In many countries, cesarean section has become the most common major surgical procedure. Most nations have high cesarean birth rates, suggesting overuse. Due to the excess harm and expense associated with unneeded cesareans, many health systems are seeking approaches to safe reduction of cesarean rates. Surveys of childbearing women are a distinctive and underutilized source of data for examining factors that may contribute to cesarean reduction.Listening to Mothers in California Survey, limited to the subgroup who had not had a previous cesarean birth and did not have a planned primary cesarean . Participants were identified through birth certificate sampling and contacted initially by mail and then by telephone, text message and email, as available. Sampled women could participate in English or Spanish, on any device or with a telephone interviewer. Following bivariate demographic, knowledge and attitude, and labor management analyses, we carried out multivariable analyses to adjust with covariates and identify factors associated with unplanned primary cesarean birth.To identify factors associated with unplanned primary cesarean birth, we carried out a secondary analysis of the Whereas knowledge, attitudes, preferences and behaviors of the survey participants were not associated with having an unplanned primary cesarean birth, their experience of pressure from a health professional to have a cesarean and a series of labor management practices were strongly associated with how they gave birth. These practices included attempted induction of labor, early hospital admission, and labor augmentation. Women’s reports of pressure from a health professional to have a primary cesarean were strongly related to the likelihood of cesarean birth.While women largely wish to avoid unneeded childbirth interventions, their knowledge, preferences and care arrangement practices did not appear to impact their likelihood of an unplanned primary cesarean birth. By contrast, a series of labor management practices and perceived health professional pressure to have a cesarean were associated with unplanned primary cesarean birth. Improving ways to engage childbearing women and implementing changes in labor management and communication practices may be needed to reduce unwarranted cesarean birth. In many countries, cesarean section is the most common major surgical procedure. Globally, the rate of cesarean birth increased by 3.7% annually from 2000 to 2015. Exceptionally wide practice variation characterizes use of cesarean birth both across and within countries. Cesarean rates of less than 10%, considered an indication of underuse, have recently been identified in 28 nations. However, most world nations have cesarean rates of 15% or higher, which is considered an indication of overuse [In the United States, following a steep rise between 1996 and 2007, the cesarean rate has plateaued for a decade at nearly one in three. The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine concluded that the steep rise was not accompanied by discernible benefits for women and newborns, and they have jointly issued guidance for safely reducing primary cesarean births .Many effective strategies for cesarean reduction have been identified. Pre-labor practices that have been associated with reduced likelihood of cesarean birth include choosing individual care providers and birth settings with lower cesarean rates, choosing types of care providers and birth settings with lower cesarean rates , childbirth training workshops, being physically active and staying fit during pregnancy, arranging for the labor support of a doula and attempting external cephalic version with non-cephalic presentation at term –8. AfterCharacteristics of women associated with lower likelihood of cesarean birth include lower body mass index, younger age and having Medicaid/public assistance versus private insurance coverage –20. CesaListening to Mothers in California Survey to examine mother-reported factors that may be associated with lower likelihood of cesarean birth. These include factors not previously reported in the literature, such as women’s attitudes, behaviors, knowledge and preferences, as well as previously reported factors, such as members of the woman’s care team and labor management practices. We also used the low-risk first birth cesarean rate at the woman’s birth hospital as a proxy for local practice style [Assessment of factors that may be associated with cesarean rates commonly use vital statistics, administrative and/or medical records as data sources. Surveys of childbearing women themselves enable us to examine the possible impact of women’s beliefs and behaviors, as well as their care arrangements and labor experiences that may not be systematically recorded in other sources , 26. Herce style . To contListening to Mothers in California Survey was developed through a collaboration of investigators from the National Partnership for Women & Families, Boston University School of Public Health and University of California, San Francisco (UCSF) Center on Social Disparities in Health, who worked with Quantum Market Research to plan and carry out the survey. The sampling frame for the Listening to Mothers in California study was drawn from California birth certificate data for births between September 1 and December 15, 2016. We excluded women less than 18, women with out-of-hospital births, women with multiple births and non-residents of California. Further exclusions during the field period included women who could not participate in English or Spanish and women who were not currently living with their baby. We oversampled Black women, women with midwifery-attended births and those with vaginal births after cesarean to increase power for better understanding the experiences and perspectives of women within these smaller groups. The field period was from February 22 through August 15, 2017. Sampled women were invited to participate through an initial and – as needed – three reminder mailings with distinctive envelopes and two inserts designed to be engaging and stand apart from typical residential mail. The mailings included a cover letter inviting participation and incorporating elements of informed consent and an insert with information about how to participate in the survey. The survey research firm contacted sampled women who did not respond to mailings by – as available from additional sources of information – email, text message and telephone calls. Sampled women could choose among multiple ways to participate: online on their own using any device or by telephone with a trained interviewer. Participants were from 2 to 11 months postpartum when they responded. Among all participants, 81% selected the English version of the questionnaire, and 19% selected the Spanish version. Among all participants, 34% completed the survey online, 28% completed by phone with an interviewer and 39% completed using both methods (a common pattern was starting on their own online and finishing later with an interviewer).The Listening to Mothers surveys, some items adapted from those previous surveys , and some items newly developed for or included with permission in the California survey. Initial English versions of outreach materials and questionnaire were pilot tested with varied populations who had recently given birth and refined over several iterations. Subsequently, these materials were translated into Spanish (with back translation) and adjusted accordingly, followed by iterative testing and refinement with varied groups of Spanish-speaking childbearing women. The survey took a bit longer than a half-hour to complete on average. The Listening to Mothers in California full survey report and related materials, including survey questionnaire, are available at websites of both the sponsor [Both outreach materials inviting sampled women’s participation and the survey questionnaire see  were dev sponsor  and fund sponsor .UCSF analysts used demographic and other relevant variables from the statewide 2016 Birth Statistical Master File to weight the final sample to be closely representative of childbearing women aged 18 and older giving birth to single babies in California hospitals throughout 2016. Our response rate calculation was based on methods of the American Association of Public Opinion Research, using their “Response Rate 2” and “Response Rate 4” methods, which exclude sampled participants found to be ineligible during the field period  and which further estimates and excludes the proportion of sampled women of unknown eligibility who were ineligible. This resulted in a response rate of 55% for the final sample size of 2,539 women.Listening to Mothers in California full survey report compares a series of demographic variables in statewide birth certificate data for women 18 + with singleton births and in our weighted dataset. The discrepancies between the state and our dataset are overwhelmingly in the range of 0 to 2 percentage points. For example, age 18–19 , age 35+ , Latina , Asian/Pacific Islander , Black , US-born , first birth , less than high school education , certified nurse-midwife birth attendant , cesarean birth , preterm birth , very low birth weight , and low birth weight  [Appendix B in our  . The rep .Listening to Mothers in California Survey. This Committee determined that the study posed a low risk to participants and approved the study and several protocol amendments. The UCSF IRB also approved the project. The California Department of Public Health Vital Statistics Advisory Committee approved and provided access to birth certificate data for sampling, contacting sampled women, data weighting and data analysis. Given the rich array of health insurance options available in California, Department of Health Care Services analysts linked birth certificate items to the Management Information System/Decision Support System Warehouse to definitively identify participants with Medi-Cal  coverage of their childbirth, defined as Warehouse evidence of a paid claim for a 2016 birth. In this analysis, privately insured women did not have such a claim and identified a source of private insurance in survey responses.The Committee for the Protection of Human Subjects, within California’s Office of Statewide Health Planning and Development, is the institutional review board (IRB) of record for the We used publicly available 2016 data to classify the nulliparous, term, singleton, vertex (NTSV) cesarean rate of respondents’ birth hospitals into four quartiles and included those data in the multivariable analysis as a proxy for local institutional culture associated with the likelihood of a cesarean birth. This first-birth low-risk (“NTSV”) cesarean rate is widely used in the United States as a measure that is case-mix adjusted and thus better suited to comparisons among facilities than total or primary cesarean rates.In this report, Latina indicates participants who self-identified as “Hispanic or Latina.” White, Asian and Pacific Islander, and Black reference participants who did not choose “Hispanic or Latina” and self-identified, respectively, as white, Asian or Native Hawaiian or other Pacific Islander, and Black. There was some apparent uncertainty over the interpretation of the term and questionnaire descriptions of “doula” among Spanish speaking respondents and/or women who did not primarily speak English in their homes, and therefore the data presented on doula responses are limited to those who primarily spoke English in their homes.We limited the present secondary analyses to women whose index birth was an unplanned primary cesarean (excluding women with planned primary cesareans that occurred before the onset of labor) and women who did not have a history of cesarean birth and gave birth vaginally. Thus, participants with a 2016 vaginal birth after cesarean or repeat cesarean were excluded. In our full survey sample, 11% of participants had an unplanned primary