Civil registration and vital statistics (CRVS) systems lay the foundation for good governance by increasing the effectiveness and delivery of public services, providing vital statistics for the planning and monitoring of national development, and protecting fundamental human rights. Birth registration provides legal rights and facilitates access to essential public services such as health care and education. However, more than 110 low- and middle-income countries (LMICs) have deficient CRVS systems, and national birth registration rates continue to fall behind childhood immunization rates.Using Demographic and Health Survey (DHS) and Multiple Indicator Cluster Survey (MICS) data in 72 LMICs, the objectives are to (a) explore the status of birth registration, routine childhood immunization, and maternal health services utilization; (b) analyze indicators of birth registration, routine childhood immunization, and maternal health services utilization; and (c) identify missed opportunities for strengthening birth registration systems in countries with strong childhood immunization and maternal health services by measuring the absolute differences between the birth registration rates and these childhood and maternal health service indicators.We constructed a database using DHS and MICS data from 2000 to 2017, containing information on birth registration, immunization coverage, and maternal health service indicators. Seventy-three countries including 34 low-income countries and 38 lower middle-income countries were included in this exploratory analysis.Among the 14 countries with disparity between birth registration and BCG vaccination of more than 50%, nine were from sub-Saharan Africa , two were from South Asia , one from East Asia and the Pacific (Vanuatu) one from Latin America and the Caribbean (Bolivia), and one from Europe and Central Asia (Moldova). Countries with a 50% or above absolute difference between birth registration and antenatal care coverage include Democratic Republic of Congo, Gambia, Mozambique, Nepal, Tanzania, and Uganda, in low-income countries. Among lower middle-income countries, this includes Eswatini, Ghana, Moldova, Timor-Leste, Vanuatu, and Zambia. Countries with a 50% or above absolute difference between birth registration and facility delivery care coverage include Democratic Republic of Congo, Djibouti, Moldova, and Zambia.The gap between birth registration and immunization coverage in low- and lower middle-income countries suggests the potential for leveraging immunization programs to increase birth registration rates. Engaging health providers during the antenatal, delivery, and postpartum periods to increase birth registration may be a useful strategy in countries with access to skilled providers. The United Nations (UN) defines civil registration as the “universal, continuous, permanent, and compulsory recording of vital events provided through decree or regulation in accordance with the legal requirements of each country” and defines vital statistics as “a collection of statistics on vital events in a lifetime of a person as well as relevant characteristics of the events themselves and of the person and persons concerned” . RecordiCRVS systems feature prominently in multiple UN Sustainable Development Goals (SDGs). Most notably, SDG target 16.9 stipulates that countries “by 2030, provide legal identity for all, including birth registration” . IncreasImmunization tracking and record systems vary in coverage and quality. Conventional tracking systems include paper-based Expanded Program on Immunization (EPI) cards and regional clinic records, and though electronic health systems are uncommon at a national level, mHealth innovations are being used to provide software for national vaccine registries connecting vaccine records and mobile parental reminders. The World Health Organization has prioritized strengthening immunization systems in LMICs as part of a well-functioning health system in the Global Vaccine Action Plan . The fraThe birth registration process typically begins with a birth attendant completing and filing a birth notification form following the birth, whether the delivery is at home or at a facility. The BCG vaccination is also typically given by the birth attendant at the time of birth and documented in the birth record. The birth notification form is filed to the civil registration authority, and the parents are issued a birth certificate. Barriers to birth registration include a lack of social or institutional awareness of the benefits of birth registration, long distances to travel, costs or fees, and inefficiencies or inequalities in how CRVS systems are administered . CurrentRoutine childhood immunization and maternal health service programs may provide opportunities for collaboration through which birth registration systems could be improved. Using demographic and health survey (DHS) and multiple indicator cluster survey (MICS) data, the objectives of this article are to (a) explore the status of birth registration, routine childhood immunization, and maternal health service utilization in LMICs; (b) analyze indicators of birth registration, routine childhood immunization, and maternal health services in LMICs; and (c) identify missed opportunities for strengthening birth registration systems in countries with strong childhood immunization and maternal health services by measuring the absolute differences between the birth registration rates and these childhood and maternal health service indicators.We constructed a database using DHS and MICS country data from 2000 to 2017, inclusive. Birth registration data were collected using DHS and MICS surveys for children younger than 5 years. In each type of survey, mothers were queried about whether each child’s birth had been registered administratively, whether they had a birth certificate, and whether they could produce the birth certificate.The DHS and MICS surveys assessed immunization coverage rates by asking mothers of children aged 12 to 23 months about the current immunization status of their children at 12 months and asked whether vaccination cards were available. Current immunization status was surveyed for vaccines against tuberculosis, measles, diphtheria, pertussis, tetanus, and polio. For this analysis, we aligned with the DHS and MICS methods for vaccine coverage using any record of vaccination, either mother’s report or vaccination cards.In addition to the birth registration and immunization coverage rates, data were extracted from DHS and MICS to analyze antenatal care (ANC) indicators, birth and delivery indicators, post-delivery care indicators for mother and newborn, wealth quintiles, and parental education and literacy indicators.The dataset included information from LMICs and income levels were defined using the World Bank Country and Lending Groups 2018 update . Low-incWe included countries based on the low- and lower middle-income countries’ classifications by the World Bank, excluding upper middle-income countries. We excluded countries with no recent DHS or MICS data available. Of the 72 countries included in the analysis, 69 had surveys providing immunization and birth registration data, and four countries reported one or the other but not both. DHS and MICS indicators in the database included birth registration for under 5 years, under 2 years, and under 1 year; immunization at 12 months in 12–23-month-old children by vaccine card or immunization record; and birth certificates in under-5-year-old and under-2-year-old children. We conducted exploratory and descriptive analyses for each type of indicator included in the database, with a focus on comparing under-1 birth registration data and 12-month-old immunization data. Stata statistical software version 14  was used to create the database and conduct the analyses.All countries reporting both under-5 birth certificates and registration rates reported higher registration than certificates, with lower birth registration and certification rates in low-income countries compared to lower middle-income countries Fig. .Fig. 1BFewer than half of children younger than 5 years in each country had a birth certificate, with great variability in national birth certificate rates ranging from very low in Rwanda (2.7%), Zambia 4.1%), and Tanzania (7.7%) to over 99% in Egypt. Parents’ reports of birth registration were higher than reports of having a birth certificate in under-5 children (65.8% vs 31.1%) and in under-2 children (65.9% and 48.5%)  and highest in the Middle East and North Africa (91.6%) and Europe and Central Asia (84.1%) , and the majority of women saw a provider by 4 months for their first visit. Women in lower middle-income countries had more ANC visits on average than those in low-income countries (data not shown).Birth registration rates and rates of maternal ANC visits are shown in Tables Women in low- and lower middle-income countries who had at least one ANC visit within the last 2 to 3 years were more likely to have seen a skilled provider (including a nurse or doctor) for their delivery care rather than an unskilled provider . Three countries  had the highest rates of women who delivered without a skilled attendant at birth (data not shown). In all countries, more women delivered in public than private facilities.Tables Plotting the differences of birth registration between the wealthiest quintile and the poorest quintile in children under 5 showed a more significant disparity in lower middle-income countries between the richest and the poorest. Figure In contrast, Fig. This study significantly contributes to global efforts to understand the status of maternal and child health service indicators and birth registration in low- and lower middle-income countries. We found variability in birth registration rates between low-income and lower middle-income countries. Birth registration in children younger than 12 months of the 72 countries included in this analysis ranged from nearly 0 to 100% (median 59.3%). Regional birth registration medians ranged from the lowest levels in South Asia (33.7%) and sub-Saharan Africa (57.5%), to the highest levels in the Middle East and North Africa (91.6%) and in Europe and Central Asia (84.1%).It was also found that reported rates of issuance of birth certificates in low- and lower middle-income countries were lower than reported birth registration rates, and the median under-5 birth certification rate for all countries is 31.1%. Having a birth certificate provides certain privileges and protections to children and parents. For example, health care services are free for children younger than 6 years in Vietnam but only if they have an insurance card, which is obtained only with a birth certificate. Some countries such as India, Kenya, and Sierra Leone provide children with universal access to health care without a birth certificate .Similarly, education administrations may require proof of birth registration for school enrollment. In Vietnam, a child needs a birth certificate to be enrolled in school . In BangNational immunization coverage rates are higher than birth registration rates in both low- and lower middle-income countries, with median BCG coverage of 89.3% and 95.2% in low-income countries and lower middle-income countries, respectively. Electronic birth registration, immunization record systems, and maternal and infant health tracking are being explored and implemented in different countries through clinic-based and community outreach programs .mHealth and digital health innovations are optimizing the use of electronic technologies to accelerate the process of bringing paper-based systems online with cell phone and digital platforms . These sIn Nigeria, Open MRS has been used since 2009 to gather data about family planning, antenatal appointments, deliveries, child health, and immunizations . DHIS2 hIn Cambodia, a periodic campaign strategy to register births using mobile or mHealth technology has been used since 2004 and contributed to reaching 90% birth registration coverage in 2015 . AnotherThe Millennium Village Project initiated in Kenya enabled community health workers to use SMS technology to register infants and monitor the health of children younger than 5 years. This strategy provided an opportunity to create and maintain a child registry and to monitor risk factors related to child mortality . In BangJust as with immunization coverage, ANC and delivery care coverage far surpasses that of birth registration in low- and lower middle-income countries. Thus, it may work to use the delivery of maternal and child services to boost birth registration coverage in low- and lower middle-income countries. For instance, pregnant women could be educated on the benefits of birth registration and encouraged to register their births. For facility deliveries, birth attendants could fill out the birth notification form to initiate the birth registration process. For home births, immunization personnel could check during outreach services or at immunization clinics to see whether births are registered and to complete birth notification forms or refer mothers to the appropriate personnel for birth registration. Birth notifications could also be incorporated into any of the electronic health information systems noted earlier to facilitate the birth registration process.There are limitations of using survey research. It is possible that we have included outdated statistics for certain countries or that more recent reports would be representative of progress in birth registration, such as in Ethiopia where birth registration has only formally started since 2016. In the case of Ethiopia, we used immunization and maternal health services data but under-1 birth registration data were not yet available from DHS. However, the DHS and MICS have provided useful data for this analysis. Future surveys should expand birth certificate and registration data among under-1 children. Further research is also needed to understand the impact of wealth inequality and the differences in birth registration and immunization coverage in LMICs.Studies indicate that better CRVS systems are associated with better health and wealth outcomes, justifying the financial and technological investments needed to strengthen CRVS systems . Birth rThe gap between birth registration and immunization coverage in low- and lower middle-income countries that this study has demonstrated suggests the potential for leveraging immunization programs to increase birth registration rates . Study f


Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition.Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire.Ninety patients  were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500 g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) were reported in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was >28 days: 1-12 months in seven; and 3.75-10.5 years in five. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism  and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity. Early diagnosis in Prader-Willi syndrome allows appropriate management of feeding difficulties to be implemented and is important for counselling as well as minimising parental uncertainty and anxiety. The prevalence of preterm birth and low birthweight is increased in Prader-Willi syndrome and is a potential source of diagnostic confusion.Although the prevalence of preterm birth (26%) and low birthweight (24%) is increased in Prader-Willi syndrome, diagnosis in preterm infants is not significantly delayed. However, clinical diagnosis in our cohort was made later than 28 days in 34% of the patients despite presence of classic features of hypotonia and cryptorchidism in males and need for nasogastric feeding in over 80%. Comparison with non-affected siblings shows that mothers detect reduced fetal movement in 80% of patients with Prader-Willi syndrome, a feature which can facilitate early diagnosis. Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from absence of paternally imprinted genes in the 15q11-13 region, caused by deletion in the paternal chromosome (del15q) in about 70% of cases or disomy of the maternal chromosome [maternal uniparental disomy of chromosome 15 (mUPD15)] in about 25% .Prompt dHypotonia is a relatively common problem in the newborn period, affecting not only otherwise healthy preterm infants but also those with sepsis, neurological disease and metabolic disorders. The challenge to the clinician, therefore, is to identify the minority of infants with PWS from the majority of babies in whom hypotonia is a transient feature and from those who are suffering from a different condition such as spinal muscular atrophy (SMA) . Our cliAn increased incidence of preterm birth and low birth weight (LBW) has been reported in PWS, together with obstetric symptoms such as reduced fetal movement (FM), polyhydramnios and malpresentation ,17,18. SA multidisciplinary PWS clinic has been held at our centre in the Royal Hospital for Children in Glasgow since 1991, providing data on a heterogeneous Scottish cohort. The aim of the study was to identify key diagnostic features of PWS to facilitate early diagnosis. These include obstetric and newborn data, feeding difficulties requiring assisted feeding and the prevalence of reduced FMs. In addition, we looked for an association between prenatal and perinatal characteristics and genotype, to further develop previous work ,17,18.All patients with proven PWS attending the multidisciplinary clinic in Glasgow, Scotland, since its inception in 1991 until December 2015 were included. Data on genotype, BW, gestation, delivery method, obstetric symptoms, postnatal complications and timing of diagnosis were collected and analysed from three sources: a birth questionnaire completed by the parent(s); the subject’s case records; and maternal obstetric records, when available. It was decided, however, that the systematic recording of phenotypic features such as hair and eye colour, bifrontal narrowing, characteristic eyes, small hands and feet and weak cry should not be included within the scope of the study. This is because these data were recorded inconsistently, if at all, during the newborn period and by multiple observers and it was felt appropriate to confine this retrospective study to the collection of hard data.Endocrine problems were documented by detailing the number of patients undergoing GH stimulation testing either with insulin or arginine and the outcome, and defining GH deficiency as peak values <15 mU/L. The numbers of patients treated with GH injections as well as the numbers of patients diagnosed with either hypothyroidism or cortisol deficiency were also documented. in utero FM in their affected and unaffected children using a simple 5 point scoring system ranging from 1: much less than expected to 5: much more than expected.The questionnaire invited parents with more than one child to submit information on the BW, gestation and delivery method of their other children. Mothers were also asked to retrospectively estimate the degree ofth percentile and operative delivery were compared with healthy siblings and contemporary Scottish population data  and expressed in kilograms and standard deviations (SD). The incidences of preterm birth (gestation <37 completed weeks), LBW, defined as BW <2500 g, small for gestational age (SGA), defined as BW <10ion data .All analyses were done using Minitab (version 13.1) at a significance level of 5%. Data distribution was assessed for normality using Anderson-Darling test. Parametric data are presented as mean (± SD) and non-parametric data as median (range) or median (range) (interquartile range) Quantitative variables were compared using t-tests and analysis of variance or Kruskal-Wallis and Mann-Whitney U tests. Qualitative variables were compared using chi-squared or Fisher’s exact tests.Approval was initially granted by the Ethical Committee of the Royal Hospital for Sick Children in Glasgow in 2004 and data collection completed in 2011. Following the tragic loss of the lead investigator, Wendy Paterson in 2012, the study was relaunched in 2015 to update the data and to include more recent patients. This second phase of the study was approved by the National Health Service of the United Kingdom Research Ethics Authority (reference 15/NW/0900). In both study periods written informed consent was obtained from parents/guardians and subjects aged ≥16 years while children <16 years were invited to give assent.Ninety  subjects with PWS born between 1950 and 2015 (median 1994) were included in the study . ExcludiQuestionnaires were sent to 72 families and returned by 60 (83%). Reasons for questionnaires not being sent to 18 families included adoption/fostering and parents no longer being contactable. Comparative birth data were collected for 97 siblings .NDN (NECDIN) gene (OMIM 602117). NDN is important for normal hypothalamic development and it has been suggested that loss of NDN contributes to both the hypothalamic hypogonadism and neurological features of PWS  in 56 (62%); maternal disomy (mUPD15) in 26 (29%); translocation (chromosome 15-16) in one (1%); imprinting defect in two (2%) and four tested elsewhere 4%). One subject was initially reported to have no defect on standard PWS genetic screening but later Comparative Genomic Hybridization Array analysis revealed a deletion in paternal 15q11.2 incorporating the s of PWS . No defe%. One suData for all PWS subjects and a comparison between term and preterm infants are shown in Polyhydramnios was reported in 10/44 (22.7%) mothers. Breech presentation was recorded in 15/65 (23.1%) with one transverse lie. Mode of delivery was spontaneous vaginal in 38/86 subjects (44%), Caesarean section in 38/86 (44%), forceps-assisted delivery in six and ventouse extraction in three. FMs were reduced with a median score in PWS of 1 in the preterm and 2 in the term infants respectively . Decreased FM were present in 66/80 (82.5%) with normal movement in 14 (17.5%). Nasogastric feeding (NGF) was given to 75 (86%) infants with no assisted feeding in 12 and no data in three. Six of the infants who did not receive assisted feeding were diagnosed after four months of age. Median (range) duration of NGF in days was 30 (2-480) (n=71) and was longer in preterm (n=21) at 42 (2-231) than in term infants (n=49) at 25 (3-480).Data on testicular position was available in all but five of the 54 males. Forty-six (94%) of the 49 boys had cryptorchidism, which was bilateral in 40, unilateral in five, unspecified in one. Only three (5.5%) male patients had normally descended testes. Cryptorchidism was present in all but one of the 12 preterm males.This was documented as present in six girls at birth, not present  in a further six, and not documented otherwise.Analysis of patients born since 1 January 2000 showed that of 35 patients  the clinical diagnosis was made within the first week of life in 12 infants, between days 8 and 27 in 11, aged 4 weeks to 12 months in seven, and after 5 years in five. Among the 12 infants who were diagnosed clinically within a week of birth, sepsis was considered in two and neuromuscular disease in another. This study of 90 patients with PWS, drawn from a geographically defined area over a 25-year period, confirms and extends existing knowledge of the prenatal, perinatal and postnatal features of PWS, the dominant trait being presence of hypotonia. It should be noted that our study is confined to describing only those infants whose hypotonia was caused by PWS so that the prevalence of neonatal hypotonia in Scotland during the study period and hence the proportion of those hypotonic infants who actually had PWS is unknown.Intrauterine hypotonia causes polyhydramnios, malpresentation and reduced FMs leading to an increased prevalence of operative delivery. All these features were seen in this study, consistent with previous reports ,12,17,18We found increased incidence of LBW (23.6%) and SGA (36%), contrasting with 12.7% for SGA in the Scottish population  althoughThe prevalence of preterm birth (25.8%) in our cohort markedly exceeds the current Scottish figures of 7.3% . This inIn contrast to our expectations that features in common with prematurity might cause delay in the diagnosis of PWS, we found that affected premature infants tended to be diagnosed earlier than their term counterparts. This might be attributable to preterm infants receiving more clinical attention as well as having a longer stay in hospital.While most prenatal features of PWS, such as polyhydramnios and abnormal presentation are too non-specific to be of value, reduced FM is of importance in indicating the congenital nature of the hypotonia, prompting consideration of disorders such as PWS or neurological conditions such as SMA. Careful comparison of maternal retrospective evaluation of FMs in affected and unaffected infants shows a striking difference, with 82.5% reporting reduced movements in PWS infants. This is consistent with the figures of 85% and 88% reported in the studies of Miller et al  and GrosIn our study mothers who had only experienced one pregnancy with a PWS infant were less likely to score FM as low. However, scores given by uniparous mothers were still significantly lower than those for the unaffected babies of other mothers. Furthermore, preterm infants had a lower median score for FMs than term babies, but despite this term babies’ scores were still significantly lower compared with unaffected babies. The most constant feature of PWS at birth is hypotonia, Dudley and Muscatelli citing a 97% incidence . Gunay-ADuring the study period the median age at diagnosis of PWS appeared to improve with a fall from 9 to 5 days between 2000-2009 and 2010-2015. However it is important to note that the number of as yet undiagnosed children with PWS is currently unknown, and that the true median age at diagnosis may prove to be higher.Consistent with previous studies we have shown an increase in parental age with mUPD15 compared with del15q . We alsoEarly diagnosis in PWS is highly desirable. Therapies to counter muscular hypotonia, including GH therapy and physiotherapy training programmes, may be especially useful in the early years. During this period PWS infants and young children may have impaired motor development and skill acquisition which has been reported to affect further development of social abilities and cognitive function . GH prodGiven the typical features of PWS, particularly the findings of hypotonia and feeding difficulty at birth, it might be expected that diagnosis would be consistently early. The additional feature of cryptorchidism in almost all males is most helpful, especially when combined with hypotonia. By contrast, hypoplasia of the labia minora was documented in only a minority of female patients. This partly reflects the lack of systematic documentation during the study period, but also the limited diagnostic value of such a subjective feature. The finding of unexplained hypotonia at birth, especially if accompanied by undescended testes in boys, should immediately prompt a search for the phenotypic features of PWS. These include characteristic up-slanting eyes with narrow palpebral fissures , narrow nose, bi-frontal narrowing and sticky saliva resulting in the “string sign” , small hAlso, the distress caused to parents when diagnosis is delayed, even for a matter of days, should not be underestimated, especially when investigations for neurological disease, such as MRI and muscle biopsy are contemplated. The mother of patient 7 in The main limitation of our study was its retrospective nature. However, in including all genetically proven PWS patients who have attended our clinic up to 2015, our cohort size was maximised. In addition, a temporal analysis of the speed of clinical and molecular diagnosis at a dedicated, specialised PWS clinic was made possible. A further limitation of our study was the subjective nature of data obtained from the mothers, especially concerning the degree of FM in affected and unaffected children. It is reassuring to compare the subjective recall of our mothers which proved to be consistent with the radiologically measured degree of FM reported by Miller et al  and GrosIn our opinion the diagnosis of PWS can and should be made within days of birth provided that the hypotonia and the feeding difficulties, which will invariably be evident to the mother and midwife, are appreciated. Subsequent rapid genetic confirmation of PWS is essential since previous work in our centre showed clinical misdiagnosis in 11/31 patients at the time our multi-disciplinary clinic was established . In the We believe that, although features such as preterm birth, LBW, SGA, operative delivery and malpresentation are not specific to PWS, their combined presence in the context of hypotonia and feeding difficulties should evoke PWS. Indeed it has been suggested that when a combination of polyhydramnios, SGA and asymmetric intrauterine growth co-exist in the absence of morphological abnormalities, prenatal methylation studies for PWS should be performed .


