistency across trimesters) of smoking to thoroughly assess distribution of prenatal exposure across trimesters: low-intensity smokers (1–19 cigarettes/day or less than a pack/day) in the first but not in the second trimester (reference group); high-intensity smokers (≥20 cigarettes/day or a pack/day or more) in the first but not in the second trimester; low-intensity smokers in the first and second trimesters; high-intensity smokers in the first and second trimesters; low-intensity smokers who started smoking in the second or third trimesters (did not smoke in the first trimester); high-intensity smokers who started smoking in the second or third trimesters; low-intensity smokers in all three trimesters; high-intensity smokers in all three trimesters; and nonsmokers (no trimester smokers).Almost 25% of pregnant women do not disclose smoking throughout pregnancy, related in part to social stigma –38. Infop = 0.05.In this study, the entire population of 2,485,743 singleton live births in the US in 2010 was separated into two gestational age subgroups: births between 20 weeks gestation and term (second and third trimester births) and births between 28 weeks gestation and term (third trimester births only). Conceptually, we first estimated preterm birth (20- < 37 weeks gestation) rates for these two gestational age subgroups across maternal race/ethnicity, age, educational attainment and marital status  exemption from the University of Maryland. The authors have no financial or other conflict of interest.Nearly 7.95% of mothers had a preterm birth (20 - < 37 weeks gestation) by the most inclusive definition and 7.49% mothers delivered preterm in the third trimester (28 - < 37 weeks gestation)  from the second gestational subgroup (i.e. third trimester births). Restricting the sample to the second gestational age subgroup   with preterm birth in the first  gestational age group,   Around tAlthough, we have come close, we cannot establish this gestational window precisely because of the lack of detailed information in the dataset on when first trimester smokers quit and when second trimester initiators began smoking. Interestingly, smoking in all three trimesters was associated with a lower risk of preterm birth than smoking in the first two trimesters (referent), and the difference in risks was statistically significant. Because smoking is less likely to be overestimated in the first and second trimesters, we attributed these findings to a potential exposure misclassification error from suboptimal maternal self-reports of trimester of smoking on the birth certificate. , 48 In sTo our knowledge, this is the first population-based study to examine how prenatal exposure measured by combined timing, duration and intensity of smoking is associated with an increased likelihood of delivering preterm. Ideally, the present study should be extended to reoccurring preterm birth and other adverse pregnancy outcomes.  Given thThe main strength of our study was the availability of a large national dataset of over 2 million live U.S. births that contains information on maternal smoking behavior during each trimester of pregnancy. Revised birth certificates with enhanced health data on mothers and infants can expand opportunities in perinatal research. There are also a few limitations. One limitation is that the study population is not representative of the entire U.S. population, because in 2010 only 76% of all US states used the revised birth certificate. This still represents an advance over previous research that used data from one individual state , 47 or fWomen appear motivated to quit smoking during pregnancy; however, behavioral change is difficult to initiate and maintain. Knowing a period of vulnerability in which smoking exposure could harm a developing fetus and raise the risk of preterm birth would help health professionals to inform reproductive age and pregnant women. Early smoking cessation interventions may have a greater effect on the reduction of preterm birth, not just because the majority of women who smoke in the first trimester continue to smoke throughout pregnancy, but because the vulnerability period for smoking exposure appears late in the first trimester. Ultimately, findings from this study may guide future research in understanding the etiology and mechanisms of other adverse birth outcomes  and in developing potential screening or risk prediction biomarkers and therapeutic targets.


Birth asphyxia (BA), assumed to be related to intrapartum related hypoxia-ischemia, accounts for one million neonatal deaths annually. In the low resource setting BA is usually defined as a failure to initiate or sustain spontaneous breathing at birth. In the resource replete setting BA is a biochemical definition related to impaired gas exchange, due to interruption of placental blood flow (PBF). An umbilical arterial pH <7.00 referred to as severe fetal acidemia, reflects a degree of acidosis, where potential risk of adverse neurologic sequelae is increased. However, even with this degree of acidemia, the likelihood of mortality or adverse neurologic sequelae remains low. The aim is to focus on the definition of BA in the low resource setting, and compare it to the diagnosis in the resource replete setting, highlighting the importance of interruption of placental blood flow as it relates to morbidity and mortality. With asphyxia, the fetus aims to redistribute cardiac output to protect more vital organs e.g., brain, myocardium, and adrenal gland at the expense of decreased flow to organs such as kidney or intestine. In an experimental newborn model, animals subjected to asphyxia immediately develop primary apnea with bradycardia sustained blood pressure and normal pH. Recovery of respirations follows basic interventions, i.e. stimulation coupled with reversal of asphyxia. However, if asphyxia is sustained, secondary apnea manifests with bradycardia, hypotension, and pH <7.00. More intensive resuscitation including bag mask ventilation ± intubation ± cardio-pulmonary resuscitation may be necessary for correction upon reversal of asphyxia. Identification of a severely acidemic state  in the newborn, may help to differentiate the truly asphyxiated intrapartum related cases that result in mortality, from those cases where mortality is related to delay in or ineffective basic resuscitation. It is estimated that globally 2.5 million newborn deaths occur annually contributing to ~47% of the under-5 child mortality , 2. BirtBA in the low resource setting is usually defined as a failure to initiate or sustain spontaneous breathing at birth and in some circumstances includes a 1-min Apgar score <7.00 . ContrasWhen placental blood flow (PBF) is compromised, the fetus redistributes cardiac output to protect vital organs such as brain, heart, and adrenal gland at the expense of flow to the kidney, intestine and skin. Several factors contribute to this response including hypoxemia which induces pulmonary vasoconstriction. This results in reduced pulmonary blood flow, left atrial blood return, and a decrease in left atrial pressure , 15. TheIn addition to the cardiovascular changes described above associated with asphyxia, characteristic changes in the breathing patterns occur. These cardio-respiratory changes with asphyxia have been elegantly described by Dawes et al.  Figure . Using tin utero to ex-utero life, significant circulatory changes occur closely intertwined with concurrent respiratory changes. Upon crying at birth, the lungs rapidly expand and pulmonary vascular resistance drops. The HR correspondingly increases rapidly from around 120 to 150 bpm within 10 to 25 s, following the onset of breathing  algorithm , followeImportantly, the diagnosis of BA based on the absence of spontaneous respirations at birth may not reflect or be related to interruption of PBF (see above). Delayed onset of breathing may be related to many causes including maternal conditions such as fever  or materDuring labor interruption of PBF leads to BA. Two elements are critical in this regard, namely duration and the severity of the interruption. A decrease in placental blood flow may be secondary to maternal conditions such as hypertension or preeclampsia secondary to altered placental vasculature. Maternal hypotension secondary to a medication effect or spinal anesthesia may compromise PBF. Indeed, in one report spinal anesthesia was the commonest cause of an unanticipated cord arterial pH <7.00 likely related to maternal hypotension and reduced PBF . PlacentSeveral factors may play a role in explaining this striking disparity in diagnosis as well as outcome  with BA. First, as noted above, absence of respiratory effort at birth may manifest in the presence or absence of a cord pH <7.00. At a physiologic or clinical level, the question is whether the infant is in primary or secondary apnea . This inSecond, it has also been previously demonstrated in the low resource setting, that time to initiation, as well as the duration of PPV, is significantly longer among infants who died