cesarean, 5% had a planned primary cesarean and 15% had a repeat cesarean .We conducted bivariate analyses, examining associations between selected maternal socio-demographic characteristics , marital status, nativity, language used at home and education level) and mode of birth. We also examined the association between various maternal knowledge, beliefs and preferences relating to the intrapartum experience, and selected labor management experiences, and the risk of an unplanned primary cesarean birth. All but the measures of pregnancy complications, labor and birth risks and gestational age were drawn from respondent’s answers on the survey. Gestational age (< 37 weeks or 37 + weeks), any pregnancy complications  and any labor and delivery risks  were drawn from the respondent’s birth certificate. While the validity of the measurement of some of the individual complications on the birth certificate may be problematic , identifThe final, fully-adjusted model examined the risk of unplanned cesarean birth and included variables chosen a priori either because they were statistically significantly related in the bivariate analysis or they have been shown to be related to cesarean births in the past. They were divided into sociodemographic , health , maternal attitudinal and experiential  and pregnancy and labor management variables . Finally, as a surrogate for maternity unit culture, a hospital-level measure of the NTSV cesarean birth rate was included . BecauseThere were 1,964 respondents in our sample who had not had a previous cesarean birth and whose current birth was either vaginal or an unplanned cesarean. We examined possible variation in experience of unplanned primary cesarean birth within demographic categories .In the stratified multivariable models, most significant relationships were confined to the nulliparous mothers. Significant differences in terms of race, mother’s age, mother’s education, amniotomy and admission at dilatation less than 5 centimeters were all limited to nulliparous mothers. Experiencing an attempted induction and feeling pressure to have a cesarean birth were significantly associated with elevated risk of cesarean in both groups, but more so in the multiparous group. However, these numbers should be interpreted with caution as the absolute number of multiparous mothers with a primary cesarean was small  or somewhat (27%) with the statement that “childbirth is a process that should not be interfered with unless medically necessary,” while just 8% disagreed. And although few actually used midwifery care and had doula support, and all gave birth in hospitals, they expressed a high degree of interest  in these high-touch, low-tech forms of care should they give birth in the future: midwife (56%), doula (59%) and birth center births (41%). Further, almost one respondent in three (30%) sought information about cesarean rates of prospective hospitals, with the great majority of these finding this information. And about one in three correctly understood that the quality of care varies across both obstetricians and hospital maternity units . HoweverBlueprint for Advancing High-Value Maternity Care recommends many resources and supports to foster engagement of childbearing women during pregnancy, childbirth and the postpartum period. These include better performance measures and user-friendly, evidence-based public reporting of results of performance measurement. Currently, there are no woman-reported nationally-endorsed measures of the experience or outcomes of maternity care. There are no endorsed measures of care coordination or shared decision making in maternity care, nor any endorsed measures of physiologic childbirth or vaginal birth after cesarean.Engaging patients and their family members and caregivers in their health care is a growing policy priority, as reflected in the United States National Quality Strategy’s priority of “Ensuring that each person and family is engaged as partners in their care” . HoweverDevelopment and routine use of high-quality, evidence-based, up-to-date decision aids would also provide essential support to childbearing women. Care navigators can help women understand how to find and interpret comparative performance information, develop care plans, work through decision aids, and complete surveys to collect information about their experience and outcomes of care . Also foBy contrast, we identified demographic characteristics, provider behaviors and labor management practices that were clearly associated with mode of birth. The finding of higher cesarean rates for Black mothers is consistent with prior research –39, thouType of insurance payer, while trending toward significance with higher rates for women with private insurance, did not achieve statistical significance. An earlier study likewise found differences by payer type in unadjusted rates, but no differences after adjustment . More imBlueprint for Advancing High-Value Maternity Care identifies payment and delivery system reform, performance measurement and accountability, consumer engagement, movement toward interprofessional education and team-based care, attention to workforce composition and distribution, and filling priority research gaps as promising strategies for maternity care transformation and reliable delivery of appropriate care for childbearing women and newborns [Our results suggest that opportunities currently exist for reducing cesarean use through broad implementation of evidence-based labor management practices. The newborns .Consistent with other research , we founp < .01). When we further limited the comparison to lower-risk first-birth (NTSV) cesareans, notable differences persisted: 28% with obstetrician-led care versus 17% with midwifery-led care (p < .01). Prenatal provider differences were also great when we looked at vaginal birth after cesarean rates, which were 14% among women with obstetrician-led care versus 33% among women with midwifery-led care (p < .02) [Some studies have found midwifery care to be associated with reduced likelihood of cesarean birth . As we op < .02) .The relationship between attempted labor induction and cesarean birth is uncertain. Although the large ARRIVE trial found reduced cesarean birth with routine induction at 39 weeks , questiomore likely to have an unplanned cesarean, but that relationship did not continue in the multivariable analysis [Some of our labor management results differ from best available evidence. Intermittent auscultation versus continuous electronic fetal monitoring has been found to be associated with vaginal birth . Howeveranalysis . Best evanalysis , though The largest adjusted odds ratio in our multivariable model, 7.45, compared women who did and did not report experiencing pressure from a health professional for cesarean birth, with experience of pressure strongly associated with having an unplanned primary cesarean. While provider pressure was likely, in some cases, the result of a concern with a medical condition, this was a low-risk population and variables for pregnancy complications and labor and birth complications (one or more item selected from either category of the participant’s birth certificate) were included as covariates in the model.Listening to Mothers survey data and other sources, for including the pressure variable in our model and thus concluding that many women experience pressure for cesarean birth that is not synonymous with provider recommendations for indicated cesarean birth. First, many women with unplanned primary cesareans did not report experiencing pressure, suggesting that they concurred that cesarean was an appropriate clinical decision. Second, rates of cesarean for subjective indications  vary widely, have contributed to the trend of increased national cesarean rates, and suggest a considerable amount of discretion in commonly identified indications [Listening to Mothers survey found that women who had cesareans without medical indication were more likely to report experiencing pressure than women with cesareans for standard indications [There is strong rationale, from ications . Notablyications . Anotherications . Anotherications .Given broad recognition that many cesareans can and should be safely avoided and widespread agreement about the importance of safely lowering the cesarean rate in many settings –4, it isThe revision and validation of the Labor Culture Survey was carried out among 110 California hospitals, and found that the hospital unit NTSV rate over 2015–2016 was associated with a series of dimensions of hospital maternity unit culture, such as unit microculture, fear of vaginal birth, physician oversight, and maternal agency . BivariaAreas for future research include examining the relationship between labor practices and unplanned primary cesarean birth with larger samples and studies that better capture timing and rationale for use of the practices. There is also a need to better understand ways to increase women’s agency and engagement in their care to the extent that their values and preferences affect the care they receive. Lastly, the small number of multiparous mothers who, by definition had given birth vaginally in the past and this time experienced a cesarean, were particularly likely to report having experienced pressure. This may be a productive area for future research on cesarean decision making with larger samples.Limitations of our study include lack of power, as discussed above, to measure some labor management practices that have clearly been associated with cesarean birth in other studies. The relatively small number of multiparous mothers in our sample who had a primary cesarean also limited our ability to analyze their experiences. We also did not have information concerning timing of decisions that would allow a more nuanced analysis. For example, we could not determine whether midwives provided care during labor prior to an obstetrician-attended cesarean birth and which maternity care provider made the decision for a cesarean, nor could we distinguish epidural use for pain relief during labor versus its initiation as an anesthetic for surgery. We were unable to determine whether women who entered the hospital with less cervical dilation might have been experiencing less productive labor. Although previous analyses of survey questions about experiencing pressure to have interventions suggest that experience of “pressure” discriminates from concurring that provider recommendations are indicated, we have not systematically asked survey participants about their interpretation of these items. We also did not know the extent to which the index birth experience influenced women’s postpartum attitude toward intervention in childbirth and whether that attitude was held prior to the birth. Further, this secondary analysis of a cross-sectional design may not have adjusted for some relevant confounders, including some related to risk and complications. For example, we adjusted for any pregnancy and labor and birth complication identified on participants’ birth certificates, yet cannot be certain that this corrected for early hospital admission or labor induction associated with conditions that increase the likelihood of cesarean birth.In the present context of overuse of cesarean birth in the United States and most other nations, women’s beliefs, preferences, knowledge and behaviors did not appear to impact their mode of birth. Additional support, educational programs and engagement strategies may be needed to enable more reliable translation of their preferences into actual care received. Such improvements should include attention to better communication and decision-making processes. Meanwhile, changes in hospital labor management provide clear opportunities for reducing cesarean overuse and associated costs, improving outcomes and providing care more concordant with women’s wishes. The strong relationship between pressure and unplanned cesareans raises concerns about contemporary maternity care practice.Additional file 1. LTM-CA Questionnaire_FINAL_8.27.18.pdf. Listening to Mothers in California: Survey Questionnaire. Complete questionnaire, in English and Spanish, used in the Listening to Mothers in California Survey