Previously, we have published univariate analyses on a cohort of all singleton, very preterm infants (N = 101) born between 23 and 29 weeks of gestation during January 01, 1998 to June 30, 2003 at The Aga Khan University Hospital in Karachi, Pakistan. Our main objective was to extend these analyses to multivariate logistic regression models and report odds ratios (ORs) for univariate and multivariate analyses. All variables in univariate were included in multivariate models.The survival incidences were 0% at 23, 16.7% at 24, 40.0% at 25, 30.0% at 26, 33.3% at 27, 68.8% at 28 and 83.9% at 29 weeks of gestation. In univariate analyses, gestational age, birth-weight and mode of delivery  were statistically significant predictors of survival (P ≤ 0.001 each). Other variables that also included antenatal steroids did not achieve significance. However, in complete-case multivariate analyses, only gestational age (per week) was associated with survival ; birth-weight (per 100 g) and C-section were not associated-1.2, 0.88–1.6, P = 0.26 and 2.4, 0.48–12.2, P = 0.28. Antenatal steroid use, maternal age, year of birth, parity, history of preterm delivery, hemoglobin levels, complications and time of birth remained not associated. Very preterm births are considered a serious, life-threatening medical emergency associated with innumerable complications and difficult decision making to prolong survival . DespiteAppropriate statistics are necessary for the decision making process of the obstetrician and to counsel parents and guardians regarding the probability of survival given a particular gestational age. Identifying predictors of survival will assist in dividing infants into high risk categories. Data on complications will enable obstetrician to know what to anticipate after delivery and prepare for interventions to ameliorate or treat these complications. There is paucity of data from Pakistan, including our hospital, on survival and predictors dictating survival of very preterm births despite its large burden in developing countries. Previously, we have published analyses on a cohort of all singleton very preterm infants born between 23 and 29 weeks of gestation during January 01, 1998 to June 30, 2003 at The Aga Khan University Hospital in Karachi, Pakistan . We condThe study base comprised of singleton very preterm infants born during the defined period above at this tertiary care center. The antenatal, perinatal and postnatal data were collected through medical records review of these infants and their mothers. The hospital course and complications of both infants and mothers were studied. Gestational age was determined from the mother’s first day of last menstrual period and early first trimester ultrasound scan, where available.We conducted both univariate and multivariate logistic regression analyses for different explanatory (independent) variables with survival as outcome. Univariate analyses were confirmed by Chi-square or Fisher’s exact test. All potential predictor variables were included in multivariate models. P < 0.05 was considered statistically significant and P = 0.05–0.10 was considered associated with a trend only. STATA 14.0 software was used for statistical analyses.101 very preterm infants were born during the defined study period. The mean maternal age was 28.1 ± 5.1 years and mean hemoglobin (Hb) of 11.0 ± 1.4 g/dL (n = 78/101) at the time of delivery; 41.6% of mothers had Hb ≤ 11 g/dL i.e. were anemic. 26 mothers had chronic hypertension, pregnancy-induced hypertension/pre-eclampsia or eclampsia and 10 mothers had pre-existing or gestational diabetes. The cause of preterm delivery was identified in 97 mothers and was preterm premature rupture of membranes , followed by pre-eclampsia/eclampsia 17/97 (17.5%), antepartum hemorrhage 12/97 (12.4%), fetal distress/oligohydramnios/intra-uterine growth restriction 6/97 (6.2%), preterm labor 5/97 (5.2%), cervical incompetence/cerclage 4/97 (4.1%), hepatic failure/HELLP syndrome 3/97 (3.1%), maternal cancer 3/97 (3.1%), per-vaginal bleed 2/97 (2.1%), hydrocephalus/myelomeningocele 2/97 (2.1%), septate/fibroid uterus 2/97 (2.1%) and cord prolapse 1/97 (1.0%).The mean birth weight of these infants was 1042.1 ± 304.8 g (range = 400–1750). 53 (52.5%) were males. 54/101 (53.5%) were born via cesarean section and 47/101 (46.5%) had vaginal delivery. The presentation at delivery was cephalic in more than half of infants . 76/101 (75.3%) of infants required intubation. The median Apgar score was 5 at 1 min and 7 at 5 min. Other detailed characteristics of these infants have been published elsewhere [In univariate analyses, gestational age  1.4–2.9); birth weight  and mode of delivery  were statistically significant predictors of survival (P ≤ 0.001 each)  as in univariate analysis showing that the effect of gestational age was partially mediated through birthweight. Similarly, removing gestational age from the model also made birthweight and abdominal delivery statistically significant  and  indicating that gestational age may be a confounder.The medical records are designed for clinical and not research purposes so there may have been misclassification in reporting data, particularly on antenatal steroids. It may have also been possible that the mother may have been given steroids but not written in the medical records by the intern/resident/obstetrician. We also did not collect data on the proportion of pregnancies where gestational age was confirmed by early ultrasound scan but records according to gestational age were obtained through ICD code and these were the most valid estimates available. The number of survival events relative to the number of predictors were few so the study could have been underpowered but the multivariate models still managed to converge. The data is from the last decade so the survival incidences may have changed over time due to advancement in pediatric/neonatal intensive care units at this institute.In conclusion, gestational age, birth weight and C-section  were statistically significant predictors of infant survival in univariate analyses. However, gestational age was the only variable that remained associated with survival in multivariate analyses ; while birth-weight and C-section became non-significant.