compared to infants with normal outcomes. Specifically, the risk for death increased 16 percent for every 30 s delay in initiating PPV up to 6 min, and 6 percent for every minute of applied BMV . Third, n = 17), required minimal delivery room (DR) resuscitation, did not require respiratory support, and had a normal neurologic outcome. The second, Group II (n = 7), all required intubation and mechanical ventilation in the DR. All seven infants evolved to the syndrome of hypoxic–ischemic encephalopathy (HIE) including seizures, which developed within the first 6–12 h after birth. The cord umbilical arterial blood gases were notable for the following: first, a lower cord pH, i.e., 6.75 ± 0.18 vs. 6.90 ± 0.09 (P < 0.005) and a higher cord PaCO2 higher, i.e., 141 ± 37 vs. 94 ± 22 mmHg (P < 0.005) in group II vs. group I infants, respectively. The mean initial postnatal pH was lower, i.e., 7.06 ± 0.15 vs. 7.25 ± 0.09 and the PaCO2 remained higher in group II vs. group 1 infants, i.e., 45 ± 14 mmHg, and 30 ± 6 mmHg, respectively (P < 0.005). These observations point to the basic difficulty in defining BA based on the absence of respiratory effort at birth, particularly without a cord arterial blood sample. Absence of respiratory effort with a normal cord arterial pH would suggest primary apnea , has facilitated a more rapid identification of an abnormal FHR, and may be a breakthrough in identifying fetuses at high-risk of intrapartum hypoxia-ischemia. In a recent study in a low risk population, it was shown that implementation of continuous FHR monitoring using the Moyo device, was associated with a 6.90-fold increased detection of an abnormal FHR, i.e., absent, FHR <120 or FHR>160 bpm, and a shorter time interval from the last FHR assessment to delivery . A cesarFinally it would be useful to have the ability to measure cord arterial umbilical blood gases following a delivery and/or or an early postnatal pH and base deficit, to provide objective measurement of the acid base status, and by default the extent of interruption of PBF around the time of birth.The overwhelming majority of newborns (85%) will initiate spontaneously respiratory effort within 15 s following birth, an additional 10 percent will respond to stimulation and/or suctioning . AnotherThe key approach to resuscitation irrespective of the setting is anticipation of a high-risk infant e.g., FHR abnormalities, prolapsed cord, prematurity. Where possible there should be two providers at the delivery capable of initiating basic stabilization/resuscitation in a timely manner. The first step should be a prebrief, where the possibility of receiving a depressed baby, and preparation for initiation of HBB or the neonatal resuscitation program (NRP) guidelines, including implementation of PPV should be discussed , 29. As The potential pathways to BA related mortality in term infants in the low resource setting was recently described . The majDespite the difficulties in defining BA in resource limited settings, potential opportunities for reducing BA related mortality exist. More than half of newborns who died of BA had a normal FHR during labor intermittently determined using a fetoscope. Continuous FHR monitoring may facilitate identification of such infants, and expedite delivery of fetuses in jeopardy . Post-deAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SN declared a past co-authorship with one of the authors JP to the handling editor.


Background: Breast milk provides nutrition for infants but also delivers other bioactive factors that have key protective and developmental benefits. In particular, cytokines are thought to play a role in immunomodulation, although little is known about their impact on health outcomes in early life.Objective: The purpose of this pilot study was to evaluate the relationship between cytokines in breast milk and infant growth outcomes in a low-income setting.Methods: 100 mother-infant pairs were followed up to 2–3 months postpartum as part of a prospective longitudinal cohort study in urban Gambia, West Africa. The concentrations of 9 pro-inflammatory cytokines , IGF-1 and TGFβ2 were measured in colostrum within 12 h of birth and in breast milk at the final visit, scheduled between day 60 and 89 postpartum. Infant weight was recorded and converted to weight-for-age Z-scores (WAZ) at the same time points. Growth outcomes were defined in our study as (a) change in WAZ between birth and final visit (b) WAZ at final visit. Linear regression analysis was used to determine the ability of colostrum and breast milk cytokine concentrations to predict growth outcomes up to 2–3 months postpartum.Results: Gambian infants demonstrated growth faltering across the first 2–3 months postpartum. There was no significant relationship between cytokines in colostrum and subsequent change in WAZ between birth and the final visit, in either unadjusted or adjusted models. However, cytokines in mature breast milk, TNFα, IFNγ, IL1β, IL2, IL4, and IL6, were weak negative predictors of WAZ scores at the final visit, in unadjusted models (p < 0.05). When adjusted for maternal anemia , TNFα and IL6 remained significant predictors (p < 0.05).Conclusions: Variations in breast milk cytokine levels do not play a substantial role in the growth faltering observed across early infancy. The potential contribution of other factors, such as micronutrients, hormones or human milk oligosaccharides, must be elucidated. Cytokine levels in mature breast milk were weakly predictive of poor infant growth, possibly reflecting a “read-out” of suboptimal maternal health and nutrition. Human breast milk (BM) provides nourishment for infants but also delivers a range of non-nutritive bioactive factors that have key protective and developmental benefits, including actively shaping and priming the infant immune system –6. It isCytokines and growth factors have been identified as important bioactive components within BM and are found in differing concentrations , 24. It Cytokines, particularly in colostrum, are thought to play a key role in immunomodulation, including promoting sIgA production, mediating infant immune responses, for example through B cell growth and differentiation, and boosting development of intestinal tolerance , 28, 29.Growth faltering in sub-Saharan Africa, including The Gambia, has been well-established previously  and poorThe aim of this study was to evaluate the relationship between the cytokine and growth factor profile in human BM and infant growth outcomes in the first 3 months post-partum in The Gambia, a low-income country in West Africa.Group B Streptococcus infection, conducted between 1st January and 31st December 2014, in an urban area of The Gambia, West Africa  and infant factors . Full details on data collection have been described previously . AnthropColostrum was collected within 12 h of birth and mature BM was collected at the final visit. After washing their hands with soap, mothers wiped each breast with a 0.02% chlorhexidine wipe and then hand-expressed their milk prior to feeding their infant; the first 0.5 mls was discarded and then 2–3 mL of colostrum and 4–5 mL of BM was collected from both breasts into sterile plastic containers. Milk samples were immediately stored on cold packs at 4°C and transported to the laboratory within 6 h of collection , 38.BM samples were centrifuged at 3,200 rpm for 30 min to separate whey and lipid layers. The lipid layer was removed with a scalpel and stored separately. The whey layer was stored in 1 mL aliquots and frozen at −70°C. It was transferred to 5 mm NMR capillary tubes for analysis , 38.Assays were run in duplicate and concentrations of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNFα, IGF-1, and TGFβ2 in colostrum and BM were determined by electroluminescence using kits from Meso-Scale Discovery Multi-Spot Kit . Laboratory experiments were run according to manufacturer's protocol, using an eight-point standard curve. Samples below the lower limit of detection were allocated a concentration for each cytokine of half the lower limit of detection to aid the statistical analysis and as per manufacturer's instructions (Supplementary Table Growth outcomes were defined in our study as (a) change in WAZ between birth and final visit b) WAZ at final visit. Children with Z scores below −2 were defined as underweight (WAZ ≤ −2) .p < 0.1 or known to be associated with infant growth (a priori) were included in the multivariate models. Maternal hemoglobin (Hb) was categorized as either Hb <11 g/dL (anemia) or Hb ≥11 g/dL  analysis was then used to determine the ability of cytokine concentrations to predict longitudinal growth outcomes in the first 2–3 months post-partum by analyzing the association between (i) colostrum cytokines and change in WAZ between birth and final visit (ii) BM cytokines and WAZ at final visit. Potential maternal and infant confounders found to be significant in variable univariate analysis with a ≥11 g/dL . Maternap < 0.05.All statistical analyses were completed using the statistical packages STATA