Preterm birth and complications are now the leading cause of death in children under 5 years globally. In Ghana, studies assessing the survival rate of preterm babies and associated factors in Neonatal Intensive Care Units (NICU) are limited. Therefore, this study was designed to assess the survival rate and associated factors in this group of babies in a teaching hospital in the Northern Region of Ghana.  This was a 7-month retrospective descriptive study conducted in the NICU of the Tamale Teaching Hospital, Ghana. It involved review of charts of all preterm babies admitted between 1 March 2017 and 30 September 2017. Data retrieved from all eligible patients was analyzed using Stata version 12.1 software to generate descriptive statistics. Relationship between dependent and independent variables was tested using Pearson chi square. A logistic regression model was estimated to assess determinants of the treatment outcome. P = 0.0001), gestational age (P = 0.0001), and survival. Preterm babies who were hypothermic at presentation, had respiratory distress syndrome, and had jaundice were 7.2 times , 10.2 times , and 2.9 times , respectively, more likely to die on admission compared to neonates who did not have these comorbidities.  The overall survival rate at discharge in this cohort was 60.73%. The survival rate was lowest in the extremely low birth weight group  and extremely preterm babies . Significant association was observed between birth weight ( We found a high mortality rate in the preterm babies admitted to our unit, and that mortality rate decreased with increasing gestational age and birth weight. A number of neonatal factors, either in isolation or in combination, were significantly associated with in-hospital mortality. Newborn babies in need of critical medical attention are normally admitted to the Neonatal Intensive Care Unit (NICU) . These iPreterm birth is defined by the World Health Organization (WHO) as all births before 37 completed weeks of gestation or fewer than 259 days since the first day of a woman's last menstrual period [Being born preterm also increases a baby's risk of dying due to other causes, especially from neonatal infections with preterm birth estimated to be a risk factor in at least 50% of all neonatal deaths .More than 1 in 10 of the world's babies born in 2010 were born prematurely , and morThe WHO classification categorizes preterm births into extreme preterm (<28 completed weeks), very preterm (28-<32 completed weeks), and moderate to late preterm (32-<37 completed weeks) [The outcome of preterm babies is assessed as survival of the preterm baby and short- and long-term morbidity associated with preterm delivery. This is usually dependent on a number of factors such as biologic maturity and technological factors . The surNeonatal survival varies with the quality of medical care . In deveStudies have found that primary causes of death for 78% of all non-malformation-related deaths in preterm babies were severe perinatal asphyxia, respiratory distress syndrome (RDS), and infection. Other causes of death were bronchopulmonary dysplasia (4%), necrotizing enterocolitis (2%), intraventricular hemorrhage (3%), and pneumothorax (2%) , 12.In Ghana, studies assessing the survival rate of premature babies and associated factors in the NICU are limited. Therefore, this study was designed to assess the survival rate of this group of neonates and associated factors in the Tamale Teaching Hospital (TTH) in the Northern Region of Ghana.The TTH is a 450-bed capacity hospital which serves as the only teaching hospital in the northern part of Ghana. It is the main center for clinical training of medical students from the University for Development Studies (UDS), Tamale, Ghana. The hospital has a 40-incubator/crib capacity NICU with a 5-bed Kangaroo Mother Care (KMC) unit attached to it. The unit is able to provide respiratory support through a bubble Continuous Positive Airway Pressure (CPAP) setup. It is unable to provide invasive ventilation. With majority of its patients coming from the Tamale Metropolis, the approximate population of the catchment area is about 4 million.This was a 7-month retrospective descriptive study conducted in the NICU of the TTH. It involved review of charts of all preterm babies admitted between 1 March 2017 and 30 September 2017.A hospital record officer was assigned to retrieve case files of all preterm babies admitted to the NICU during the study period. The records retrieved were retrospectively reviewed for birth weight, gestational age, sex, mode of delivery, place of delivery, length of stay, and outcome of admission. Maternal information including age, parity , and illness in pregnancy was also retrieved.All preterm babies admitted at the TTH NICU during the study period (1 March 2017 to 30 September 2017) were eligible for inclusion in the study. The participants included both inborn and outborn babies.We excluded babies whose folders could not be retrieved from the records and low birth weight babies who were born at term.The data were entered into Excel and exported into Stata (V12.1). The treatment outcome was categorized into discharged and died on admission while birth weight and gestational age at birth were categorized using WHO standards. The explanatory variables included gestational age at birth, comorbidities at presentation , sex, mode of delivery, and birth weight. Gestational age was available for 187 participants while 161 participants had their birth weight data recorded. Therefore, analysis with respect to gestational age and birth weight was conducted on only 187 and 161 participants, respectively. The first part of the analysis dealt with descriptive statistics to ascertain the frequency of basic infant, maternal, and obstetric characteristics and to screen all the potential independent variables individually for their relationship with the dependent variable using a chi-squared test. In other words, the chi-squared test was used to establish if there was any association between basic infant, maternal, and obstetric characteristics and treatment outcome. Bonferroni's correction was applied to correct for multiple testing. The chi-squared test is a nonparametric test that is appropriate for examining whether there is a significant relationship between nominal categorical variables. The test is based on the crosstabulation of the relevant variables and compares the observed frequencies in each cell of the crosstabulation to the frequencies expected if there were no relationship between the variables . A chi-sP values less than 0.1 in the chi-squared analysis were included in the final logistic regression model. P value < 0.05 at 95% CI was considered statistically significant.All independent variables with Ethical clearance for this study was obtained from the TTH Ethical Review Committee with clearance no.: TTHERC/20/04/18/02.A total of 192 preterm babies were included in the study. This translated to 19.2% (192/1000) of the total admissions to the unit during the study period.Of the babies with a birth weight documented at admission, 13.04% have extremely low birth weight and 40.99% have very low birth weight while 45.34% have moderately low birth weight. About 10.7% of the babies were extreme preterm and 31.02% were very preterm while 58.29% were moderate to late preterm according to the WHO classifications. Out of the total records, 52.13% were female while 47.87% were males. Over 55% were born through spontaneous vaginal delivery (SVD) compared to about 44.8% who were born via cesarean section (C/S). P ≤ 0.0001). Similarly, those with gestational age of <28 weeks (80.0%) and 28-<32 weeks also had significantly higher mortalities (P ≤ 0.0001). This implies that gestational age and birth weight at birth were statistically significantly associated with the treatment outcome. The overall survival rate at discharge in this cohort was 60.73%. The survival rate was lowest in the extremely low birth weight group (14.3%) and highest in the moderately low birth weight group (82.2%). The survival rate was also the lowest among the extremely preterm babies  (20%) compared to the moderate to late preterm babies (75.0%). Survival was lower among preterm babies admitted in the first 3 days of life (58.04%) compared to older babies (80.0%). In the bivariate analysis, neonates with birth weight < 1000 g (85.7%) and those with birth weight between 1000 g and 1499 g (5%) had significantly higher mortalities  compared to those who were not (16.4%). Moreover, those presenting with RDS were also more likely to die (72.3%) compared to those without this diagnosis (13.9%). Further analysis of the data revealed that neonates who were hypothermic and at the same time hypoglycemic at the time of admission were also more likely to die (68.42%) compared to neonates who were either hypothermic or hypoglycemic (36.05%). Further, neonates who had both RDS and hypothermia were also more likely to die (73.08%) than those who had either RDS or hypothermia (33.94%). P = 0.0001), RDS (P = 0.0001), hypothermia and hypoglycemia combined (P = 0.006), and RDS together with hypothermia (P = 0.0001) had a statistically significant less favorable outcome . Moreover, neonates who had RDS at presentation were about 10.2 times more likely to die on admission compared to those who did not have RDS at presentation . Finally, preterm babies with jaundice diagnosis were also 2.9 times more likely to die on admission compared to those who had no jaundice at presentation   .Neonatal mortality attributable to preterm birth and complications remains a huge challenge globally and in low- and middle-income countries like Ghana. A few studies in Ghana have looked at predischarge mortality in this group of neonates . This reMany of the patients in our cohort were born with extremely or very low birth weight and were in the gestational age ranges categorized by WHO as extremely or very preterm . These tWe documented an overall mortality rate of about 39% in this cohort prior to discharge from the NICU during the study period. Our mortality was comparable to the preterm-specific mortality rate reported in a study conducted at the NICU of the Korle BU Teaching Hospital in Accra, Ghana .In another study conducted in the Mother-Baby Unit of the Komfo Anokye Teaching Hospital, Kumasi, Ghana , the surSimilarly, high preterm-specific mortality has been documented in countries across sub-Saharan Africa  and someAmong the neonatal factors we assessed, lower gestational age, lower birth weight, RDS, presence of jaundice, and hypothermia at presentation to the NICU were significantly associated with death in the bivariate analysis. Neonates who had more than one of these risk factors were more likely to die than those who have none or just one risk factor . Some ofP = 0.0001). In the present, the study survival rate below 28 weeks of gestation was 20% which is close to the less than 20% found in Nigeria for 27-28 weeks of gestation in 2010 [P = 0.001) and multiple logistic regression (P = 0.0001) analyses. Our center is unable to deliver surfactant therapy and only provide bubble CPAP for babies requiring respiratory support [The association between lower gestational age and mortality was significant in bivariate analysis  and multiple logistic regression (P = 0.008) analyses that babies with hypothermia at the time of admission were significantly likely to die compared to those who had normal body temperature (Tables P = 0.006) and those with both hypothermia and RDS (P = 0.001) were significantly more likely to die on admission. Hence, it is important to observe and adhere strictly to the warm chain protocol across the continuum of care in order to