Background: Bronchogenic cysts are congenital malformations from abnormal budding of embryonic foregut and tracheobronchial tree. We present a case of bronchogenic cyst with severe back pain, epigastric distress and refractory nausea and vomiting.  Case Presentation: A 44-year-old Hispanic female presented with a 3-week history of recurrent sharp interscapular pain radiating to epigastrium with refractory nausea and vomiting. She underwent cholecystectomy 2-years ago. Computed tomography (CT) abdomen at that time showed a subcarinal mass measuring 5.4 X 5.0 cm. Subsequent endoscopic ultrasound diagnosed it as a bronchogenic cyst. Endobronchial ultrasound (EBUS) guided aspiration resulted in incomplete drainage and she was discharged after partial improvement. Current physical examination showed tachycardia and tachypnea with labs showing leukocytosis, elevated inflammatory markers, and hypokalemic metabolic alkalosis. CT chest showed an increased size of the bronchogenic cyst (9.64 X 7.7 cm) suggestive of possible partial cyst rupture or infected cyst. X-ray esophagram ruled out esophageal compression or contrast extravasation. Patient’s symptoms were refractory to conservative management. The patient ultimately underwent right thoracotomy with cyst excision that resulted in complete resolution of symptoms.Conclusion: Bronchogenic cysts are the most common primary cysts of mediastinum with the prevalence of 6%. The most common symptoms are chest pain, dyspnea, cough, and stridor. Diagnosis is made by chest X-Ray and CT chest. Magnetic resonance imaging chest and EBUS are more sensitive and specific. Symptomatic cysts should be resected unless surgical risks are high. Asymptomatic cysts in younger patients should be removed due to low surgical risk and potential late complications. Watchful waiting has been recommended for asymptomatic adults or high-risk patients. This case presents mediastinal bronchogenic cyst as a cause of back, nausea and refractory vomiting. Immediate surgical excision in such cases should be attempted, which will lead to resolution of symptoms and avoidance of complications. They can present as a mediastinal mass that may enlarge and cause local compression. They are the most common primary cysts of the mediastinum with a prevalence of 6%2. Approximately 79% of cysts are located in the middle mediastinum, 17% in posterior mediastinum and 3% in the anterior mediastinum3.Bronchogenic cysts are congenital malformations of the bronchial tree. They result from the anomalous development of ventral foregut and tracheobronchial tree3.Almost 75% of bronchogenic cysts are asymptomatic. Symptoms vary with age at presentation and with size and location of the cyst. The common symptoms include chest pain (22%), dyspnea (12%), cough (7%), stridor (7%) and respiratory compromise due to tracheal/bronchial compression (10%). Unusual manifestations are dysphagia (1%), pneumothorax (1%), and superior vena cava syndrome (1%)4. MRI chest can provide additional information about the consistency and nature of the cyst depending upon the presence of proteinous contents in the fluid. In general, bronchogenic cyst appears hypo-intense on T1-weighed images and hyper-intense on T2-weighed images5. Endoscopic ultrasound (EUS) is a relatively invasive procedure for the diagnosis of the bronchogenic cyst.Diagnosis is made by chest X-Ray and computed tomography (CT) chest although magnetic resonance imaging (MRI) chest and endobronchial ultrasound are highly sensitive and specific6. Thoracotomy is performed for difficult cases. Asymptomatic cysts in younger patients should be removed due to low surgical risk and potential late complications such as infection, hemorrhage or neoplasia. Watchful waiting has been recommended for asymptomatic adults or high-risk patients. Percutaneous drainage or alcohol ablation has been performed in selected cases4. We present a case of a mediastinal bronchogenic cyst in a 44-year-old female presenting in the form of severe back pain, epigastric distress and nausea.Treatment options depend on patient’s age and symptoms. Symptomatic bronchogenic cyst are managed surgically with resection, Endobronchial ultrasound (EBUS) guided aspiration, and video-assisted thoracoscopic surgery being a minimally invasive procedureA 44-year-old Hispanic female presented with a three-week history of recurrent sharp interscapular pain radiating to the mid-sternal and epigastric region associated with refractory nausea and vomiting. She underwent cholecystectomy for intermittent epigastric pain two years ago. CT abdomen at that time showed a subcarinal mass measuring 5.4 X 5.0 cm . Subsequ3/uL , elevated inflammatory markers , and hypokalemic metabolic alkalosis. Electrocardiogram showed non-specific T wave changes. Chest X-ray showed right posterior mediastinal mass  and respiratory rate of 20/min . Initial labs showed white cell count of 10.58X10al mass .CT chest showed an increase in the size of the bronchogenic cyst (9.64 X 7.7 cm) with small right pleural effusion .The X-ray and CT findings were consistent with partial cyst rupture or an infected cyst. X-ray esophagogram ruled out esophageal compression or contrast extravasation. The patient’s symptoms were refractory to conservative analgesic and antiemetic measure like Dilaudid (hydromorphone) 1 mg IV every 3 hourly and Zofran (Ondansetron) 4 mg IV every 4 hourly for pain and nausea/vomiting respectively. Cardiothoracic surgery was consulted and the patient underwent right thoracotomy and surgical cyst excision. Cyst pathology was consistent with severe inflammatory changes. Within 24–48 hours after the surgery, the resolution in the patient’s symptoms were noted in terms of decrease in need of pain and nausea medications. Repeated labs showed resolution of leukocytosis.1. They are part of the bronchopulmonary foregut malformations. They are more commonly found in the mediastinum in the paratracheal and subcarinal regions. Less commonly they are found in the lung parenchyma.Bronchogenic cysts are the rare benign congenital malformation resulting from the anomalous budding of ventral foregut and tracheobronchial tree7. Most common presentation in adult patients includes chest pain, cough, dyspnea and dysphagia8.Bronchogenic cyst may present with unusual symptoms posing a diagnostic challenge. Signs and symptoms of bronchogenic cyst mainly depend upon its location, size, and compression of surrounding structures like esophagus, trachea, and bronchus9.Our patient presented with unusual symptoms of severe backache, epigastric discomfort, refractory nausea, and vomiting. It is believed that the back pain is caused by stretching of the nerves supplying the parietal pleura while the epigastric distress is caused by the stimulation of the vagal nerveIn our case, repeat CT chest confirmed an increase in the size of a bronchogenic cyst with small right pleural effusion. Considering that approximately 10% of the patients develop respiratory problems due to tracheal or bronchial compression, we performed X-ray esophagogram and ruled out esophageal compression or contrast extravasation.10.At present management of symptomatic bronchogenic cyst is surgical as discussed. Management of asymptomatic cyst is controversial. It has been suggested that as most of the cysts eventually cause some symptoms or serious complications like respiratory distress from airway compression, infection and airway fistulae, surgical resection in asymptomatic patients is recommended. Also, postoperative surgical complications are more common in patients with symptomatic cysts as compared to asymptomatic cysts further implying the benefits of surgical resection of asymptomatic cystsThis case highlights the importance of recognizing bronchogenic cyst as a cause of severe back pain, refractory nausea, and vomiting. Back pain is caused by stretching of nerves supplying the parietal pleura; while nausea is caused by stimulation of vagus nerve. Prompt surgical excision can lead to complete symptom resolution and avoidance of future complications.Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.All data underlying the results are available as part of the article and no additional source data are required. This is a case report of bronchogenic cyst. It highlights the importance of imaging, including computed tomography. The article is well-written. One minor suggestion is to consider adjusting the position of the arrows in Figures 1 and 3 as it points at the right lung rather than the cyst - instead an asterix over the cyst can also be practical without hiding parts of the figures.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Bronchogenic cyst diagnosis on EBUS and complication of Infection. Needs to alert that Needling with EBUS needle is a recognised complication and some practitioners caution against using EBUS needle if diagnosis can be secured by other means but sometime if there is uncertainty about the diagnosis one has to do the EBUS needling. One has to understand the potential chance of recurrence in absence of complete removal of cyst wall after surgery and possibly need mentioning. On the whole the article is well written.1 similar article we presented: Mogal et alI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Median (IQR) maternal concentrations in α1-acid glycoprotein and C-reactive protein in the first and third trimesters were 0.65 (0.53–0.76) and 0.40 (0.33–0.50) g/l, and 0.56 (0.25–1.54) and 1.07 (0.43–2.32) mg/l, respectively. α1-acid glycoprotein was inversely associated with birth size: weight, length, head circumference and chest circumference were lower by 116 g (P = 2.3 × 10−6), and 0.45 (P = 3.1 × 10−5), 0.18 (P = 0.0191) and 0.48 (P = 1.7 × 10−7) cm, respectively, per 50% increase in α1-acid glycoprotein averaged across both trimesters. Adjustment for maternal age, parity, gestational age, nutritional and socio-economic status and daily micronutrient supplementation failed to alter any association. Serum C-reactive protein concentration was largely unassociated with newborn size. In rural Nepal, birth size was inversely associated with low-grade, chronic inflammation during pregnancy as indicated by serum α1-acid glycoprotein.Maternal systemic inflammation during pregnancy may restrict embryo−fetal growth, but the extent of this effect remains poorly established in undernourished populations. In a cohort of 653 maternal−newborn dyads participating in a multi-armed, micronutrient supplementation trial in southern Nepal, we investigated associations between maternal inflammation, assessed by serum  Small birth size is a major risk factor for infant morbidity and mortality in low- and middle-income countries (LMICs). More than 20 million babies are born with low birth weight  each year . The higα1-acid glycoprotein (AGP) and C-reactive protein (CRP). Both are acute-phase proteins whose concentrations reliably increase during infection and inflammation: CRP spikes in the early phase of infection while AGP rises more slowly and remains elevated during convalescence [Preterm birth, SGA and stillbirth in LMICs have been strongly associated with antenatal infection –7. Yet, lescence . They arlescence . Serum Clescence . Insuffilescence . HoweverIn 1999–2001, we conducted a five-arm, cluster-randomised, double-masked, controlled trial of daily antenatal micronutrient supplementation, starting in the first trimester, to improve birth outcomes and infant survival , 13. As The Nepal Nutritional Intervention Project-Sarlahi-3 (NNIPS-3) study was the third trial conducted by the NNIPS Project in the rural southeast plains District of Sarlahi in Nepal from 1999 to 2001, described previously , 15. BriIn a subset of 81 wards balanced across the study area, consenting