version 12 , GraphPad Prism version 6.0  and R package version 3.4.1. Differences were considered statistically significant at A total of 100 mother-infant pairs were included in the analysis. The mean ± 1 SD maternal age was 25.6 ± 5.7 years and mean ± 1 SD maternal weight at delivery was 63.4 ± 9.8 kg. The infants were born at mean gestational age of 39 weeks and followed up to a mean ± 1 SD of 61.6 ± 1.3 days postpartum; although scheduling allowed for final visits to occur up to 90 days postpartum, all final visits in this cohort took place between 60 and 66 days postpartum. All infants were exclusively breast fed throughout the duration of the study. Demographic characteristics of mother-infant pairs are summarized in Table p = 0.505) and final visit (p = 0.791). Similarly, the odds ratio of being underweight and having a decline in WAZ by 2–3 months postpartum did not differ significantly between the sexes: for male infants, the odds ratio was 1.4  and 1.69 , respectively.Infants were born with a mean weight ± 1 SD of 3.36 ± 0.48 kg and WAZ ± 1 SD of 0.10 ± 0.99 Table . Howeverp < 0.001) (Supplementary Table p < 0.05), with the exception of TNFα, IGF1, TGFβ2, and IL6 . Of note, the levels of IGF1 in colostrum and BM were below the assay limit of detection in >75% of subjects and, therefore, this data has been removed from further analysis  (Supplementary Table 83 samples of colostrum (from 100 women) and 90 samples of mature breast milk (from 94 women) were successfully collected. In the remaining cases, insufficient sample was available, either because the mother was unable to express milk, or due to insufficient sample remaining after the primary analysis was complete. Colostrum at birth contained significantly higher concentrations of nearly all cytokines than BM (p < 0.05)  Table . There wThe association between colostrum cytokines and change in WAZ between birth and final visit was non-significant in both the unadjusted and adjusted models in this Gambian cohort.p < 0.05). Although significant, the β -coefficients were small. When these models were adjusted for maternal anemia, only TNFα and IL6 remained significant predictors of WAZ at final visit (p < 0.05)  , 48; in A cross-sectional preliminary study by Fields et al. suggested that BM concentrations of cytokines  and hormones/growth factors  may differentially influence weight gain and the development of fat and lean body mass in infants in the early postpartum period. WHO indicators of infant growth (Z scores), however, were not calculated or applied in their analysis . By contOn the other hand, our findings suggest that cytokines in mature BM may predict infant growth measured at that same point in time. Higher levels of specific pro-inflammatory BM cytokines were negatively associated with WAZ at the final visit in our cohort, although the relationship was weak and clinical significance remains as yet unclear. The relationship between a pro-inflammatory environment and poor weight gain, both in the fetus and infant, has been previously described , 51–54. Cytokines in mature BM may impact infant growth through immunomodulation, as discussed earlier. Equally, these associations may represent context-specific correlations, rather than causation. For example, the cytokine profile in BM may reflect maternal health at this specific time point, including nutritional and disease status, which in turn may play a key role in growth outcomes. Further elucidation of factors that shape mature BM cytokine profile and understanding of underlying mechanistic or causational processes is therefore needed. This may have translational implications, such as the identification of maternal groups with high risk of underweight infants, and initiation of appropriate interventions subsequently.Our study has several limitations. Firstly, it is a pilot exploration of outcomes in a small maternal-infant cohort within a limited time period. Given that (a) growth faltering is thought to start in the first few months of life, reaching its peak by 2 years of age in poorly-resourced settings and (b) cytokine profiles vary within and between mothers, it would be worth analyzing BM composition and growth outcomes in a larger cohort, at multiple time points and beyond 3 months postpartum. This would enable a more accurate WAZ trajectory to be plotted and the longer-term impact of BM cytokine differences to be fully appreciated. Of note, infants are thought to demonstrate a non-linear weight gain over this early post-partum period, and so weight at the final time point could either reflect a change in recent infant mass/weight or infant size more globally. Moreover, analysis of different types of BM and at various time points not evaluated in our study  may be valuable and has previously been shown to be important , 16, 55.Furthermore, our focus was on one primary growth outcome: weight and associated WAZ scores. The latter is a well-established WHO growth indicator, especially at birth (when length measures may be difficult) and throughout the early postnatal period. Weight-for-length (WLZ) and length-for-age (LAZ) Z scores are equally important beyond the first year of life; stunting in early childhood has been shown to predict future risk of morbidity and mortality , 56 althIn addition, our study eligibility criteria were strict, for example, infants born very prematurely or in poor condition requiring resuscitation  or women with high risk conditions in pregnancy were excluded. Future studies focussing on these high-risk groups may provide further insight into variables that regulate BM profile and, subsequently, boost or protect against growth faltering.Finally, our study did not measure the contribution to early postpartum growth of other sources of immune factors, including the ante-and perinatal environment  and endogenous postnatal production (infant serum). In parallel, the interplay of other bioactive factors, such as hormones and human milk oligosaccharides, must be explored.In conclusion, our findings suggest that the interactions of cytokines in both colostrum and BM do not play a substantial role in the early growth faltering observed in Gambian infants. Above all, this preliminary study is valuable as a strong foundation to direct further investigation into the impact of bioactive factors in BM on infant growth and development, a topic with limited studies to date. Improved understanding of the early postnatal determinants of growth may be important for developing successful interventions to boost growth and health outcomes, particularly in infants at highest risk or in poorly resourced settings.All subjects gave informed consent in accordance with the Declaration of Helsinki. Each participant signed an informed consent form or, in case of illiteracy, thumb-printed and the consent form was signed by an impartial witness. The study was approved by and carried out in accordance with the recommendations of the joint Gambian Government/Medical Research Council Research Ethics Committee, SCC1350V4.AS was responsible for manuscript writing and had input into the data analysis. DM, SM, and KL had input into the manuscript writing. AF was involved in laboratory analysis. OB was responsible for statistical analysis. KL was responsible for the original study design, data and statistical analysis and original idea for manuscript. All authors had access to the data and input into the final manuscript.KL has received funding from Pfizer to attend a seminar in 2016. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To evaluate the association between early metabolic profiles combined with infant characteristics and survival past 7 days of age in infants born at 22-25 weeks of gestation.This nested case-control consisted of 465 singleton live births in California from 2005 to 2011 at 22-25 weeks of gestation. All infants had newborn metabolic screening data available. Data included linked birth certificate and mother and infant hospital discharge records. Mortality was derived from linked death certificates and death discharge information. Each death within 7 days was matched to 4 surviving controls by gestational age and birth weight z score category, leaving 93 cases and 372 controls. The association between explanatory variables and 7-day survival was modeled via stepwise logistic regression. Infant characteristics, 42 metabolites, and 12 metabolite ratios were considered for model inclusion. Model performance was assessed via area under the curve.The final model included 1 characteristic and 11 metabolites. The model demonstrated a strong association between metabolic patterns and infant survival . Furthermore, a model with just the selected metabolites performed better  than a model with multiple clinical characteristics .Use of metabolomics significantly strengthens the association with 7-day survival in infants born extremely premature. Physicians may be able to use metabolic profiles at birth to refine mortality risks and inform postnatal counseling for infants born at <26 weeks of gestation. Recent