reduce the risk of babies developing these conditions associated with hypothermia.Hypothermia was common at presentation to our NICU  during te Tables  and 5. IOur study could not find a significant relationship between sepsis, mode of delivery, age at presentation, maternal age, and risk of death.We did not do routine blood cultures for all babies admitted with prematurity. This could limit our ability to identify many of the babies with accompanying sepsis as signs and symptoms of sepsis may mimic many of the features of prematurity. We acknowledge this as one of the limitations of the study.As a retrospective hospital-based study, our study had a number of limitations. One of them was the fact that our analysis was limited to the information found in the patient records we were able to retrieve. This could have introduced bias in the sampling. Our findings may also represent the profile of patients we admit and may not be generalizable to other units. We also mainly assessed neonatal risk factors, except the maternal age. The fact that our unit is unable to do routine blood cultures means our diagnosis of sepsis may be an underestimation of the problem. Despite this, our findings were similar to those from other studies on the same topic in similar settings, and we think it serves as a baseline for more comprehensive studies to be conducted in the future.In conclusion, we found a high mortality rate in the preterm babies admitted to our unit and that mortality decreased with increasing gestational age and birth weight. We also found that a number of neonatal factors, either in isolation or in combination, were significantly associated with in-hospital mortality. The fact that there are much improved outcomes in more developed countries means that there is an opportunity to change the narrative for this vulnerable group by improving the quality of care provided during the antenatal and perinatal periods. In line with this high burden of hypothermia, we recommend routine feedback to all referring facilities and units, especially regarding maintenance of the warm chain during transport. Further studies are required to document the maternal risk factors associated with preterm birth and mortality in our hospital.


In Tanzania only an estimated one-quarter of births are registered and certified. Birth registration uses a centralized system with geographic and cost barriers for families. A pilot decentralized birth registration system has been trialled in 11 of 26 regions, substantially increasing registration points, and enabling notification, registration and certification to occur in one step.This study compares completeness of birth registration and certification and achievement of key birth registration milestones in two districts where the birth registration system decentralized and two districts with the existing centralized system.Registration, notification, census and survey data were used to estimate birth registration completeness and quantify achievement of key registration milestones for births in 2012–16. These were compared between districts of Mbozi  and Iringa  and districts of Dodoma and Kibaha which remained centralized.For births that occurred from 2012 to 2016, completeness of birth registration/certification (by early 2017) was higher in districts that decentralized  than remained centralized . Introduction of the decentralized system saw completeness for births registered within 12 months of occurrence increase in Iringa from 1% in 2014 to 67% in 2016, and in Mbozi from 15% in 2012 to 36% in 2013 before falling and subsequently increasing to 53% in 2016. In contrast, completeness in centralized districts did not increase. Although a higher proportion of births are notified in centralized than decentralized districts, registration and certification occurs for all notified births in decentralized districts but only one-third in centralized districts.Benefits of a decentralized system are more proximate registration points and the merging of notification, registration and certification steps. The findings, while demonstrating the immediate impact of the decentralized system on completeness, also show that continued efforts are necessary to sustain these improvements. Birth registration has many benefits for individuals, including to provide legal identity for citizenship and voting rights, as a requirement to access social security benefits and health and education services, and, more generally, as a fundamental human right . At a soComplete birth registration by 2030 is the aim of Sustainable Development Goal 16.9, however in many countries, including Tanzania, birth registration is incomplete . A revieIn Tanzania, civil registration has existed for over 100 years, but only relatively recently has compulsory birth and death registration been enforced [Tanzania’s completeness of birth registration is low, and the CRVS system cannot reliably be used to produce vital statistics. Just 24% of the UN-estimated 2,052,000 births in the country in 2017 were registered and certified . Hence, Many Tanzanian government functions have decentralized in recent decades. In general, the term decentralization refers to the transfer of authority and responsibility for public functions from the central government to subordinate or quasi-independent government organizations and/or the private sector . BeginniBased on a comprehensive CRVS Assessment in 2014, Tanzania mainland has developed a national CRVS Strategy for 2015/16 to 2020/21 , which aims to establish a fully functioning and complete CRVS system and address the challenges of the centralized birth registration system. However, decentralization of the birth registration process has been advanced by the government through RITA with the development of the Under-Five Birth Registration Initiative (U5BRI). The U5BRI has declared health facilities and the Ward Executive Offices (WEOs) as official registration points; made registration free for the user; and made the first copy of certificate provided free of cost immediately after the registration. The initiative was piloted in Temeke District in Dar es Salaam in 2012. The U5BRI is now implemented in 13 out of 26 regions and has increased registration points from 183 district offices to 4,817 registration centres, comprising 1,736 ward offices and 3,081 health facilities. The larger number of registration centres that are health facilities rather than ward offices reflects that, nationally, 63% of births occur in health facilities [The introduction of the decentralized U5BRI can potentially reduce the barriers faced by many Tanzanians in registering births and improve registration completeness. This study compares the performance of the system in two districts where decentralized birth registration has been introduced with two other districts where the existing centralized system still operates, in terms of:Completeness of birth registration/certification, including within 12 months of the birthQuantification of key birth registration milestones, specifically notification and registration/certificationThis study was conducted in four districts of Tanzania: Mbozi in Songwe region, Iringa Urban in Iringa region, Dodoma in Dodoma region and Kibaha in Coast Region . Kibaha In the study, two districts (Dodoma and Kibaha) with a centralized birth registration system were analyzed and compared with two districts (Mbozi and Iringa Urban) with a system that decentralized during the study period. In Mbozi district the decentralized birth registration system was launched in 2013 and in Iringa it was introduced in 2016. In Mbozi and Iringa, upon introduction of the decentralized system, all children born from 2012 onwards were eligible to be registered.In the centralized birth registration process in Tanzania, the system is mainly paper-based with only a few districts implementing a semi-digital system at the certification stage. While notification of births occurs at health facilities and, more rarely, ward offices, registration and certification occurs at the district headquarters. Therefore, parents or family members must travel to a district headquarters to register a birth and receive a birth certificate, often for long distances and at significant cost. This may be the explanation for variation of registration and certification coverage between large districts and small districts shown in Measurement of achievement of milestones within a birth registration system, from the occurrence of the birth through to certification, is necessary to fully understand the system’s strengths and weaknesses. Past research has identified ten CRVS milestones that every CRVS system must fulfil to achieve its objectives; notification, validation and verification, registration, certification, sharing information, storage and archiving, compilation, quality control, generation and dissemination . In thisFor purpose of this study the first four CRVS milestones were defined and quantified.Notification is the capture and onward transmission of minimum essential information on the fact of birth or death by a designated agent or official of the CRVS system using a CRVS authorized notification form (paper or electronic) with that transmission of information being sufficient to support eventual registration and certification of the vital event . In TanzValidation is the act by which a relevant authority confirms that all necessary documentation about a vital event is correct. The registration process can then continue. It includes standard checks and procedures to ensure the information contained in the notification is correct .In the centralized birth registration system validation is done once the notification forms reach the district registrar; further validation is also done when a parent visits the district registrar to finalize registration and obtain a birth certificate. In the decentralized system, validation is done at the time of registration and certification, however further validation might need to be done once records have been uploaded onto the database, and each uploaded record is further compared with a scanned image of the registration form.Registration is defined as the act of formally registering an event at a civil registration office where details of the event are entered into the official civil register by the Registrar . In the Certification is the issuance by the Civil Registrar of a legal document certifying a birth or death. This is usually in the form of a birth or death certificate . In the A range of data sources were used in the analysis: Numbers of registered and certified births for 2012 to 2016 from RITA, numbers of notified births for 2012 to 2016 from district registrars of Kibaha and Dodoma, population and birth data from the 2002 and 2012 Tanzania Census from Tanzania National Bureau of Statistics (NBS) and IPUMS-International, and regional percentages of deliveries in health facilities estimated by the 2015–16 Demographic and Health Survey ,18,19.Completeness of birth registration/certification was estimated as registered and certified births divided by the estimated true number of births. Separate databases exist for centralized districts and decentralized districts. Data were consolidated for the entire period from 1 January 2012 to 31 December 2016. We firstly measured completeness for all births that occurred from 2012 to 2016 and that were registered by early 2017. Even though Mbozi did not decentralize until 2013 and Iringa until 2016, it is expected the introduction of the decentralized system would improve completeness in earlier years because all children born from 2012 onwards were eligible to be registered. Data for centralized districts include all births which were certified as of 6 January 2017 whereas data for decentralized districts include all births which were certified and their records uploaded into the database as of 27 April 2017. This may partly explain low completeness rates in centralized districts