mothers participated in a substudy involving biochemical assessment at each trimester visit . As presAnthropometric measurements were obtained as soon as possible after birth, and within 72 h; the median interval was 10.8 h after birth. Birth weight was measured to the nearest 2 g using a digital scale . Recumbent length was determined to the nearest 0.1 cm on a length board . Head and chest circumference were measured to the nearest 0.1 cm using an adult middle upper arm circumference insertion tape . For all measurements except weight, the median of three values was used in the statistical analyses.s.d.) gestational ages at the first- and third trimester blood draws were 9.9 (4.1) and 32.3 (3.9) weeks, respectively. Venous blood was collected into 7-ml trace metal-free vacuum test tubes  at home by trained phlebotomists. The blood was kept on a frozen cold pack, and brought to the project laboratory for centrifugation at 750 × g for 20 min to separate the serum. Aliquots of serum were stored in liquid nitrogen tanks in trace element-free cryotubes  and shipped to the Johns Hopkins Bloomberg School of Public Health in Baltimore, MD, where they were stored at −80 °C until analysis. AGP, expressed in g/l, was measured with a radial immunodiffusion assay with commercially available kits , and CRP, in mg/l, was measured by ELISA with a commercial kit from ADI . Retinol, zinc and transferrin receptor were also measured, as previously described [The mean  were examined using generalised estimating equations. We specified the identity link function for Gaussian distribution of dependent variables and used an exchangeable correlation structure to account for the cluster effect associated with sector vs. individual randomisation in the antenatal supplementation. Because the AGP and CRP concentrations were skewed and a 1 g/l change in AGP is physiologically unlikely, we modelled the relationship between inflammatory markers and birth size as log-linear. We used log2 transformed AGP and CRP concentrations as independent variables, allowing birth size outcomes to be interpreted as differences per 50% increase in concentrations of AGP and CRP. For example, the mean difference in birth weight is interpreted as ‘x’ g per 50% increase in serum AGP concentration, whether, for example, the difference in AGP is 0.60−0.90 g/l or 1.0−1.5 g/l. We included maternal age, parity, mid-upper arm circumference (MUAC), serum retinol, zinc and transferrin receptor at baseline, literacy, household SES (radio ownership and caste), season at time of each blood draw, gestational age at birth to distinguish birth size attributable to fetal growth restriction vs. due to duration of gestation, and antenatal micronutrient supplementation arm (n = 5) in the fully adjusted models to control for possible confounding factors. Data were analysed using SAS and the R Environment for Statistical Computing . The dataset of maternal and household characteristics and infant birth outcomes reported in this study is available in a Supplementary Table.Distributions of birth measurements and serum inflammation markers were evaluated for normality. Maternal baseline characteristics were compared between women included and women excluded in the study using chi-square tests. Gestational age and anthropometric measures of size at birth were compared between male and female newborns using two-sample Inflammation was minimal in the first trimester of pregnancy, reflected by median (IQR) serum AGP and CRP concentrations of 0.65  g/l and 0.56  mg/l, respectively . Only 5.s.d.) gestational age at birth was 39.1 (2.9) weeks (P = 0.019).Mean (9) weeks , with 14The association between maternal AGP and newborn size metrics are summarised in The largest decrements in birth size were observed with an elevated mean serum AGP concentration across both trimesters, whereby a 50% increase was associated with an unadjusted 116 g decrease in birth weight , a 0.45 cm  decrease in length, a 0.18 cm  decrease in head circumference and a 0.48 cm  decrease in chest circumference.First-trimester serum CRP was not associated with any newborn size dimension . During Foetal growth restriction is a profound public health problem, particularly in South Asia where it affects half of all live born infants and contributes to excessive infant and childhood morbidity, mortality and developmental delay , 18. AmoThe levels of AGP in our study are similar to those previously noted in studies of pregnant women –22, inclOur results, which reveal a smaller birth size correlated with elevated AGP during pregnancy, strengthen the hypothesis that this protein is involved in regulating complex immune interactions between mother and foetus during pregnancy. In rats, AGP has been shown to be concentrated in the decidua capsularis of the placenta in early pregnancy, and may be involved in controlling immune interactions during implantation , 31. In CRP is more commonly studied, especially in relation to cardiovascular disease in the developed world, but also in pregnancy. During pregnancy serum CRP becomes elevated as early as the 4th week , and cann = 99) than CRP (n = 81) [Our study is distinct in the literature because two markers of inflammation were measured in both first and third trimesters and assessed for their potential influence on FGR, a burden affecting more than 40% of live born infants in South Asia , which mA limitation of the study was that we had complete first- and third trimester biomarker and infant size data from only 653 (48%) of the original 1361 women. Missing values were 95% due to miscarriage, women transferring to their parental home for third trimester care, failure to measure AGP or CRP, newborn anthropometry obtained after 36 h, perinatal death or refusal . Women wIn summary, in this rural South Asia population, we revealed a strong inverse association between higher maternal serum AGP and growth restricted, small newborn size. Little association was observed with CRP. In similar populations, assessing maternal AGP during pregnancy may be an important, predictive biomarker of impaired intrauterine growth.


This study aimed to investigate the short-term effect of exposure to air pollutants on risk preterm birth during 2014–2016 in Ningbo, China.Exposure to air pollutants has been related to preterm birth, but little evidence can be available for PM2.5, PM10, SO2, NO2, O3 and CO) in Ningbo during 2014–2016. A General Additive Model extend Poisson regression was used to evaluate the relationship between preterm birth and air pollution with adjustment for time-trend, meteorological factors and day of the week (DOW). We also conducted a subgroup analysis by season and age.We conducted a time-series study to evaluate the associations between daily preterm birth and major air pollutants  for an increase of IQR of air pollutant concentrations were 4.84  for PM2.5, 3.56  for PM10, 3.65  for SO2, 6.49  for NO2, − 0.90  for O3, and 3.36  for CO. Sensitivity analyses by exclusion of maternal age < 18 or > 35 years did not materially alter our results.In this study, a total of 37,389 birth occurred between 2014 and 2016 from the Electronic Medical Records System of Ningbo Women and Children’s Hospital, of which 5428 were verified as preterm birth. The single pollutant model suggested that lag effect of PM2.5, PM10, SO2, NO2) are positively associated with risk of preterm birth in Ningbo, China.This study indicates that short-term exposure to air pollutants (including PMThe online version of this article (10.1186/s12887-018-1282-9) contains supplementary material, which is available to authorized users. Preterm birth, defined as less than 37 weeks of gestations, is the second largest direct cause of child deaths among children less than 5 years . There aThere is increasing evidence that exposure to ambient air pollutants is associated with preterm birth –9. A sysIn this study, we used birth data during 2014–2016 in Ningbo, Zhejiang Province, China, and conducted a time-series study to investigate the association between exposure to ambient air pollutants and risk of preterm birth.n = 2305), non-live birth records (n = 230), twin pregnancy and multiple pregnancies (n = 1274) and birth records with extreme gestational age (< 20 weeks) (n = 160) were excluded from this study. Finally, a total of 37,389 eligible births were included in our study.This study was conducted in Ningbo, which located in the southeast of China and composed of six districts and has a metropolitan area population of 7.8 million. We obtained anonymous births information from the Electronic Medical Records System (EMRS) in Ningbo Women and Children’s Hospital  from 2014 January 1st to 2016 December 31st. A total of 40,968 birth records were included in the EMRS. Duplicated records (Preterm birth was defined as a singleton live-birth delivery before 37 completed weeks of gestation(< 259 days) . GestatiDaily meteorological data including mean temperature (degree Celsius) and relative humidity(percent) were collected from the Ningbo Meteorological Bureau. Daily values for temperature and relative humidity were calculated by averaging 24 hourly monitoring data.2.5) and 10 μm (PM10)), sulfur dioxide (SO2), nitrogen dioxide (NO2), Ozone (O3) and carbon monoxide (CO) during 2014 to 2016, were collected from the Environmental Monitoring Center of Ningbo City (http://www.nbemc.net/aqi/home/index.aspx). The daily concentrations of each pollutant were averaged from the available monitored results of eight stations which were monitored by the China National Quality Control. The eight stations were “Shi Jian Ce Zhong Xin”, “Tai Gu Xiao Xue”, “San Jiang Zhong Xue”, “Wan Li Xue Yuan”, “Huan Bao Da Lou”, “Long Sai Yi Yuan”, “Qian HuShui Chang” and “Wan Li Guo Ji”. The distribution of these 8 monitor stations in Ningbo was shown in Additional file 3) except milligrams per cubic meter (mg/m3) for CO.Daily mean concentrations of air pollutants, including particulate matter  extended Poisson regression  to exploWe firstly built a basic model based on the daily number of preterm births without air pollution variables. To control for non-linear trend between preterm birth and time or weather conditions, we added time-dependent variables including calendar time, temperature and relative humidity via natural spline functions. Degree of freedom (df) for natural spline functions were adopted by generalized cross-validation (GCV) scores . Day of t represents the day of the observation; Yt represents daily number of preterm births, E(Yt) stands for the expected values for the number of premature births on day t. α is residual, β is the regression coefficient, and Zt is the average concentration of air pollutants on the observed day or over several days. S  is the calendar time smoothing spline function, S  is the daily temperature smoothing spline function, S  is the daily relative humidity smoothing spline function, and DOWt is a dummy variable with Monday as a reference. The corresponding degree of freedom for time, temperature and relative humidity in the spline function were 7, 7 and4 in the final model.In this formula, We investigated the acute effect on the risk of preterm birth by adding the concentration of each pollutant into the model for a 1-day exposure window with lag-time from 1 to 6 days before birth. Cumulative effect was also calculated by including the lag moving average (Avg1-Avg6) into the model. Relative risks (RRs) and 95% confident intervals (CIs) were calculated by the regression coefficient β of air pollutants. And we reported excess risks (ERs) and 95% CIs that represented a percent increase in daily preterm birth risk per IQR increase in air pollutant concentrations. ER was calculated as follows: ER = (RR ‐ 1) × 100%. We also examine the exposure-response curve by using a natural spline function for certain pollutants in the GAM model. Goodness of fit of the model was assessed by using Akaike Information Criterion (AIC). The best df for each air pollutant was indicated by the lowest AIC value in the GAM model.Sensitivity analysis by exclusion of maternal age < 18 or > 35 years in preterm birth records was conducted to evaluate the robustness of our results, because women aged < 18 or > 35 years had a higher possibility to develop a preterm birth . And we Where Q1 and Q2 are the adjusted estimates from two strata (e.g. cold and warm period), and SE1, SE2 are the corresponding standard errors .P < 0.05 was considered statistically significant. All statistical analyses were conducted by using R 3.3.1.Continuous variables with normal distribution were presented as mean ± standard deviation (SD), and non-normal variables were reported as median ± interquartile range (IQR). Spearman’s correlation coefficient was used for the correlations between ambient air pollutants and meteorological factors. 