improvements in neonatal resuscitation and intensive care have led to an increase in survival among infants born at 22-25 weeks of gestation.Given the uncertainty surrounding clinical management of periviable newborns, the American Academy of Pediatrics recommends that decisions regarding care should be individualized and family centered, taking into account conditions and risk factors known to affect outcomes.17The use of unique sources of data and novel possible predictors may improve survival prediction for infants born at <26 weeks of gestation. One such opportunity is the use of metabolic data measured as part of newborn screening (NBS) for rare inborn errors of metabolism.25The objective of this study was to assess the relationship between survival to 7 days of age and metabolic markers in concert with common infant characteristics. We hypothesized that the incorporation of metabolites would strengthen the association with survival beyond the capacity of infant characteristics alone.This was a nested, case-control study within a retrospective cohort of data collected by the California Office of Statewide Health Planning and Development on births from 2005 to 2011 in California. This database contains information from hospital discharge, birth certificate, and death records from birth to 1 year of age. This database was combined with results from NBS using date of birth, hospital of birth, birth weight, and birth time. In California, the Newborn Screening Program  screens all newborn infants for rare inborn metabolic diseases by measuring markers in a heel-stick blood spot taken between 12 hours and 8 days after birth. The program has been described extensively elsewhere.27www.jpeds.com). The population was then limited to infants born at <26 weeks of gestation, leaving 1238 infants eligible for analysis. From the final population, infants who died within 7 days were matched to 4 controls by gestational week of birth and birth weight z-score category, which left a final sample of 93 cases and 372 controls (7 infants who died could not be matched to a control).There were 2 664 595 infants in the source cohort after linkage with vital statistics. Infants were excluded if the birth weight was >4 SDs from the mean for gestational age by sex ,International Classification of Diseases, Ninth Revision, Clinical Modification codes 772.13, 772.14). Criteria for choosing these specific variables included availability, occurrence before NBS, and previous evidence of an association with early infant mortality. Administration of TPN was obtained from the NBS data and was defined as receiving TPN before the blood spot was taken. There were 42 metabolites entered into the model consisting of 12 amino acids, 26 acylcarnitines, free carnitine, 2 hormones, and 1 enzyme (www.jpeds.com). In addition, 12 metabolic ratios were considered in the model. We used the same ratios created by NBS to detect known inborn errors of metabolism. No additional ratios were created.The outcome of interest for this study was survival past 7 days of age. Henceforth, “survival” in our study will be defined as alive after 7 days and “death” will be defined as deceased at <7 days. Mortality data were obtained from death certificate and death discharge information within the California Office of Statewide Health Planning and Development dataset. Infant and maternal characteristics used in analyses included birth weight, gestational age, sex, delivery type, maternal education, race/ethnicity, Medi-Cal status , use of total parenteral nutrition (TPN), birth weight small for gestational age, and any intraventricular hemorrhage (IVH) diagnosis (Standardized mass spectrometry (tandem mass spectrometry) was used to measure the amino acids, acylcarnitines, and free carnitine. Thyroid-stimulating hormone and 17-hydroxyprogesterone were measured by high-performance liquid chromatography, and galactose-1-phosphate uridyltransferase was measured with a fluorometric enzyme assay.t tests and χ2 tests for continuous and categorical variables, respectively, to compare infants that survived and those that did not.All metabolites underwent a natural log transformation before being used in analyses to minimize the skew and influence of outlying observations. Birth weight was transformed into z scores using standardized growth curvesP value from univariable analyses and then removes any variables with newly recalculated P values that eclipse the predetermined threshold. To maximize model performance, all possible explanatory variables had the potential to enter the model, and the criteria for remaining in the model was P < .10. In addition, variables with a P ≥ .05 and < .10 were removed if their inclusion raised the Akaike information criterion or had no discernible positive effect on area under the curve (AUC) from a receiver operating characteristic (ROC) curve. If both base metabolites and their ratio were selected for inclusion in the model, severe multicollinearity was assessed and the components were evaluated independently with P values and contribution to model AUC and Akaike information criterion. Age at NBS collection and TPN were entered into the model build, as both are well-known to influence values of NBS metabolites,Multivariable logistic regression was used to model the association with survival. We used a stepwise regression procedure that consecutively adds explanatory variables based on minimizing Performance of the final model was evaluated with AUC, and variables were summarized via OR, 95% CI, and standardized parameter estimates. Cross-validation was applied to assess the model fit, and the final model underwent conditional logistic regression to test for bias due to matching. The final model also was compared  to models consisting of metabolites only and clinical characteristics only . ROC-derived probability cut points were used to calculate sensitivity and specificity, and odds of survival above particular cut points were compared with that of the referent cut point (<0.3) to generate ORs with 95% CIs.All analyses were performed with SAS 9.3 . Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California and the institutional review board of the University of California, San Francisco.The matched study sample included 93 infants who died and 372 survivors from a retrospective source population of 1238 infants born in California at 22-25 weeks of gestation from 2005 to 2011 with completed NBS. Within the source population, 100 (8.1%) infants died at <7 days, and 305 (24.6%) died within the first year with an average age of survival of 35.0 days. Each infant who died at <7 days was matched to 4 infants surviving >7 days of the same gestational age week and approximate birth weight. In the matched sample, variables that differed significantly between infants that survived and those that did not were TPN administration, IVH diagnosis, and age at NBS collection . In univThe model most strongly associated with survival was adjusted for age at collection and contained 12 variables: IVH diagnosis, alanine, ornithine, C-3, C-3DC, C-5OH, C-6, C-10:1, C-12:1, C-14:1, C-16, and C-16:1 and had an area under the ROC curve (AUC) of 0.885 (95% CI 0.851-0.920). Of all the variables in the model, the 2 amino acids alanine and ornithine were most robustly linked to survival with standardized estimates of –0.60 and 0.52, respectively .Table IIP = .278) or a clinical characteristics-based model .The model maintained strong performance after cross-validation . The full model also performed better when compared with a metabolites-only model  survived. These 240 infants also accounted for 64.5% of all infants who ended up surviving, and they were 360 times more likely  to survive when compared with infants with a probability score <0.3. Alternatively, no infants with probability scores <0.1 survived. This cut point successfully discriminated the mortality of 15 (16.13%) infants without misclassifying a survivor . When clUsing metabolic markers that are collected as a part of routine NBS, we were able to successfully build an algorithm that reliably classified infants who survived past 7 days of age when born at 22-25 weeks of gestation. The final model consisted of IVH diagnosis and 11 metabolites (9 acylcarnitines and 2 amino acids).Past predictive models have exclusively used maternal and infant characteristics to predict survival.Newborn metabolomics have been shown to be related to gestational age and birth weight, especially in infants born preterm.IVH was the only clinical diagnosis included as a variable in our model due to the fact that approximately 50% of cases occur on the first day of life and 90% by day 3,Both age at NBS collection and administration of TPN were entered into our model because they are known to affect the concentrations of metabolites.Our study had several strengths and limitations. Perhaps the most potent strength of our study is that our matched sample was derived from a population-based dataset that supports the potential generalizability of the model. Although