in 2016. We also measured completeness for births registered and certified within 12 months from the date of birth, to assess the timeliness of registration and certification. All tabulations were made by mother’s usual residence.To estimate the true number of births, 10% samples of the Tanzanian Census datasets for 2002 and 2012 were used. These samples were chosen systematically with sample weights provided and used in our analysis to calculate results weighted to the Census population. Data on births in the last year and children ever born for women aged 15 to 49 years were available for all four districts. Using these data and standard fertility schedules, adjusted age-specific fertility rates and total fertility rates for the two periods were computed using the Relational Gompertz model . The RelThe quantification of milestones in the birth registration system was analysed and presented using Sankey charts, that show where births go missing in the system . Sankey Birth notification greater than 100% is possible in centralized districts and would occur where notified births are higher than the estimated number of births. This would be caused by an under-estimate of the true number of births occurring in health facilities due to either the estimate of the true number of all births or the percentage of all births occurring in health facilities (from the DHS estimates for the region) being too low. Another reason for birth notification exceeding 100% in Kibaha District could be due to its geographical nature, which makes it easily accessible by mothers residing outside the district tor better health care and whose births may be included as part of that district’s figures. Removing the numbers of births to mothers residing outside of Kibaha District from notification data was not possible.For births that occurred during the period 2012 to 2016, the completeness of birth registration/certification in districts that decentralized during the study period (54%) was more than two times higher than districts that remained centralized during the study period (24%) . CompletTrends over the period show that birth registration/certification completeness increased in districts that decentralized during the study period, reaching 60% in 2016 . In centThe completeness of birth registration/certification, when only including births registered within 12 months of occurrence, increased sharply in the year of decentralization in Mbozi district in 2013 (from 15% in 2012 to 36% in 2013), before falling to 13% in 2015 and increasing again to 53% in 2016 . In IrinThe steps of birth registration quantified were notification, validation, registration and certification. There is a time gap between registration and certification; all registered births are also certified. In both systems reported notified births are those which were validated and registered. It is not easy to quantify all notified births which are not validated and later registered, because once a notification tag is issued, it is dependent upon the registrar to check its validity; if it is not valid, it is discarded and the event is not registered.Overall, during 2012 to 2016 the districts that remained centralized had a higher percentage of births (68%) notified compared with districts that decentralized (54%) . In KibaDespite districts that remained centralized having higher levels of notification of births, the districts that decentralized performed much better on certification due to notification, registration and certification all occurring at the same time  compared with just over one-third of births in centralized districts . In Kibaha in 2016, only one-fifth of notified births were certified.The performance of birth registration for births that occur in health facilities and the community were analysed separately using Sankey diagrams showing flows of notified and non-notified births towards registration and certification. While notification happens in health facilities, any birth can be notified within 90 days when the parent gets into contact with a health facility. Analysis from the Sankey charts for districts that remained centralized shows that births that occurred in health facilities were more likely to be notified, registered and lastly certified than births that occurred in the community; about 84% of health facility births were notified as compared to only 6% of community births. One-third of all births that occurred in health facilities in centralized districts were certified compared with less than 1% of community births . The vasIn districts that decentralized during the study period, notification, registration and certification occur together, with births needing to be notified within 5 years of occurrence. Similar results were observed under this system, with health facility births more likely to be notified, registered and finally certified (68%) as compared to community births (20%), although the figure for community births is higher than for centralized districts . All cerFindings from the study show that in two districts in Tanzania where a decentralized birth registration system was introduced, there was a substantial increase in completeness of birth registration and certification within 12 months compared with districts that retained a centralized system. For births occurring in 2016, 60% of births in decentralized districts were registered  compared with just 14% in centralized districts and the estimated 24% completeness for all Tanzania. The introduction of the decentralized system had a significant impact in Iringa in particular, with completeness of registration and certification within 12 months increasing from less than 1% in 2014 to 67% in 2016. There was also an increase in completeness in Mbozi in 2013, before falling to 2015 and increasing again in 2016, three years after the introduction of decentralisation, because RITA, with support from UNICEF, re-trained registration assistants, public awareness campaigns were conducted and improved devices for data uploading were introduced.The introduction of the decentralized system also resulted in a higher level of registration and certification of births that occurred between 2012 and 2016 when compared with the centralized system, because all births from 2012 were eligible to be registered and certified under the new system. Closer examination of the registration milestones shows that a higher percentage of births in centralized districts were notified than in decentralized districts. However, only about one-third of these notified births were registered by early 2017, compared with all births in the decentralized system. These findings are similar to those by Kabadi et al that showed a routine CRVS system certified very few births following notification . The finThe introduction of the U5BRI in Iringa and Mbozi has improved access to birth registration by increasing the numbers of registration centres from only two district offices to 140 centres comprising of wards and health facilities. In both districts, the majority of parents can now access the service at no cost within five kilometers from their residence regardless of their rural/urban setting. This finding is consistent with evidence from a study that identified transport and cost as among issues that hinder households to certify births . FurtherAlthough the introduction of the decentralized birth registration system has improved birth registration, completeness is still well below 100%. Eighty per cent of community births and 32% of facility births are not notified; without improvement in notification of births, birth registration will remain incomplete. Another issue preventing the greater completeness in decentralized districts is the increased time to notify a birth from 90 days in the centralized system to five years. Parents may simply delay registering a child since they have ample time and in some cases they may forget or fail to register the child within defined period.This study showed substantial increases in birth registration completeness in two districts during the year that each decentralized the registration process. However, the evidence is less clear about the longer-term sustainability of the decentralized system, which is a limitation of the study. In Mbozi, there was a decline in completeness in 2014 and 2015 before another increase in 2016 due to the interventions described above, while in Iringa we do not have any data after the year of decentralization. It is apparent that although the introduction of a decentralized system, based on this evidence, may lead to an immediate increase in completeness, continued efforts need to occur to sustain these improvements over the medium- and long-term. Another limitation of the study is that the estimates of birth registration completeness are reliant on estimating total annual births in each district using demographic methods that make assumptions of population dynamics. The higher number of notifications in Kibaha than estimated annual births suggests that either the estimate of annual births is too low, or potentially births of non-residents of this district are included. However, the impact of such issues would most likely be consistent over the period of analysis, and so the trends in completeness would be unaffected.The study provides some evidence on the immediate impact of the new decentralized birth registration system on completeness, but also, based on the experience of Mbozi, demonstrates that continued efforts are necessary to sustain these improvements. This lesson is important for other districts in Tanzania that will introduce this decentralized system. Additional qualitative research could further inform how to improve birth registration amongst sections of the population for whom it remains low, even in decentralized districts, and which might highlight how to raise awareness of the benefits of birth registration. The study findings also suggest that one strategy for countries to attain complete birth registration by 2030, as stated in Sustainable Development Goal 16.9, is to consider implementation of decentralized district-level registration systems and processes that include increased numbers of registration points and more efficient steps in the registration and certification process. Further studies could be extended to determine how such decentralization also benefits the completeness of death registration which is currently lower than birth registration.This study has shown that, compared with the two districts that retained a centralized birth registration system, completeness of birth registration by the end of the study period was higher in the two districts that decentralized their system and that completeness within 12 months of birth increased substantially during the year they decentralized. However, the experience in one of the decentralized districts suggests that ongoing efforts are required to maintain those initial gains to later years, and more information should be collected from other decentralized districts to identify best practices that can inform roll-out of decentralized birth registration to other districts. The steps in birth registration have varying quantities between the two systems; while a centralized system indicates better performance in notification but poorer in registration, a decentralized system has been able to improve both notification and registration steps but after varying notification times. It can be concluded that decentralization is important towards reaching completeness of birth registration, however, the need to re-consider the reduction of notification times under this system is important considering timeliness of production of vital statistics that can be used by decision-makers. Improvement of birth registration completeness will provide more Tanzanians with legal identity, improve their access to social security benefits and health and education services, and also strengthen fertility statistics.