2.5, PM10, SO2, NO2, O3 and CO during 2014 to 2016 were 43.73 μg/m3, 69.69 μg/m3, 16.56 μg/m3, 40.50 μg/m3, 64.33 μg/m3, 1.06 mg/m3, respectively. Concentrations of air pollutants were higher in the cold period than those in the warm period except for O3. Daily mean ambient temperature and relative humidity were 17.4 °C and 76.8%.The descriptive results of air pollution and meteorological data are shown in Table A total of 5428 preterm births were identified among the total valid births of 37,159. Overall prevalence of preterm birth was 14.61%. The number of births in women with the maternal age < 18 or > 35 years was 3452, among which 714 births were diagnosed as preterm birth (20.68%). And the corresponding prevalence of preterm birth during cold and warm periods was 14.63% and 14.58%, respectively.2.5 was positively associated with SO2, NO2, PM10 and CO, but negatively associated with O3. The strong correlation was observed for PM2.5 and NO2 . And two weather variables were negatively related to SO2, NO2, PM2.5, PM10 and CO, but positively related to Ozone.Table 2.5, PM10 and NO2, Lag6 for SO2 and Lag 4 for CO. No significant associations were observed for Ozone and preterm births. The associations between cumulative concentrations and preterm births at different lag days (Avg1-Avg6) are shown in the Additional file 10, SO2 and preterm births.Fig 2.5, PM10, SO2, NO2 and preterm birth tended to be attenuated after we restricted the analysis in women with the maternal age of 18–35 years, but the associations still remained significant. In season-specific analyses, the adverse effect of PM2.5, SO2 and NO2 on preterm birth were stronger in cold period and attenuated in warm period as compared with the whole year. Similar results were observed for the effect of four air pollutants  in cold and warm periods when maternal age was restricted from 18 to 35 years. No significant associations were observed for Ozone. No significant interaction effect was observed for season and maternal age on the association of short-term exposure to air pollution and preterm birth  for PM2.5, 3.56  for PM10, 3.65  for SO2, and 6.49  for NO2, respectively.In this study, we performed an ecological time-series study to examine the short-term effect of air pollutants on preterm birth during 2014–2016 in Ningbo. We found that PM2.5, PM10) were consistent with several previous studies [10 on preterm-birth risk. An updated meta-analysis 10 of 23 studies has showed an increased risk with an IQR increase in PM10 exposure during pregnancy . Limited studies in China can be available to evaluate the effect of PM exposure on preterm birth. A birth cohort conducted in Lanzhou, China between 2010 and 2012 [10 could increase the risk of preterm birth, and another prospective birth cohort in China confirmed the adverse effect on preterm birth risk of PM2.5 exposure [2.5, PM10 exposure and preterm birth, but the RRs were relatively lower. The discrepancies could be explained by the different design, population and particulate matter level.The observed effect of particulate matter . Our study also had several limitations. Average data from fixed monitoring locations were used to represent air pollution exposure, which could affect our results. And ecological study design could underestimate the effect of air pollution when monitoring data was used to represent individual exposure level [Our study had several important strengths. Firstly, we used time-series Generalized Additive Model extended Poisson regression to adjust for the confounding effects of long-time trends, meteorological factors and season. In addition, our study provided evidence for the effect of previously less well-studied air pollutants  and risk of preterm birth in Ningbo. Our results suggested that short-term exposure to four pollutants  were associated with preterm birth risk in Ningbo. These findings might have important implications in preventing preterm birth while further studies are still needed.In summary, this study examined the association between concentrations of air pollutants Additional file 2:Table S1. Association between cumulative air pollution concentrations and risk of preterm birth. (DOCX 18 kb)Additional file 3:Table S2. Excess risks (ERs) and 95% confidence intervals of preterm birth per IQR increment in air pollutant concentrations stratified by season and maternal age in Ningbo, China. (DOCX 36 kb)Additional file 4:Table S3. Difference of estimates and 95% confidence intervals (95% CIs) of air pollutants on risk of preterm birth between subgroups. (DOCX 20 kb)


Elucidating developmental trajectories of white matter (WM) microstructure is critically important for understanding normal development and regional vulnerabilities in several brain disorders. Diffusion Weighted Imaging (DWI) is currently the method of choice for in-vivo white matter assessment. A majority of neonatal studies use the standard Diffusion Tensor Imaging (DTI) model although more advanced models such as the Neurite Orientation Dispersion and Density Imaging (NODDI) model and the Gaussian Mixture Model (GMM) have been used in adult population. In this study, we compare the ability of these three diffusion models to detect regional white matter maturation in typically developing control (TDC) neonates and regional abnormalities in neonates with congenital heart disease (CHD).iso), and the intracellular volume fraction (Vic) derived from the NODDI model. Further, we used two novel measures from a non-parametric GMM, namely the Return-to-Origin Probability (RTOP) and Return-to-Axis Probability (RTAP), which are sensitive to axonal/cellular volume and density respectively. Using atlas-based registration, 22 white matter regions  were selected and the mean value of all 7 measures were calculated in each region. These values were used as dependent variables, with GW as the independent variable in a linear regression model. Finally, we compared CHD and TDC groups on these measures in each ROI after removing age-related trends from both the groups.Multiple b-value diffusion Magnetic Resonance Imaging (dMRI) data were acquired from TDC neonates (N = 16) at 38 to 47 gestational weeks (GW) and CHD neonates (N = 19) aged 37 weeks to 41 weeks. Measures calculated from the diffusion signal included not only Mean Diffusivity (MD) and Fractional Anisotropy (FA) derived from the standard DTI model, but also three advanced diffusion measures, namely, the fiber Orientation Dispersion Index (ODI), the isotropic volume fraction , the Inferior Fronto-occipital Fasciculus (IFOF), and the Superior Longitudinal Fasciculus (SLF). Overall, the group comparison between CHD and TDC revealed lower FA, Vic, RTAP, and RTOP for CHD bilaterally in the a) UF, b) Corpus Callosum (CC), and c) Superior Fronto-Occipital Fasciculus (SFOF). Moreover, FA was lower for CHD in the a) left SLF, b) bilateral Anterior Corona Radiata (ACR) and left Retrolenticular part of the Internal Capsule (RIC). Vic was also lower for CHD in the left Posterior Limb of the Internal Capsule (PLIC). ODI was higher for CHD in the left CC. RTAP was lower for CHD in the left IFOF, while RTOP was lower in CHD in the: a) left ACR, b) left IFOF and c) right Anterior Limb of the Internal Capsule (ALIC).Linear analysis in the TDC population revealed significant correlations with GW (age) in 12 projection pathways for MD, VIn this study, all three methods revealed the expected changes in the WM regions during the early postnatal weeks; however, GMM outperformed DTI and NODDI as it showed significantly larger effect sizes while detecting differences between the TDC and CHD neonates. Future studies based on a larger sample are needed to confirm these results and to explore clinical correlates. •Determine developmental trajectories of several white matter regions in typically developing neonates.•Compare white matter abnormalities in brain regions between congenital heart disease neonates and typically developing controls.•Compare DTI, NODDI and Gaussian mixture model (GMM) and found GMM to be most sensitive to tissue abnormalities. WM is tSimilarly, individuals with Congenital Heart Disease (CHD) make up a population that has been associated with a history of neurologic and neuro-developmental impairments such as motor and visuospatial skills, as well as cognitive impairments such as working memory, attention, and language . MoreoveWhile DTI  is a claTo overcome the limitations of DTI, several compartmental models of diffusion have been proposed. For example, the NODDI  model atAn alternative approach to DTI and NODDI is the Gaussian Mixture Model (GMM). Unlike DTI, the GMM does not assume Gaussian diffusion and, unlike NODDI, the GMM is independent of tissue models, i.e., it does not make any assumption about the number of compartments or their diffusivities. Instead, the GMM estimates the Ensemble Average diffusion Propagator (EAP), which describes the probability distribution of the displacement of water molecules within an experimentally set diffusion time . The EAPIn this paper, we explore the potential of both NODDI and the GMM to characterize regional WM development in TDC neonates as well as to detect abnormalities in specific WM regions in neonates with CHD. We also compare these novel measures with the standard DTI based measure of fractional anisotropy (FA) and mean diffusivity (MD). Thus, the present study also aims to compare different dMRI models to determine: 1) the sensitivity of different diffusion measures in their ability to detect age-related  regional WM changes in TDC neonates, and 2) which measures detect regional WM differences in CHD compared to TDC neonates.22). Acquisition parameters were: TR = 3700 ms, TE = 104 ms, flip angle = 90°, 2 mm isotropic spatial resolution, with two b-value shells at b = {1000, 2000} s/mm2 each shell having 30 gradient directions, with a total acquisition time of about 6 min.The cross-sectional study included 16 Typically Developing Controls (TDC)  and 19 with Congenital Heart Disease (CHD) . All the CHD and TDC neonates were screened at the Boston Children's Hospital and have birth gestational week (GW) greater than 36 weeks. The TDC cohort included typically developing neonates recruited from a well baby nursery with uneventful deliveries, including Apgar scores greater than 8 at 5 minutes and no clinical signs or symptoms concerning any brain disorder. The CHD cohort included three different subtypes of CHD: 6 neonates with transposition of great arteries (TGA), 10 single ventricle physiology, and 3 bi-ventricle physiology. The details of the specific cardiac anomalies are summarized in 2.1All DWI images first went