we did not use separate training and validation datasets because of the very small number of babies born at very early gestations, we did use cross-validation as a means for ensuring our results were not due to overfitting. Our source data set was retrospective in nature, limiting us to the use of predetermined explanatory variables and outcome data. This was especially important as related to the NBS data. Infants who died before NBS could be obtained were not included in the model build. Although this limited our ability to examine survival no sooner than at 7 days and produced a smaller sample, we do not think it biased the results. We suspect that infants who died before NBS was completed would likely have had compromised metabolic functions to an even greater extent, and this may have improved the performance of our model. Nevertheless, future studies should assess metabolic function in infants who die within hours of birth. Given the retrospective data, we may not have been able to control for all factors affecting metabolic concentrations. Blood transfusions, for example, could have affected the values of metabolites, although, only in rare scenarios in which a transfusion occurs before NBS. An additional limitation of our data was the lack of information about antenatal corticosteroid exposure, which has been shown to be a powerful predictor of survival,Our model should be validated in other clinical and population-based samples, preferably in a prospective setting. Validation of the model is essential to determine whether these metabolic patterns have predictive capacity. Moreover, the population of California that was used in this study is especially diverse, and the majority of infants in our study were of Hispanic ethnicity. Testing the model in other populations will help expand the generalizability of our results. In addition, our study focused on the association with survival at just one time point (7 days), and it may be that metabolic profiles are linked to survival at time-points beyond 7 days. Our study also focused on a single measurement of metabolic markers. To truly examine the probability of survival and elucidate the metabolic pathways that differentiate infants, measuring markers at multiple time points may be especially important. Furthermore, although NBS results currently require time for processing and interpretation that preclude them from being actively included in real-time decision-making, developing point of care testing is essential. Finally, given the value of metabolic correlates shown here, additional studies using them in the prediction of morbidities associated with preterm birth are warranted.This study examined the link between routinely available metabolic markers and survival in extremely preterm newborns. We successfully built a model showing strong associations and demonstrated that infants who survived beyond 7 days were metabolically different from those infants who died in the first 7 days. Physicians potentially could use metabolic profiles measured shortly after birth to refine mortality risks and inform postnatal counseling for extremely premature infants.


Cystic echinococcosis (CE) is a worldwide zoonosis and the liver is the most commonly affected organ. Clinical manifestations range from completely asymptomatic cysts to a potential lethal cyst rupture and anaphylaxis.Severe chest allodynia was an unusual clinical presentation of hepatic cyst rupture in the retroperitoneal space, without any other specific symptoms. CE diagnosis was confirmed by computed tomography scan and magnetic resonance. The patient underwent hepatectomy with complete resolution of the neuropathic pain.Retroperitoneal hydatid cyst rupture is a rare event and its clinical manifestation may mimic other chest neuropathies. Echinococcus granulosus sensu lato. More than 1 million people have been estimated to be infected worldwide . Hepatic enzymes profile was unremarkable with a γ-glutamyl tranferase (GGT) of 33 Us/L, and both Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) of 19 Us/L. No alterations of amylase and lipase levels were detected.Abdominal CT scan showed a thick walled cystic lesion with egg-shell calcification in the right lobe of the liver measuring about 93 × 70 mm Fig. . The walAn interruption in the posterior face of the wall, hypointense in T2 weighted image, was visualized, confirming the cyst rupture and the extravasation of the cyst contents Fig. .Fig. 4T2Echinococcus granulosus  was positive with both tests. In addition, an experimental test based on IL-4 detection after whole blood stimulation with AgB peptides was performed. The IL-4 level was 0.62 pg/mL, suggesting the presence of viable cysts based on the previously identified cut-off of > 0.59 pg/mL in serology-positive patients [Serology for Based on the findings, the diagnosis was spontaneous rupture of hepatic hydatid cyst, as no history of major trauma was reported. No symptoms of anaphylaxis  were detected. Treatment with oral albendazole (400 mg twice daily) was started immediately, and the patient underwent right hepatectomy and the operatory field was protected with 20% hypertonic saline to help preventing secondary echinococcosis. Macroscopically the cyst contained many daughter vesicles, compatible with a CE2 stage Figs.  and 6. SOne month after operation the physical conditions of the patient were good. The treatment with albendazole was continued for additional 6 months.Written informed consent for publication of clinical details and clinical images were obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.We describe a case of atypical presentation of spontaneous rupture of a hepatic CE cyst. Chest pain is a common complaint and reason for consultation in primary care. This may be due either to visceral disease, including pleural, gallbladder, cardiac and vascular conditions, or to diseases of the chest wall, such as musculoskeletal diseases, radicular pain, local neuritis (herpes zoster), vertebral body involvement by inflammation, infectious disease (tuberculosis) or tumors, and fractured ribs. As chickenpox was reported in the medical history, chest allodynia was associated to herpes zoster neuralgia, and gabapentinoids/acetaminophen treatment was prescribed before hospital admission. However, the absence of vesicles after 1 week of acute pain onset and the inflammation status found on laboratory work up, led to further investigations. Imaging results suggested the diagnosis of a retroperitoneal rupture of a hepatic hydatid cyst, which is a rare event and an unusual cause of chest allodynia. Moreover, serology and the experimental whole blood testing confirmed the diagnosis of cystic echinococcosis.The CT images showed a calcification of the cyst wall. This is characteristic of CE, but is not a feature restricted to CE5 and CE4 stages; it may be present across all cystic stages and therefore cannot be considered indicative of the death of the cyst . Cyst stRecently, a whole-blood assay based on AgB synthetic peptides has been suggested to provide information on the cyst biological viability, mainly in CE patients with a positive serology . The expSurgery maintains a key role in the management of complicated cysts . SurgeryPrimary retroperitoneal hydatid cysts have been described in literature, however this is the first reported case of hepatic echinococcosis with rupture of the cyst into the retroperitoneal space, presenting as severe chest allodynia. Moreover, spontaneous cyst rupture is rare and the lack of traumatic events may induce the clinician to exclude a priori a diagnosis of CE. However, CE is endemic in Italy and in the region of Abruzzo where the patient spent her childhood. Abruzzo has been recognized as the third Italian region for CE prevalence after Sicily and Calabria, as shown by Hospital Discharge Records and Italian Register of CE  data , 17. The