Intrahepatic arterial pseudoaneurysms are a rare, life-threatening complication after pediatric liver transplantation. Treatment of choice represents interventional radiological management with endovascular embolization of the segmental artery proximal and distal to the aneurysm. However, this technique results in loss of arterial perfusion distal to the aneurysm with subsegment arterial ischemia.We report a case of a 1-year-old girl with a pseudoaneurysm in the split-liver graft. Direct percutaneous, transhepatic access to the pseudoaneurysm was performed followed by super selective coil application into the aneurysm.Super selective percutaneous, transhepatic coil application is feasible even in pediatric patients after liver transplantation and results in preservation of the entire course of the liver artery. Pseudoaneurysms of the hepatic artery occur in 0.3–2.6% of cases after liver transplantation  for biliary atresia at the age of 7 months. Three months after liver transplantation the patient experienced stenosis of the hepaticojejunostomy that was treated with percutaneous transhepatic biliary drain placement. An initially placed 6 french biliary drain was gradually upsized to 10 french. By the age of 13 months (body weight: 10.9 kg) the drain showed slightly bloody bile fluid. Immediately performed ultrasound and magnetic resonance imaging (MRI) diagnosed an intrahepatic pseudoaneurysm (5 × 6 × 7 mm) located within the central aspects of segment III artery. MRI was executed for treatment planning and to rule out additional vascular and non-vascular pathologies.After removal of the biliary drain three attempts of percutaneous ultrasound-guided thrombin injections failed to occlude the pseudoaneurysm permanently. Consequently, coiling of the aneurysm was scheduled:The right femoral artery was accessed and 100 IE heparin per kilogram body weight were administered. A microcatheter was placed in segment III artery using the coaxial technique . The attempt to access the pseudoaneurysm with an endovascular placed catheter failed, due to anatomy and narrowing of the pseudoaneurysm’s neck and resulted in vasospasm of the segment III artery. Hence, the decision was made to access the pseudoaneurysm via a percutaneous, transhepatic approach. The microcatheter was advanced distal to the pseudoaneurysm to prevent coil dislodgement into the segmental artery and to facilitate coiling of the segmental artery proximal and distal to the pseudoaneurysm in case of rupture. Using ultrasound guidance, the pseudoaneurysm was successfully percutaneously punctured with a 22-gauche needle  and was completely filled with pushable coils  (Fig. Pseudoaneurysms of the intrahepatic arterial branches are a well-known complication after interventional biliary procedures (Tessier et al. Because of the very small diameter of segmental arteries and the pseudoaneurysms, as well as localization and configuration of pseudoaneurysms in pediatric split-liver transplants, surgery, stent placement, endovascular coiling of the aneurysm, and embolization of the segmental artery may be associated with an unfavorable risk-benefit profile resulting in loss of arterial perfusion and high morbidity. Ultrasound-guided thrombin injection has been reported as a treatment option for the occlusion of a pseudoaneurysm after liver laceration in an infant. However, this technique failed to occlude the aneurysm permanently in our case (Lorenz et al. Direct percutaneous access and highly selective, exclusive embolization of the aneurysm prevents complications related to open surgery and even related to endovascular approaches.We favored CEUS for follow-up since this technique is able to generate real time imaging without sedation and radiation exposure. Moreover, this technique has already proved to be a safe imaging technique in children after liver transplantation (Torres et al. Super selective percutaneous, transhepatic coil application for treatment of intrahepatic pseudoaneurysm after split liver transplantation is feasible even in pediatric patients and CEUS proved to be an adequate tool for follow-up. Although, this reported minimally invasive management of a pseudoaneurysm after pediatric split liver transplantation requires an experienced multidisciplinary team, we think that this technique should be considered especially in pediatric patients to preserve arterial perfusion, to minimize graft ischemia, and consequently to reduce morbidity.


The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton’s Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton’s jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes.Human umbilical cords were obtained from consenting caesarian section donors. The Wharton’s jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles.All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Pro-inflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles.There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton’s jelly formulation analyzed. The amount of these factors in Wharton’s jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries. Ligament, muscle, and tendon injuries produce pain, loss of function, instability, and secondary osteoarthritis , 2. TradOver the last decade, there has been an increased interest in the use of biologics for regenerative medicine applications . BiologiStem cells, including mesenchymal stem cells isolated from bone marrow, periosteum, adipose tissue, trabecular bone, and deciduous teeth, have produced marked interest for their applications to regenerative medicine . Stem ceHyaluronic acid, a polysaccharide found in most tissues, is a major component of extracellular matrix of the skin, joints, and eyes . HyaluroExosomes are small extracellular vesicles with diameter ranging from ~ 30 to 150 nm, developed from a sequential process of multivesicular body membrane remodeling . ExosomeThe increasing applications of biologic therapies for regenerative medicine have led to considerable marketing, patient demand, and clinical utilization . To be cWharton’s jelly is a primordial mucous connective tissue of the umbilical cord present between the amniotic epithelium and the umbilical vessels . The keyThe present study reports the results of experiments aimed to characterize a novel umbilical cord-derived Wharton’s jelly formulation and to evaluate the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes. We hypothesized that numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes are present in Wharton’s jelly; all may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.Cytomegalovirus), HIV-1/HCV (hepatitis C antibody)/HBV NAT Ultrio, WNV (West Nile Virus) NAT.Human umbilical cords were obtained from consenting caesarian section donors following standards established by the FDA and the American Association of Tissue Banks. Donors underwent comprehensive medical, social and blood testing prior to donation. Infectious disease testing was performed at an independent certified laboratory in accordance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and 42 CFR part 493 and the FDA. Each donor was tested for HIV I/II Plus O Ab (antibodies to human immunodeficiency virus type 1 & 2), HBsAg (HEPATITIS B surface antigen), HBcAb (hepatitis B core Antibody), HBcTotal, HCV NAT (hepatitis C virus nucleic acid test), HTLV (Human T-lymphotropic virus) I/II Ab, RPR (Rapid plasma reagin) syphilis screening - nontreponemal, CMV , or isolation and in vitro expansion of cells. This formulation is prepared according to the criteria of minimal manipulation by FDA, does not include any combination products, and is not intended to depend on the metabolic activity of living cells.A total of 60 samples from three different batches (20 samples per batch) were tested for sterility at an independent CLIA accredited laboratory, Eurofins VRL Laboratories , under United States Pharmacopeia Chapter 71 - Sterility Testing guidelines. Six randomly selected samples from two different batches were sent to an independent laboratory, RayBiotech , and were analyzed for the presence of growth factors and cytokines using Quantibody® Human Growth Factor Array 1 and Quantibody® Human Inflammation Array 3 respectively. The signals were visualized using Innopsys InnoScan  at Cy3 wavelength . Data were analyzed using Q-Analyzer tool and the concentration of cytokines was determined using serial standard curve provided by the manufacturer . In addition, six randomly selected samples from two different batches were analyzed for the presence of hyaluronic acid using Hyaluronan Quantikine ELISA (enzyme-linked immunosorbent assay) kit  according to the manufacturer’s protocol.Twelve randomly selected samples from the three different batches were sent to an independent laboratory, Extracellular Vesicle Core at Children’s Hospital Los Angeles , and were analyzed by nanoparticle tracking analysis for the presence of particles in the extracellular vesicle size range using Malvern Panalytical Nanosight NS300. These samples were also analyzed after staining with a general fluorescent membrane marker, CellMask Orange™ , as previously described .All samples passed the sterility test. Growth factors, including, Insulin-like growth factor binding proteins (IGFBP) 1, 2, 3, 4, and 6, transforming growth factor alpha (TGF-α), and platelet-derived growth factor-AA (PDGF-AA) were detected in the formulated Wharton’s jelly , interleukin 6 receptor (IL-6R), interleukin 16 (IL-16), and interferon gamma (IFN-γ) was also detected Table .Table 2Additionally, the expression of pro-inflammatory cytokines such as macrophage colony stimulating factor (MCSF), macrophage stimulating protein 1-alpha (MIP-1α); anti-inflammatory cytokines, such as tumor necrosis factor receptor