through a semi-automatic quality control pipeline (in-house MATLAB script) that detects signal intensity drop in each slice by measuring the divergence of signal intensity between adjacent slices. Any dMRI volume with significant motion artifact or signal loss was manually inspected and removed. Next, we performed head motion and eddy current correction for each data set using the FSL FLIRT software  where th2.2http://www.slicer.org), using weighted linear least squares fitting to obtain the eigenvectors and eigenvalues, which were then used to calculate Fractional Anisotropy (FA) and Mean Diffusivity (MD).Diffusion tensors were estimated at each voxel in Slicer Version 4 (2.3ic) of the NODDI model represents diffusion within the axons and cells. The isotropic compartment (Viso) estimates the volume fraction of freely diffusing extracellular water such as cerebrospinal fluid. The normalized signal, A, in the NODDI model is given by the following equation:Aic is the signal contribution from the intra-cellular compartment and Aec is the signal due to diffusion in the extra-cellular space. We should note that the NODDI model assumes an a-priori fixed diffusion coefficient, 1.7 × 10−3 mm2/ s, along the principal diffusion direction for both the intra- and extra-cellular compartments. We used the default fixed parameters while estimating all the measures  for the NODDI model using the MATLAB software that is publicly available .The GMM estimates the 3-dimensional probability distribution of the displacement of water molecules in a given experimental time. Analytical expressions for computing measures such as RTOP and RTAP were proposed in 2.53 to match the resolution of JHNA. Advanced Normalization Tools (ANTs)  defined by the JHU atlas for each individual subject.To analyze the microstructure in different brain regions, we used the John Hopkins Neonate Atlas (JHNA)  to defins (ANTs)  were use2.6ic, Viso, ODI, RTAP and RTOP for the TDCs using R software package. False discovery rate (FDR) correction was used to account for multiple comparisons. We particularly focused on three WM regions namely, PLIC, CC and SLF to perform qualitative comparison to determine which ROI has the highest and lowest values during the early postnatal developmental stage.Our first analysis focused on understanding the changes in diffusion measures in TDC neonates at different postnatal weeks (age) in all the 11 WM regions. We grouped the 11 ROIs into two groups: 1) projection fibers, and 2) association and callosal fibers see . Regress2.7t-test was used to estimate statistical differences between the two groups for each of the 7 measures and the 22 WM regions . FDR correction was used to account for multiple hypothesis testing.Since there were age differences between the CHD and TDC neonates, we first regressed out the effect of age from all TDC and CHD subjects. Subsequently, a 33.1Linear regression model allows estimating the maturation of WM regions as a function of age. Age-related changes in diffusion measures in the 22 WM (11 LH and 11 RH) regions included: Uncinate Fasciculus (UF), Inferior Fronto-occipital Fasciculus (IFOF), Superior Fronto-occipital Fasciculus (SFOF), Superior Longitudinal Fasciculus (SLF), Anterior Corona Radiata (ACR), Posterior Corona Radiata (PCR), Superior Corona Radiata (SCR), Anterior Limb of Internal Capsule (ALIC), Posterior Limb of Internal Capsule (PLIC) and Retrolenticular part of the Internal Capsule (RIC). The overall results of this analysis are summarized in 3.1.13.1.1.1MD measures the total amount of water diffusion in the brain tissue. 1) CC, SLF, and ACR have the highest MD values.2) PLIC has the lowest MD values.3.1.1.2FA measures the relative diffusivity of water molecules along the WM regions compared to the perpendicular or radial direction. 1) PLIC has the highest FA values.2) SLF and ACR had the lowest FA values.3.1.23.1.2.1ic is the intra-cellular volume fraction obtained through the NODDI model. ic as a function of age in TDC. The results can be summarized as follows:Vic value.1) PLIC has the highest Vic value.2) SLF and ACR has the lowest V3.1.2.2iso measures the isotropic diffusion compartment in the tissue. iso at different ages in TDC neonates. The results can be summarized as follows:Viso values.1) CC has the highest Viso values.2) RIC and IFOF have the lowest V3.1.2.3ODI models the orientation dispersion of fibers in tissue. 1. ALIC has the highest ODI values.2. CC has the lowest ODI values.3.1.33.1.3.1RTAP is sensitive to the axonal density, diameter, and myelination. 1. PLIC has the highest RTAP values.2. SLF and ACR have the lowest RTAP values.3.1.3.2RTOP is thought to reflect the packing density and volume of fiber bundles . Fig. 1.1) PLIC has the highest RTOP values.2) SLF has the lowest RTOP values.In supplement , we pres3.2We compared each of the diffusion measures between the TDCs and CHD subjects. An overall table of p-values for all measures is given in , where wic was lower in the CHD subjects in the bilateral SFOF and left PLIC  showing greater maturation than those of the dorsal language pathway (SLF). Similarly, a past DTI study has shown that the SLF has a slow maturation rate extending into childhood . This ca4.1.4ic were the closest between PLIC and CC, indicating that there might be a possibility of partial volume effects from the lateral ventricles in the CC affecting the DTI and GMM measures, and removing such effects in the NODDI model brought the values closer between these two regions (by modeling an isotropic diffusion fraction Viso).We observed the expected pattern of change with age across the three models used. However, when comparing PLIC with CC using FA, we see much fewer differences between the values between these two WM regions as compared to the greater difference seen with GMM. This increase in FA could be either due to increase in myelination from the PLIC or coherence from the CC. The values obtained from V2/s, whereas the default value is 0.0017 mm2/s. Further, as shown in 2/s, much lower than the axial diffusivity of 0.0021 mm2/s observed in the CC. This demonstrates that fixing axial diffusivity may be an inherent limitation of the NODDI model.However, it is also important to note that estimated parameter values for the NODDI model might be suboptimal as the diffusivity values that are by default fixed into the NODDI model may not be accurate for neonate's brains. For example, our estimate of the axial diffusivity in the TDC neonates in the CC is 0.0021 mmIn summary, we found that all measures were sensitive to age-related changes in TDC neonates in the regional WM structure. However, DTI and NODDI models simplify the modeling of biological tissue thereby limiting its sensitivity to capture all the variations during the developmental period of the brain. Since GMM does not assume any tissue model, it allows more freedom to capture the variability of each WM region.4.2In this study, we identified region-specific WM abnormalities related to CHD. The differences between CHD and TDC were most prominent in the CC as well as the association fibers of the ventral language pathway  and dorsal language pathway (SLF). Furthermore, assessing WM regions with seven different dMRI measures, provided more information as to the nature of WM structural abnormalities in CHD neonates.4.2.1The DTI results demonstrate the lower integrity of WM regions in CHD neonates. A previous DTI study in neonates with CHD demonstrated slower maturation of WM regions including the posterior part of the CC . Similar4.2.2In addition, the results from DTI demonstrate lower FA in the UF of CHD neonates implying delayed or abnormal maturity of this WM region. RTAP and RTOP were also significantly lower in this region. A previous DTI study in young adults with CHD showed lower FA in the left UF compared to controls, and the lower FA was positively correlated with verbal memory . In our 4.2.3Our results also demonstrate significantly lower FA in the left SLF of neonates with CHD. SLF is part of the dorsal language pathway which is responsible for the phonological processing of language . Unlike 4.2.4Measures derived from the NODDI model showed far fewer statistical differences than those from DTI and GMM measures, indicating a lower sensitivity of the NODDI measures in capturing differences between CHD and TDC. Further, GMM-derived measures showed the highest sensitivity in terms of the effect size differences observed between TDC and CHD population. By carefully changing the default parameters, the sensitivity of NODDI might improve, yet it still might be suboptimal for several regions as the axial diffusivity is regionally very different (as discussed earlier). Further, axial diffusivity also might differ substantially in developing population and those affected by diseases. These reasons make it difficult to optimize this parameter in the NODDI model. Hence, in our study, we used default parameters setting in the NODDI mode. Overall, our study leveraged advanced diffusion imaging to obtain several parameters which allowed us to observe region-specific WM maturation in TDC and detect abnormalities in neonates with CHD in early post-natal weeks.4.2.5Our study is limited in that 3 subjects were imaged postoperatively and 4 of 19 subjects (two imaged preoperatively and two imaged postoperatively) showed a recent injury on diffusion imaging. However, these acute lesions were small and, since recent, only two lesions were associated with decreased FA. Therefore, these lesions are likely to have little effect on our findings. Our study is also limited in assessing functional impairments associated with language development in the early postnatal weeks because speech production specific to native language only progresses between 6 months and the first year of the postnatal year . Therefo5Our results demonstrate the feasibility of using advanced multiple b-value diffusion imaging to characterize regional white matter maturation in neonatal brains and to detect micro-structural abnormalities associated with CHD. Our analysis of 22 different WM regions (both hemispheres) in TDC neonates showed significant changes in all diffusion metrics but MD and Viso in 12 different regions . Thus, in this cross-sectional study, these 5 measures were sensitive to microstructural changes with age. Our analysis also showed statistically significant group differences between CHD neonates and TDC, with RTAP and RTOP providing the strongest statistical significance in terms of effect sizes and the number of abnormal regions. Furthermore, a major finding from our study indicates the presence of WM differences  in bilateral CC and UF and left IFOF and left SLF in CHD. To the best of our knowledge, this is the first study to use advanced diffusion measures to better characterize regional WM differences in congenital heart disease in a systems based approach. The left lateralization of these differences in CHD suggests that the delayed language development often observed in CHD may be connected to the abnormalities seen in our study in the early postnatal weeks. Further, this study also compared different models used in the diffusion MRI field and found that the GMM and DTI measures are more sensitive at detecting differences in tissue structure than the NODDI model, as measured in terms of the number of regions found to be abnormal. Long-term follow-up of the CHD neonates is planned to assess their cognitive outcomes especially in the domain of language to determine the predictive power of these differences. Moreover, our work may aid in the monitoring of future early interventions targeting functions related to these specific WM regions.The following are the supplementary data related to this article.