Large for gestational age (LGA) infants are more prone to be obese and are at a higher risk of metabolic complications later in life. It is established that Asians have lower skeletal muscle mass and excess body fat for a given body mass index. Thus, objective of this study was to determine the relationship between leptin, insulin, C-peptide in cord blood on the birth weight of newborns and to determine whether these parameters are deviated from data already published from other populations.  Umbilical cord blood was collected from 90 newborns  which comprise of 43 LGA and 47 appropriate for gestational age (AGA) newborns. Serum leptin, insulin and C-peptide levels were measured and anthropometric parameters of the newborn and maternal characteristics were recorded. P < 0.001) concentrations of leptin, insulin and C-peptide levels  were observed in the LGA group compared to AGA group  and all three parameters showed positive and significant correlations with anthropometric parameters of the newborn and maternal characteristics.  Significantly higher ( Although increased leptin, insulin and C-peptide levels may be involved in insulin resistance, increased adiposity and macrosomia, they were not significantly deviated from published data from other populations. Other factors may contribute to higher fat mass found in Asian populations and finding this relationship during neonatal period is useful to predict risk factors for childhood obesity. Childhood obesity has increased to pan-epidemic proportions in the recent past along with a collateral increase in obesity associated morbidity. The etiology of childhood obesity is complex and multifactorial . There iDuring the third trimester of gestation, body composition and the weight of a fetus changes drastically. Thus, over 90% of fetal body fat is deposited and more than fourfold increase in fetal weight is observed during this period . Total bOver the years, a lot of evidence has emerged on pre- and perinatal predictors of childhood adiposity. Some of the examples, as reported by Parker et al. include maternal smoking, excessive gestational weight gain, pre-pregnancy body mass index, gestational glucose tolerance, low adiponectin and high leptin levels in umbilical cord blood at delivery . It was Adipose tissue produces and secretes a number of hormones collectively called as adipocytokines which are important in modulating metabolism and energy homeostasis. Leptin which was identified as a product of obesity (ob) gene is an important member of this adipocytokine family. According to Tung et al., cord blood leptin level has been positively correlated with fetal adiposity at birth . ExperimMitanchez established the link between maternal glucose homeostasis and the fetal pancreatic response . It has In recent years, there is accumulating evidence to suggest that the relationship between BMI and percentage body fat differs between ethnic groups. According to Wang et al., Asians' have a lower BMI but a higher percentage body fat compared to Caucasians of the same age group . Howeverth and 90th percentile for age and gender based on the CDC 2000 growth charts) and large-for-gestational-age (birth weight above the 90th percentile for age and gender based on the CDC 2000 growth charts) who did not suffer from any complication were recruited to the study. Mothers who had singleton pregnancies and uncomplicated deliveries were considered to obtain the consent. Infants who were small for gestational age (weight for gestation less than 10th percentile) were regarded as high-risk newborns and were not included in this study. Additionally, infants with anomalies or who required intensive care were also excluded. Children who were exposed to maternal chronic disease  and preeclampsia and children with neonatal respiratory distress syndrome i.e children with an Apgar score of <7 at 5 min were also excluded.A hospital based cross sectional study was conducted between May 2017 and November 2017 at the professorial unit, Teaching Hospital, Mahamodara, Sri Lanka. The study protocol was reviewed and approved by the Ethical Review Committee of the Faculty of Medicine, University of Ruhuna, Sri Lanka. The objective of the study was explained to each pregnant woman and written informed consent was obtained before enrollment to the study. Term  neonates born appropriate for gestational age (birth weight between 103 × 100), where infants with PI 2.25 < PI < 3.1 were considered symmetric.90 mother-child pairs were included in the study. A data extraction sheet was used to extract maternal, obstetric and perinatal data from hospital records. Maternal characteristics such as weight and maternal BMI before pregnancy, weight gain during pregnancy, number of children were recorded. Anthropometric indices such as infant weight and length were measured within 24 hours after delivery. Each measurement was taken by a trained personnel in triplicate and the average result was recorded. Birth weight was determined using a calibrated electronic scale with an accuracy of 2 g. The length was measured with the infant in the supine position with an infantometer containing a stationary headboard, a movable footboard and a built in centimeter scale. Occipital frontal head circumference, chest, mid upper arm, abdominal, hip, thigh and calf circumferences were measured using a nonstretchable tape. The gestational age was estimated by the last menstrual period, confirmed by ultrasonography before 20 weeks of gestation. Symmetry was evaluated by Rohrer's Ponderal Index (PI = birth weight (g)/birth length (cm)th percentile or 2 standard deviation score (SDS) above the mean for gestational age were classified as large-for-gestational-age (LGA) and birth weights between the 10th and 90th percentiles were classified as appropriate for gestational age (AGA).Newborns were divided into two groups according to the birth size. Specifically, birth weights above the 905 ml of cord blood samples were collected after double clamping the umbilical cord before separation of the placenta into ethylenediamine tetraacetic acid (EDTA) tubes immediately after delivery and were stored at 4°C up to a maximum of 12 h. They were then centrifuged, and the plasma was aliquoted and stored at −70°C until assayed.Leptin and insulin concentrations were measured by enzyme linked immunosorbent assay (ELISA). Fetal insulin resistance was estimated via cord blood C-peptide estimation using ELISA technique.p < 0.05.Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) 16.0 for Windows software. Data were expressed as mean ± standard deviations (SD), number (percentages) or frequency. Differences in categorical variables were tested using a chi-squared test. The relationship between leptin, insulin, C-peptide and anthropometric indices were assessed by Pearson's correlation while Kruskal–Wallis test was used to assess the significance between parameters. The multiple logistic regression analysis examined influences of maternal parameters on biochemical parameters in cord blood as covariates on the birth of large for gestational age infants. Statistical difference was defined as P ≤ 0.001), birth length (P = 0.001) and ponderal index (P = 0.005) were significantly higher in the LGA infants compared to the AGA infants. However, a significant difference was not observed in the gestational age at delivery between the two groups but all the circumferences except the calf and abdominal circumferences measured between the two groups were statistically significant. When maternal characteristics were considered, weight (P = 0.002) and BMI before pregnancy (P = 0.012) were significantly different between LGA and AGA groups. The characteristics of the mother and the newborn enrolled in the study are shown in P ≤ 0.001) in the LGA group (18.725 ± 0.644 µIU/mL) compared to the AGA group (13.081 ± 0.428 µIU/mL) (P < 0.001) was observed for the LGA groups compared to 7.108 ± 0.906 ng/mL and 5.439 ± 0.192 ng/mL in the AGA groups.Mean insulin concentration was significantly higher ( µIU/mL) . Same trr = 0.296, p = 0.006) and maternal characteristics such as BMI before pregnancy , weight before pregnancy , C-peptide level , and insulin level . On the other hand, C-peptide level was positively correlated with birth weight of the newborn , insulin concentration in cord blood  and leptin concentration . Insulin concentration was correlated with only the leptin concentration  and the C-peptide concentration . Although the correlation between insulin and leptin was significant and positive as shown in When the whole study population was considered, leptin level was positively correlated with birth weight of the newborn  [According to published data, cord blood concentrations of leptin are associated with high BMI and increased central adiposity in children . Catalan < 0.05) . These s < 0.05) .P < 0.001), and correlated positively with birth weight. This finding is consistent with the results of previous studies [µIU/mL in LGA vs. 13.081 ± 0.428 µIU/mL in AGA, P < 0.001) as shown earlier by others.Consistent with previous studies [As expected, leptin, a thoroughly investigated adipocytokine, was found in significantly higher levels in LGA newborns in this study when compared with AGA group  was observed between leptin and insulin levels in cord blood in the present study. Collectively, the present study provides evidence for a direct association between fetal leptin levels and birth weight in LGAs and AGAs. The correlation of cord blood insulin with birth weight is the result of the correlation between insulin and leptin. The data may suggest that, in addition to the direct anabolic action, part of insulin's effect on birth weight is mediated by leptin. It can also be speculated that insulin stimulates fetal adipocyte leptin synthesis. According to the results reported by Simental-Mendía et al. [μU/mL in the cord blood of LGA neonates who had an average birth-weight of 4175 ± 197 g, and it was 52% higher than that was reported in the AGA group. In our study, we observed a median birth weight of 3700.00 kg (3550.00–3850.00) in the LGA group, and a higher insulin concentration (18.725 ± 0.644 µIU/mL) which was 43% higher than the AGA group. These