superfamily member 1A and 1B (TNF-RI and TNF-RII), interleukin 1 receptor antagonist (IL-1RA); and homeostatic cytokines, such as tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) was also observed Table .Table 3Cytokines associated with wound healing including intercellular adhesion molecule 1 (ICAM-1), granulocyte-stimulating factor (G-CSF), growth differentiation factor 15 (GDF-15), and regenerative properties such as growth hormone (GH) were also expressed Table .Table 4Hyaluronic acid (average amount of 8.7 μg/mL) was detected in the formulated Wharton’s jelly. The nanoparticle tracking analysis demonstrated the presence of billions of particles (average amount of 17.4 billion/mL) in the extracellular vesicles size range in the light scattering mode. CellMask Orange™ staining showed the presence of 4.18 billion particles/mL in the fluorescent mode, indicative of true membrane-enclosed particles, i.e. extracellular vesicles. Representative images for nanoparticle tracking analysis in the light scattering and fluorescent mode are shown as Fig. Biologics hold great potential in treating a variety of musculoskeletal ailments . At presNumerous growth factors were detected in our Wharton’s jelly formulation. We detected IGFBP 1, 2, 3, 4 and 6, which acts as a carrier protein for insulin-like growth factor – 1 (IGF-1). IGF-1 improves osteogenic differentiation, induces chondrogenic differentiation of mesenchymal stem cells, and stimulates extracellular matrix production . We alsoSeveral immunomodulatory cytokines essential for regenerative medicine were identified. We detected high levels of chemokine (C-C motif) ligand 5 (CCL5), also known as RANTES , which has been reported to be involved in modulation of macrophage phenotype from M1 (pro-inflammatory) to M2  leading to enhanced osteogenesis . RANTES We detected pro-inflammatory and anti-inflammatory cytokines in the formulated Wharton’s jelly. Pro-inflammatory cytokines usually exert deleterious effects, including mediation of foreign body response and initiating inflammatory response against implants leading to their premature failure. Recent studies have explored their potential as initiators of regeneration. These studies have proposed a pro-regenerative function of the inflammatory signals initiated by these cytokines, and that a proper sequence of inflammatory signals followed by anti-inflammatory signals is essential for proper healing . We deteWe also identified interleukin 1 receptor antagonist (IL-1RA), a specific interleukin-1 (IL-1) receptor antagonist that competitively binds to the same receptor as IL-1 (including inflammatory IL-α and IL-1β), thereby blocking IL-1 mediated cellular changes . IL-1RA We identified several cytokines involved in wound healing. For example, we detected intercellular adhesion molecule-1 (ICAM-1), which promotes leukocyte accumulation into the wound site required for wound healing . ICAM-1 We detected expression of hyaluronic acid. The umbilical cord tissue contains high molecular weight hyaluronic acid (HMW), which is associated with high fluid retention in joints and has strong anti-inflammatory properties . In addiWe also detected the presence of membrane-enclosed particles in the extracellular vesicle size range. Extracellular vesicles including exosomes have demonstrated potential anti-inflammatory and pro-regenerative effects essential for inducing healing in different tissue types . They poThese results confirmed our hypothesis that growth factors, cytokines, hyaluronic acid, and extracellular vesicles are present in the formulated Wharton’s jelly. Several published basic science and preliminary clinical studies indicate that the combination of these factors may have added advantages for regenerative medicine applications . For exaWe also compared the amount of growth factors, cytokines, hyaluronic acid, and exosomes in Wharton’s jelly with other biologics based on the published literature. The amount of growth factors in Wharton’s jelly is higher compared with the umbilical cord artery . Jin et Our study has several limitations. Basic science studies have demonstrated the presence of a large number of growth factors in Wharton’s jelly . HoweverOur Wharton’s jelly formulation demonstrated the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles in clinically relevant quantities, in amounts greater compared with other biologics. The presence of multiple factors within one formulation may help reduce inflammation, decrease pain and augment healing of musculoskeletal injuries. These factors represent potential expanded applications for regenerative medicine.


Globally, 15 million infants are born preterm each year, and 1 million die due to complications of prematurity. Over 60% of preterm births occur in Sub-Saharan Africa and south Asia. Care at birth for premature infants may be critical for survival and long term outcome. We conducted a prospective audit to assess whether women giving birth preterm could be identified, and to describe cord clamping and neonatal care at hospitals in Africa and south Asia.+ 0 and 33+ 6 weeks gestation and/or the birthweight was 1.00 to 1.99 kg. A pre-specified audit plan was agreed with each hospital. Livebirths before 28 weeks gestation with birthweight less than 1.0 kg were excluded. Data were collected on estimated and actual gestation and birthweight, cord clamping, and neonatal care.This prospective audit of livebirths was conducted at six hospitals in Uganda, Kenya, India and Pakistan. Births were considered preterm if between 28Of 4149 women who gave birth during the audit, data were available for 3687 (90%). As 107 were multiple births, 3781 livebirths were included, of which 257 (7%) were preterm. Antenatal assessment correctly identified 148 infants as ‘preterm’ and 3429 as ‘term’, giving a positive predictive value of 72% and negative predictive value of 97%. For term births, cord clamping was usually later at the two Ugandan hospitals, median time to clamping 50 and 76 s, compared with 23 at Kenyatta (Kenya), 7 at CMC (India) and 12 at FBH/LNH (Pakistan). At the latter two, timing was similar between term and preterm births, and between vaginal and Caesarean births. For all the hospitals, the cord was clamped quickly at Caesarean births, with Mbale (Uganda) having the highest median time to clamping . For preterm infants temperature on admission to the neonatal unit was below 35.5 °C for 50%, and 59 (23%) died before hospital discharge.Antenatal identification of preterm birth was good. Timing of cord clamping varied between hospitals, although at each there was no difference between ‘term’ and ‘preterm’ births. For premature infants hypothermia was common, and mortality before hospital discharge was high. Being born preterm (before 37 weeks gestation) has major impact on survival and quality of life for the child, on psychosocial and emotional stress on the family, and on costs for health services and society –3. GlobaCare at birth, particularly for infants born preterm or sick, may be critical for survival and long term outcome. Optimal timing for umbilical cord clamping for both term and preterm births is controversial . TraditiOur objectives were to describe care at the time of preterm birth in low and middle income hospital settings, and to assess whether a randomised trial of alternative policies for timing of cord clamping at preterm birth might be feasible. Assessment of gestation in many maternity units in low and middle income settings often relies primarily on menstrual history and clinical examination. Therefore, we conducted a prospective audit to assess whether women giving birth preterm could be identified, and to describe timing of cord clamping and neonatal care.This prospective audit was conducted between May and September 2015 at six hospitals in four low and middle income countries: Mulago National Referral Hospital, Kampala and Mbale Regional Referral Hospital in Uganda; Kenyatta National Hospital, Nairobi, Kenya; Christian Medical College (CMC), Vellore, India; and Fatima Bai Hospital and Liaquat National Hospital (FBH/LNH), Karachi, Pakistan. These hospitals were selected based on their interest in conducting a randomized trial evaluating alternative strategies for the timing of cord clamping at preterm birth. Hospitals varied in terms of available resources and funding/management structures, though this was not considered for selection purposes. At one hospital , a neonatal unit was in the process of being established and there was no capacity for mechanical ventilation. The other five hospitals had some form of neonatal unit with some capacity to provide mechanical ventilation. All the hospitals had busy maternity units, with high levels of preterm birth and perinatal mortality. Ethics approval for each hospital was obtained according to local requirements. The study was observational, with all aspects of care being according to local practice.