Chronic kidney disease (CKD) pregnancies are at high risk of developing adverse outcomes. In non-pregnant subjects with CKD, higher urinary IgM levels are associated with poor renal survival and higher rates of cardiovascular deaths. In this study, we assessed whether urinary IgM levels are associated with an increased risk of adverse pregnancy outcomes (APO) in CKD pregnancies.We performed a nested case–control study within a cohort of CKD patients with singleton pregnancies attended at a tertiary care hospital. The study included 90 CKD patients who eventually developed one or more APO and 77 CKD patients who did not. Urinary IgM excretion was determined from the 24-h urine samples at enrollment by an ultrasensitive enzyme immunoassay.The risk for combined APO and for preeclampsia (PE) was higher among women with urinary IgM and proteinuria levels values in the highest quartile or with CKD stages 4–5 , compared with the lowest quartile or with CKD stage 1. Urinary IgM levels were more closely associated with the risk of either combined or specific APO  than either the degree of total proteinuria or CKD stages. Among patients with CKD stage 1, the risk of combined APO, PE, and preterm birth was higher in women with urinary IgM levels values in the highest quartile (OR ≥ 4.8), compared with the three lower quartiles, independently of proteinuria.In CKD pregnancies, at the time of initial evaluation, proteinuria and CKD stage are associated with increased risk of combined APO. However, urinary IgM concentrations appear to be better predictors of an adverse outcome and may be useful for risk stratification in CKD pregnancies. Chronic kidney disease (CKD) is increasing worldwide, and its prevalence is estimated to be 8–16% in the general population . PregnanIn non-pregnant subjects, several factors may influence the clinical outcome of CKD such as type of kidney disease, race, gender, age, and hypertension. Moreover, the degree and type of proteinuria are a good indicator of the extent of kidney damage and are involved in the pathophysiology of disease . UrinaryNevertheless, there is no available information on the uIgM levels in pregnant women with CKD. The goal of the present study was to investigate whether differences in uIgM levels in patients with CKD may identify those patients at high risk to develop APO.The protocol study was approved by our institute’s review board. Written informed consent was obtained from all participants. Between March 2011 and December 2017, all women with singleton pregnancies diagnosed with CKD before o during pregnancy were recruited from the Department of Maternal-Fetal Medicine of a tertiary care level hospital. Patients with systemic lupus erythematosus were excluded from the study because lupus nephritis per se has been associated with worse pregnancy outcomes for multiple reasons .CKD stage was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines . Given tHypertension was defined as systolic or diastolic blood pressure ≥ 140 mmHg or ≥ 90 mmHg, or antihypertensive therapy prior to 20 weeks’ gestational age. Preeclampsia (PE) was defined according to The American College of Obstetricians and Gynecology criteria . PE withOther APO included any of the following: preterm delivery , the neonatal death  and small-for-gestational age (SGA) infant, defined as an infant whose birth weight was below the 10th percentile.A 24-h timed urine collection was obtained at enrollment to estimate GFR using standard creatinine clearance corrected for the body surface area and to measure total protein and IgM excretion. Samples were centrifuged, and the resulting sediment-free urine specimens were aliquoted and stored at − 80 °C until assayed. All samples were collected before clinical suspicion or diagnosis confirmation of any studied APO. Clinical and delivery outcomes were recorded to classify the patients with APO.IgM concentrations in urine were measured by an ultrasensitive enzyme immunoassay for human IgM developed in our laboratory to measure small amounts of IgM. Polystyrene 96-well plates  were coated with 100 µl/well of polyclonal antibodies specific for human IgM  at a concentration of 1 µg/ml in 0.1 M carbonate–bicarbonate buffer, pH 9.0. Plates were incubated for 2 h at 37 °C and stored at 4 °C until used. Optimum blocking conditions for nonspecific binding were achieved using 300 µl/well of 5% skimmed milk in phosphate-buffered saline (PBS), pH 7.4, containing Tween-20 at 0.05% (PBST), for 2 h at 37 °C. After washing five times with PBST, the samples were added in duplicate at different dilutions to ascertain parallelism with the standard curve . The plates were left for 1 h at 37 °C, then washed five times with PBST, and subsequently incubated with monoclonal antibodies specific for human IgM  at a concentration of 1 µg/ml. Following 1 h of incubation at 37 °C, the plates were washed five times with PBST and subsequently incubated with a peroxidase-conjugated goat anti-mouse serum , at a 1:2000 dilution for 1 h at 37 °C. Plates then were washed five times with PBST before the reactions were revealed with o-phenylene diamine . Optical density was read at 492 nm using an ELISA reader . The minimal detectable quantity was 3.0 ng/ml, and the intra- and interassay coefficients of variation were 3.5 and 5.6%, respectively. Urinary protein and creatinine were measured as previously described .2 test with linear tendency for variables with > 2 categories). Association between uIgM and total protein levels, and CKD stages, and the subsequent risk of APO, was calculated. Test results were grouped into quartiles  and kidney disease was grouped via CKD stage; due to the clinical severity and sample size, the groups were collapsed into four groups, CKD stage 1, 2, 3 and CKD stage 4–5; and the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between quartiles or CKD stage and the risk of APO. The lowest quartile was used as reference category for both proteinuria and IgM-uria, and for CKD stage, group 1 (CKD stage 1) was the reference group. Logistic-regression analysis was used to adjust the ORs for proteinuria, IgM-uria, and CKD stage because these variables were significantly different among the groups studied by univariate analysis, as well as for chronic hypertension considering that this variable may distinctly affect the adverse outcomes. In addition, the ORs for preterm delivery were also adjusted for PE, and for neonatal death were adjusted for gestational age at delivery. A two-tailed p < 0.05 was considered statistically significant.Differences between continuous variables were determined by the unpaired Student t test . Differences between categorical variables were determined by the Chi square test with Yates continuity correction or the Fisher exact test for small samples  were excluded for the following reasons: two patients for congenital defects, one patient for molar pregnancy, and one patient for loss to follow-up at week 30. Therefore, a total of 167 CKD pregnancies were available for final analysis. Each patient was included only once in the study. The mean maternal age was 28.9 ± 6.2 years with a median gestational age at enrollment of 21 weeks (IQR 15–25). The majority of patients were multigravida (57.9%). In 130 of 167 cases (77.8%), the diagnosis of CKD was made during pregnancy. Glomerulonephritis was the main cause of CKD (69.4%), followed by diabetes (20.4%) and tubulointerstitial (10.2%). Chronic hypertension was present in 50.9% of patients. Of the 167 patients, 59 (35.3%) had CKD stage 1, 48 (28.7%) CKD stage 2, 38 (22.8%) CKD stage 3, 15 (9.0%) CKD stage 4, and 7 (4.2%) CKD stage 5. Hemodialysis was required in four patients with CKD stage 5.Ninety patients (53.1%) had ≥ 1 APO, including PE 66 (39.5%), SGA infant 61 (36.5%), preterm birth 53 (31.7%), and neonatal deaths 21 (12.6%). Among the 53 patients who delivered at < 34 weeks of gestation, 47 of deliveries were indicated for PE, two for fetal distress, two for preterm premature rupture of membranes, and two for spontaneous preterm labor.Tables Compared to patients without combined APO or PE, patients with these outcomes had higher serum creatinine levels, lower baseline creatinine clearance, as well as a higher baseline excretion of both total protein and IgM (p < 0.001). Patients who developed combined APO or PE had lower gestational age at delivery, delivered infants with lower birth weights, and had a greater proportion of preterm birth, SGA infants, and neonatal deaths than those patients without these APO (p ≤ 0.04). Although there was an overall increase in the frequency of cesarean section (88.6%), there was no significant difference between patients who developed combined APO or PE and patients who did not develop these outcomes (p ≥ 0.13).Logistic regression analyses were used to determine the association between quartiles of 24-h urinary excretion of proteins and IgM, and CKD stages and risk of combined and specific APO Table . The risTo determine the effect of eventual differences in uIgM excretion on the association with the development of APO, a further analysis was carried out, limited to stage 1 CKD patients. For this analysis, patients were divided into two groups according to quartiles based on the distribution of uIgM levels among all stage 1 CKD patients. The first group included 30 patients whose values for uIgM levels fell within the three lowest quartiles, and the second group comprised the 29 remaining patients in the highest quartile (> 8.95 µg/24 h). The demographic, clinical, and obstetric characteristics of the patients are shown in Table Additionally, ORs for quartiles of uIgM levels were calculated. A further adjustment for proteinuria levels was made because this variable differed significantly between groups at univariate analysis. The outcomes of SGA infant and neonatal deaths were not analyzed because of their very low frequency in both groups. Table To the best of our knowledge, the present report is the first to have prospectively examined the association between basal uIgM excretion and the risk to subsequently develop APO in CKD pregnancies. In the present nested case–control study, involving a large number of pregnant women with CKD with a wide spectrum of renal disease severity and using detailed diagnostic criteria to define APO, we found that uIgM levels were significantly higher in CKD patients who eventually developed either combined APO or PE. Furthermore, in CKD patients whose uIgM levels fall within the higher quartiles, the risk of combined APO and the various individual APO, including PE, preterm birth, and SGA infant, was progressively higher as uIgM levels quartiles increased, even after taking into account the degree of proteinuria, CKD stages, and PE. Moreover, we also demonstrated that patients with CKD stage 1 whose values for uIgM excretion fall within the highest quartile have an increased risk for combined APO, as well as for PE and preterm birth compared to CKD stage 1 patients in the three lower quartiles, regardless of the degree of proteinuria, suggesting that changes in uIgM concentration effectively reflect the extent and intensity of damage to the glomerulus and, probably as well, to the systemic vascular endothelium. Further, we identified that uIgM levels are superior to the degree of proteinuria and CKD stages in predicting the risk of combined APO, as well as of other specific APOs studied.It has been suggested that very large proteins, like IgM, with a molecular radius of 120 Å, and red blood cells are able to pass the glomerular capillary wall (GCW) through the “large pores” or “shunt pathways”. The intact GCW exhibits a very small number of these defects, and a repairing apparatus normally seals these shunts , 27. VarPrevious studies have demonstrated that patients with stage 1 CKD are at higher risk than healthy women for developing APO independently of hypertension, degree of proteinuria or type of renal disease , 30, 31,Consistent with the notion that CKD pregnancies are at high risk for developing APO, and that these complications increase incrementally with the severity of renal function impairment , 9, we cThe main risk factors that are associated with APO in patients with CKD include the following: renal function, degree of proteinuria, hypertension, and systemic diseases , 30–34. Particularly noteworthy is the fact that, in our study, a total 130 (77.8%) patients were diagnosed to have CKD during pregnancy. This contrasts with data reported in other studies, which found frequencies ranging from 17.5 to 27.5% . This diThe strengths of our study include a well-defined, large population of women with CKD  who had received the same standardized medical protocol, and the fact that all samples were collected before clinical suspicion or diagnostic confirmation of APO, which evidently avoided a selection bias. Further, we believe that the incorporation of sFlt-1/PlGF ratio in the definition of PE allowed us better to identify this disease in our patients . To ruleFinally, uncovering the mechanism of altered uIgM excretion in CKD may also provide insights into novel therapeutic options. Further prospective longitudinal studies are still needed to assess the relationship between uIgM excretion and surrogate markers of endothelial dysfunction and atherosclerosis in pregnant women with CKD.In conclusion, our results demonstrate that uIgM levels are associated with the risk of combined and specific APO in patients with CKD. Furthermore, uIgM levels appear to be better biomarkers than the classic risk factors such as CKD stage, proteinuria, or hypertension, and may be useful for risk stratification of APO even in the early stages of CKD. Lastly, the determination of uIgM concentration is an easy assay to perform and is cheap (the cost approximately is 40 USD per 96-well plate).