results are also consistent with what was reported earlier with Caucasians and we didn't observe any deviations in the Sri Lankan population.A significant correlation (a et al. , mean inFurthermore, Catalano et al.  also repCurrent study also shows that LGA newborns had significantly higher cord serum C-peptide levels in addition to higher leptin and insulin levels than AGA newborns, which is consistent with previous studies revealing that C-peptide levels in macrosomia were significantly higher than in AGA infants. C peptide is secreted by pancreatic beta cells in amounts equimolar with insulin, and its levels provide a direct indication of endogenous fetal levels of insulin despite the presence of maternal insulin antibodies.However, longitudinal studies are necessary to clarify whether adipokines produced within the intrauterine and neonatal environment play an important role in fetal or neonatal programming of diseases occurring in adulthood, such as diabetes mellitus, hypertension, and coronary heart disease.Strengths of this study include its study design which raises interesting questions regarding the interplay of leptin, insulin and C-peptide during the neonatal period and how it would influence the programming of obesity during infancy, childhood and may be adulthood. According to the recent notions that obesity may be influenced by maternal-fetal interactions, a prospective study following children from before birth would be of great use for the understanding of all parameters concerned. However, the main limitation of this study is the small sample size and we intend to continue the study to collect more data and investigate the relationships between adipocytokines and the future markers of metabolic syndrome.According to the results of this study, significantly higher leptin, insulin and C-peptide concentrations were observed in infants born large-for-gestational-age compared to infants born appropriate for gestational age and they were also positively correlated to birth weight of the newborns and some of the maternal characteristics. These findings were comparable with results reported from other parts of the world. Hence, there may be other factors that contribute to the higher fat mass found in Asian populations and the previous finding that Asians have a higher body fat mass for BMI compared to other ethnic groups, is worth investigating in detail further. Finding this relationship as early as neonatal period will be useful in the prediction of risk factors and identification of infants who will be at risk of developing obesity related complications during childhood and adulthood.


We would like to thank Heazell AEP et al. In fact, to our surprise, in our study, we found that there were no signs of a decrease in cardiac output in the supine position as observed in traditional stretchers according to the studies in the literature.We believe that there were no significant hemodynamic changes and that the parameters remained within normal levels when the pregnant women were in the supine position on the special stretcher for up to 6 minutes for two reasons. First, reduced compression of large vessels occurs; this is due to the slight 15-degree elevation of the dorsal region of the woman's body with a pillow to support her lumbar spine and to the shape of the stretcher, which contains an opening that creates a space to accommodate and support her pelvic region, thus anatomically maintaining the curve of her lumbar spine. Second, pain occurs when women are lying on traditional stretchers, which can lead to changes in hemodynamic parameters due to the stress this position creates; however, the women in our study indicated no pain or discomfort in the supine position.Regarding safety in the prone position, Nakai et al. We would like to note that all pregnant women in both groups in our study were in the prone position twice and that their blood pressures decreased, which allowed us to affirm that this position was safe during the 6 minutes of evaluation on the special stretcher.As we mentioned in the discussion of our study, we agree that further research is necessary to analyze the effects of the prone position on the special stretcher for longer than six minutes, such as for the total duration of a physical therapy session or medical procedure. We are certainly striving to carry out such research. We appreciate the words of encouragement.


The premature birth rate in Korea has increased from 13.5% in 2008 to 15.7% in 2013. The complications of premature birth are a major determinant of neonatal mortality and morbidities. The purpose of this study was to estimate the burden of premature birth in Korea using disability-adjusted life years (DALY). DALY consists of years of life lost (YLL) and years lost due to disability (YLD). In this study, preterm birth complications refer to nine diseases: P07, P22, P25, P26, P27, P28, P52, P77, P612, and H351 . YLL was calculated using mortality data from the 2012 National Health Insurance Data. YLD is a function of the prevalence, disability weight (DW), and duration of each complication. DW was determined by the Korean Disability Weight Study for National Burden of Disease in Korea 2013/2015. The burden of premature birth in Korea is 79,574 DALY . The burden for men  is higher than that of women . This study could provide essential data for evaluating the effects of policies intended to reduce preterm birth. Preterm birth is defined as giving birth earlier than 259 days since the last menstrual period or before 37 weeks of gestation . There aPreterm birth is an important cause of neonatal mortality as well as increased perinatal diseases due to the immaturity of various organs in the surviving newborns. Furthermore, preterm birth is a potential risk factor for permanent disabilities, such as impaired neurodevelopmental functioning and respiratory distress . DespiteAccording to the 2010 Global Burden of Disease (GBD) study, preterm birth complications are responsible for 3.1% of the worldwide disease burden. However, owing to its low disease burden in South Korea (0.47%), there is little attention given to this issue. Nevertheless, one must be aware that preterm birth complications comprise the biggest proportion of neonatal diseases in South Korea . MoreoveThe World Health Organization has been measuring and comparing the world’s disease burden through the GBD study. However, an identical disease scope and disability burden were applied to all countries. Although this allowed for comparison of disease burden between countries, the GBD study results could not be used to set health service priorities and distribute limited healthcare resources, which are major advantages that studies on disease burden can offer. Our study took a different approach to overcome the limitations of the traditional GBD study and to measure the disease burden of preterm birth complications specifically in South Korea. In South Korea, the disease burden of preterm birth complications was measured using disability-adjusted life years (DALY) from the GBD 2000 study . DALY isThe causes of preterm birth complication were based on the hierarchical disease cause list from the GBD 2010 study . The claIn this study we calculated the DALY of preterm birth complication using data from Korea. We considered the appropriateness of defining the study population as under 5 years, similar to WHO. After conducting a literature review and consulting experts, we decided to expand the study population because there is limited data on this subject for Korea. Thus we extended the study to 0–9 years.The criteria for the use of medical institutions were determined by the literature review and expert opinions. The patients selected for the study were aged 0–9 years who had visited at least 1 inpatient and 3 outpatient clinics for preterm birth complications.We conducted literature searches and expert consultations to set the severity criteria. There was no literature indicating the severity of preterm birth complications. Therefore, we decided to follow the advice of experts. First of all, we analyzed the most frequent diseases of preterm birth complications through an analysis of healthcare screening assessment service claim data. As a result, the frequency of cerebral palsy (G80) was shown to be the highest. Analysis of the data from the Health Insurance Review and Assessment Service in 2012 showed that there were 2274 patients admitted for cerebral palsy (G80), which was 1.5 times the number of patients (1475) who were admitted for mental retardation (F70–79). Therefore, cerebral palsy (G80) was set as the standard for severity categorization of preterm birth complications ,20,21. RTo assess the severity ratio between cerebral palsy and retinopathy of prematurity, data from the 2011 Survey of Disabled People were used . The SurCerebral palsy was categorized as a behavior disorder with or without cognitive impairment, similar to the categorization of the disability weight. From the analysis of the data on cerebral palsy from the Survey