+ 0 weeks and 33+ 6 weeks gestation or the birthweight was 1.00 kg to 1.99 kg; and as ‘term’ if they were 34+ 0 weeks or above and birthweight was 2 kg or more. We used 34 weeks as the upper gestational age cut off as above this mortality is low and the infants usually do not require admission to a neonatal unit. As menstrual history is often unknown, and can be unreliable for assessing gestation, and a dating ultrasound scan is not usually available, we included birthweight as a surrogate for gestation, a common practice at the participating hospitals and more widley in low and middle income countries. For all infants admitted to a neonatal unit we requested a gestational age assessment using either the Dubowitz [For the purpose of this audit, we focused on preterm births associated with high mortality and morbidity. Therefore, we considered births as preterm if they were between 28Dubowitz  or New BDubowitz , whichevThe aim was to collect data for at least 30 preterm births at each hospital, which we estimated would require surveillance of 500–700 births. Continuous surveillance was not realistic in these settings, so we agreed a pre-specified plan for when the audit would be conducted within each hospital. To ensure a representative sample, this included day and night, weekdays and weekends, and was across different staff shifts. During each pre-specified audit period all livebirths on the delivery unit were eligible to be included. Births before the woman arrived on the delivery unit, stillbirths, and livebirths before 28 weeks gestation with birthweight less than 1 kg were excluded. Before the audit began at each hospital, the local staff who would be conducting the study attended 3 days of training in study procedures. As time of cord clamping and some other delivery room care is not usually recorded in the clinical notes, this included training in observing the birth, timing events with a stop watch, and recording the information. Staff were also trained in how to extract relevant information from the clinical notes onto our data collection forms, and to enter the data onto the database.During each pre-specified audit period, we collected data on: estimated gestation and how this was estimated , clinical assessment, and/or dating ultrasound scan as per local practice); estimated birthweight and how this was estimated ; assessment of gestation after birth, and how this was assessed  identified by a unique study ID. At each hospital, data were entered into a secure online database developed and maintained by the Nottingham Clinical Trials Unit.For each hospital we described: births missed during the audit period; estimated gestation at birth and birthweight, ; timing of cord clamping for ‘preterm’ and ‘term’ births; the number of births identified as preterm before birth; clinical staff present at these preterm births; neonatal care provided at birth and after birth; and serious neonatal morbidity. Mortality was described both overall and per site; analysis by timing of cord clamping and mortality was not performed due to the observational study design and risk of bias. We classified neonatal units as: Level 1 if they had no access to ventilation support, Level 2 if there was limited access to ventilation support, and Level 3 if they provided neonatal intensive care including the capacity to provide prolonged mechanical ventilation , 20. LevFor assessment of gestation before birth, we calculated the positive predictive value (PPV) and negative predictive value (NPV) of being preterm. If data were missing for either gestation or birthweight, then the single measure (gestation or birthweight) was used. If data for both gestation and birthweight was missing, the infant was excluded from the PPV/NPV calculation. We conducted three sensitivity analyses: using only infants with complete data for gestation and birthweight; categorising infants with missing birthweight solely on gestation; and assuming that all infants with missing data were born at term.Variables were described as median (interquartile range) or mean (standard deviation) when continuous, and N (%) when categorical. All analyses were performed in Stata version 14.2 or later.Overall, 4149 women gave birth during the audit period; 399 of these births were not observed; for 74 women this was because she was known to be having a stillbirth  had a preterm birth, 241 (74%) a spontaneous vaginal birth, 80 (25%) caesarean section and 4 (1%) a vaginal breech or instrumental birth. Audit data were available for 3750 (90%) women, of whom 63 were excluded  were correctly identified as preterm and 3429 (92%) were correctly recognised as term  of the total births were by Caesarean section (Table 7% of thewww.embraceinnovations.com) (52%), airway suction (54%) and oxygen (54%) (data not shown).For the 130 preterm infants born vaginally, one member of staff was present at the birth for 90, and for all but three births this was a midwife (data not shown). A paediatrician or neonatologist was present for just over a quarter of all preterm births , and for the majority this was in CMC (India)  or FBH/LNH (Pakistan) . Of these preterm infants, 230 (89%) had some neonatal care in the delivery room, the most common being wrapped in plastic or Embrace (Thirteen (5%) of the preterm infants were taken to the postnatal ward and not admitted to a neonatal unit Table . For theIn order to conduct research to improve the quality of delivery room care for preterm infants it is important to be able to correctly identify those likely to be born preterm. In this prospective audit conducted in delivery units at a range of hospitals in low and middle income countries, we found that using information from antenatal assessments of estimated gestational age and birthweight resulted in reasonable identification of those giving birth preterm . Overall, the PPV was 72% and NPV 97%. Timing of cord clamping varied between hospitals, although within each hospital there was no real difference between timing of cord clamping for ‘term’ and ‘preterm’ births. At all hospitals, for caesarean births cord clamping was largely immediate (within 30 s). For vaginal births, cord clamping was usually immediate at CMC (India) and FBH/LNH (Pakistan), and usually deferred at Mulago and Mbale in Uganda and Kenyatta (Kenya). With the exception of FBH/LNH (Pakistan), hypothermia following preterm birth was common, with half the preterm infants having a temperature below 35.5 °C, and 14% below 34.5 °C on admission to the neonatal unit. Although the numbers are relatively small, our study also confirms the high mortality associated with preterm birth in these settings.Recently, the evidence base for alternative policies for timing of cord clamping at very preterm birth has increased, including publication of a large international trial co-ordinated from Australia  and our This study has shown that women giving birth preterm can be identified in these settings, and so conducting a randomised trial evaluating delivery room interventions for these births would potentially be feasible. Improving assessment of gestational age before birth would increase the proportion of potentially eligible women correctly identified. A future trial design would need to consider the implications of the PPV and NPV reported here and anticipate the inclusion of some births that were thought to be preterm and so randomised, but after birth are assessed as being term.Despite conducting the audit in places with a warm climate, a surprisingly high proportion of the preterm infants were cold by the time they arrived at the neonatal unit. Keeping newborns warm, particularly those born preterm, is a key element in newborn life support , as thisCranial ultrasound scans were performed on a small number of infants at two of the hospitals in our study. This is not surprising as such scans are often unavailable in low and middle income settings .Strengths of this study are that data were collected prospectively, with births observed to collect information not routinely available in the clinical notes; that we ensured a representative sample of all births was included; that data were available for 90% of births; and that we included a range of hospitals from four countries in low and middle income settings from four countries in Africa and south Asia. Limitations are that although the study was observational, conducting it may have changed care, as at some sites delivery unit midwives were trained to conduct the audit. Therefore they might also have been doing clinical shifts providing care at births included in the audit. Also, just the presence of an observer may have influenced care. As is common for audit data collected from clinical records, we were not able to assess the quality of these data. As our definition of preterm included birthweight, infants who were small for gestational age may potentially have been misclassified, although if a neonatal assessment was available this misclassification could be avoided. Finally, the hospitals contributing data may not be typical of wider practice within each country. Nevertheless, we consider that we included a representative range of units within low and middle income settings where conducting research at the time of preterm birth is feasible.Identification of women having a preterm birth, using our definition based on gestational age and/or birthweight, was good, with a PPV of 72% and a NPV of 97% based on antenatal assessment. Therefore conducting research, including randomised trials, to improve the quality of delivery room care for very preterm births would be feasible in hospitals in low and middle income countries. Timing of cord clamping varied between hospitals, although within each hospital there was no difference between ‘term’ and ‘preterm’ births. For caesarean births cord clamping was largely immediate. For vaginal births, timing varied. This variation in practice suggests a randomised trial comparing alternative policies for cord clamping may be feasible. The high levels of hypothermia amongst infants born preterm also suggests that implementing strategies to ensure these infants are kept warm following birth should be a priority. Given the high level of variation in practice in the delivery room and neonatal units, conducting quality improvement initiatives to promote high quality newborn care is also important.Additional file 1: Figure S1. Timing of cord clamping for term and preterm births by mode of delivery.Additional file 2: Table S1. Identification of preterm and term infants in the audit.