of Disabled People, the distribution of severity of disability in patients with behavior disorders without cognitive disorders was 2% mild, 90% moderate, and 8% severe, while the distribution in patients with cognitive disorders was 90% moderate and 10% severe. Retinopathy of prematurity was categorized using the same method, and the distribution of patients was as follows: 78% mild, 8% moderate, 14% severe, and 0.3% blinded. By applying the ratio calculated from the above numbers, years lost due to disability (YLD) values of behavior disorders with and without cognitive impairment and visual impairment and blindness from retinopathy of prematurity were calculated.Disability weight due to preterm birth complications was obtained using the Korean disability weight study . The disTo measure the burden of disease from preterm birth complications, we estimated the prevalence-based DALY that incorporates years of life lost (YLL) and YLD. The basic formula for DALY is shown in Equation (1):For YLL, the mortality rate was calculated using the cause-of-death data from Statistics Korea. In the case of causes that cannot or should not be considered an underlying cause of death, we followed the GBD’s redistribution algorithm for garbage codes. Years lost due to premature death were derived from the standard expected years of life lost. Life expectancy was based on the general population’s life expectancy by age, using the life tables of Statistics Korea in 2012.The YLD was calculated using the number of prevalent cases and the disability weight. Disability weights were generated from a self-administered web-based survey of physicians and medical college students using a paired comparison for valuation method. The frame of the Korean Burden of Disease 2012 study and calculation of disability weights are described in more detail elsewhere . The calculated YLD, YLL, and DALY values were standardized to the value per 100,000 members of the population. The population per 100,000 people was calculated based on the middle-aged population of Korean Statistical Information Service in 2012 . The souA sensitivity analysis was performed because of the uncertainty of the data. The sensitivity analysis was performed by changing the prevalence and the number of deaths. First, only the prevalence was changed, second, the number of deaths was changed, and finally, the numbers of both were changed.This study was approved by the Korea University Institutional Review Board (No. 1040548-KU-IRB-13-164-A-1[E-A-1]). Informed consent was waived by the board.YLD values by severity are summarized in The YLD value was 782  for mild retinopathy of prematurity, 80.0  for moderate retinopathy, and 141  for severe retinopathy. Similarly, the YLD value was higher in men. The YLD value for blindness was 301 and was higher in men (157) than in women (144).The total YLD value from disabilities due to preterm birth complications was 35,849  with men having higher YLD values. Based on age, patients less than 1 year of age had the highest YLD at 30,167 . The YLL value due to premature death from preterm birth complications was 43,725 . Based on age, patients younger than 1 year of age had the highest YLL at 43,495.0  .The total DALY value from preterm birth complications was 79,574. The total YLD value was 35,849, and the YLL value was 43,725. YLL was 55% of total DALY, higher than YLD. The DALY per 100,000 population was 34,632  .The sensitivity analysis was calculated assuming a decrease or increase of 3%, 5%, 7%, and 10%. As a result of performing the sensitivity analysis, it was shown that the change in YLL value is more influential on the DALY value than the YLD value is. The DALY value decreased further when the YLL value decreased by 10% . In addition, a 10% increase in the YLL value  showed a higher DALY value than a 10% increase in the YLD value  . HoweverThis study measured the burden of preterm birth complications using DALY. The disease burden of preterm birth complications was 79,574 . The total DALY of preterm birth complications was 34,632 per 100,000 population . The results of this study were lower than those of GBD 2010  and GBD 2016  worldwide ,25. The results of this study are different from previous studies for several reasons . First, The second difference in the methods of the two studies was the disability weights used. In this study, disability weights of preterm birth complication calculated from Korean data were used. The reason for using Korean disability weights is the issue of universality of disability weights being steadily raised since the early days of research on the burden of disease . The advAnother reason for this study to be different from the GBD 2010 study is that it applied severity to the sequelae in calculating YLD. The disability weights were divided into mild, moderate to severe, and severe by disease sequelae, and the YLD were calculated. However, traditional GBD studies did not take severity into consideration . It coulThe YLD results indicate that disabilities caused by preterm birth complications almost always result in moderate or severe disabilities rather than mild disabilities. YLD values from disabilities due to preterm birth complications (including retinopathy of prematurity) were 912 for mild and 34,937 for moderate and severe complications, indicating a 40-fold higher disease burden. From these results, it appears that the majority of disabilities in the neonatal stage are greater than moderate-level severity. Therefore, a policy to minimize disabilities from preterm birth complications is urgently needed. However, healthcare policies regarding pregnancy and childbirth in South Korea include support for emergency childbirth, treatment for infertile couples, healthcare for the mother and the newborn, childbirth by women with disabilities, medical costs for preterm babies and babies with congenital abnormalities, congenital metabolic disorder examination and management, hearing disability examination, and full-body examination of children aged 6 years or less. The majority of these policies are supportive policies after childbirth; the only pre-birth management, which is the health management support system for the mother and the newborn, is very limited. The support is available only if the combined health insurance cost for the mother and her partner is below 65% of the national average monthly income and if the mother is within 40 days of her expected due date or 30 days after childbirth. Practically, there is no policy to prevent premature birth or to manage premature infants and preterm labor. Therefore, a policy to prevent and manage premature births is strongly required.Compared to the GBD 2016 DALY of preterm birth complications with the Western-Pacific high-income countries group, Korea and Australia were similar but they were both higher than Japan and Singapore . This diThis study used national data, but there are uncertainties due to missing data when estimating the prevalence of preterm birth complications and deaths due to preterm birth. A sensitivity analysis was conducted to evaluate the uncertainty surrounding the DALY. The sensitivity analysis showed that DALY were lowered when YLL decreased more than when YLD decreased. However, when both YLD and YLL were decreased, DALY decreased significantly. On the other hand, DALY increased significantly when YLD and YLL were both increased. These results suggest that preterm birth management policy is important for continuous care for the prevention of death and disability.Although the authors made an effort to ensure the validity of the methods by using all available data in South Korea, there were limitations. First, there was a lack of severity data to calculate the burden of preterm birth complications, and there was a limit to the calculation of years lost due to disability. To overcome these issues, the severity was calculated through a literature review and expert consultation. However, YLD may be underestimated or overestimated. Second, there is a possibility that underestimation was made because of the use of medical claim data. Nonetheless, this study is valuable in that it is the first study of the burden of preterm birth complications considering Korea’s disability weight and severity. The Korean government is making efforts to provide medical care for pregnant women and to provide vouchers for safe pregnancy and childbirth. Nonetheless, the results of this study and the GBD 2016 studies suggest that more effort is needed to reduce complications and death due to preterm birth. Therefore, a detailed analysis of complications of preterm delivery is needed. To this end, it is important to continuously analyze the burden of preterm birth complications among the mother and the child. It is also necessary to carry out this analysis in countries with high disease burden due to preterm birth complications. However, in this study, only the preterm birth complications of the child were analyzed. Therefore, it is necessary to study the maternal preterm birth complications.