A considerable number of previous studies have examined the trends, correlates, and consequences of premarital childbearing among adolescents and young women in Africa. However, very little is known about whether and how soon single mothers have another premarital birth in sub-Saharan African countries. This study examines the timing of a second premarital birth among single mothers and assesses how it may differ across key socio-demographic variables.We pooled recent Demographic and Health Surveys from 25 sub-Saharan African countries to create a database of 57, 219 single mothers aged 15–49 years. Cumulative incidence graphs and Fine and Gray’s competing risk models were used to delineate the timing of a second premarital birth and its socio-demographic correlates.(p < 0.05) in most countries. Residence in an urban area compared to rural, was also significantly associated with a low incidence of second premarital birth in 10 countries (p < 0.05).More than one-third of single mothers in 16 countries have had a second premarital birth in their reproductive life. We also observed that more than 15% of the single mothers in Angola, Benin, the Republic of Chad, Liberia, Namibia, Nigeria, Sierra Leone, and Uganda, have had another premarital birth three years after the first. The incidence of a second premarital birth was significantly lower among women with secondary or higher education, compared to women with less than secondary education Findings indicate a rapid progression to having a second premarital birth in some sub-Sahara African countries, particularly among socio-economically disadvantaged women. The findings suggest the need for tailored interventions for improving the quality of life of single mothers, to reduce the associated burden and consequences of having a premarital birth. Premarital childbearing in sub-Sahara African (SSA) countries is becoming an important phenomenon—demographically and socially –7, in paHaving a premarital birth has diverse implications, especially for unmarried mothers, rather than their male counterparts , 11. ForOver the past decade, evidence on the benefits of marriage for the well-being of children in sub-Saharan Africa, its timing and events within it, has continued to mount. Previous studies have shown that the children of single mothers have higher mortality risks, and poorer health outcomes compared to children born to married mothers , 21, 22.Despite the economic hardship and the implication of premarital childbearing for children and women’s health, it remains unclear whether women would have a second premarital birth as well as the timing of this event. Emerging research has only given considerable attention to the socio-economic factors associated with first premarital childbearing in Africa, its implications for the marriageability of single mothers, and child health , 14, 20.In this article, we draw from the recent scholarly interest in premarital childbearing to elucidate the timing of a second premarital birth among single mothers in sub-Saharan African countries. We anticipated lower rates of second premarital childbearing and differing patterns across countries, especially in countries where premarital childbearing is highly stigmatized for a few reasons. First, emerging studies have highlighted the health returns of premarital childbearing for children and their mothers , 22. As We also assess how the timing of second premarital childbearing differs by key socio-demographic characteristics. We hypothesize that the timing of a second premarital birth will differ across key socio-demographic characteristics, mainly because the health disadvantages of premarital childbearing are not evident across all socio-economic spectrums. Secondary or higher levels of maternal education reduce the effect of premarital childbearing on child health and well-being , 22. As In this study, we used cross-sectional data from the recent (2013–2018) Demographic and Health Surveys (DHS) of 25 countries in the sub-Saharan African region. For most countries, the surveys were the sixth or seventh round. The DHS is a nationally representative survey that monitors the demography and health of populations in developing countries. The DHS collects rich information about women’s reproductive histories, including the number of children ever born per woman, their age at the birth of individual births (for women who reported having at least one birth), as well as the month and year of each birth. The women were also asked to give substantial information about their current marital union, including whether they had ever married, and if so, the month and year of their first marriage. The survey’s rich information on women, including their marital status and fertility behaviors, made it a valuable resource for this study.The full data sample for this study comprised of 63,431 women from the selected countries who have had at least one premarital birth at the time of the survey. We considered only women who had their first premarital birth at 15 years or older because the pattern of childbearing at younger ages are likely to differ and could have been biased by the inability of the women to report the date of their first birth accurately. As a result, we excluded about 9% (5853) of the women who were less than 15 years at the time of their first birth. A similar exclusion criterion has been used in a prior study, although they excluded only women with first births before 13 years , the risk of a second premarital birth was higher for women who had their first premarital birth after 25 years, compared to those who had their first premarital birth between 15 and 24 year. In Namibia , South Africa , Liberia , and Nigeria , the incidence of a second premarital birth was lower for women who had a first premarital birth at age 25 years or more, compared to 15–24 years. Residence in an urban place of residence was also associated with a low incidence of a second premarital birth in Kenya , Rwanda , Namibia , South Africa , Zambia , Ghana , Benin , Nigeria , and Senegal . The ability to read was not associated with the incidence of second premarital birth in all West African countries, but a significant association was observed in Angola, Kenya, Tanzania, Uganda, Malawi, and South Africa.In this study, we examined the timing of a second premarital birth among single mothers in 25 sub-Saharan African countries. We were able to delineate country-level and regional variations in the progression to a second premarital birth among single mothers. The results from this study extend and expand on previous research in two ways. First, our study is one of the first to show that families formed outside of marriage are increasing, not only in number but also in size. Our analysis also highlights how long single mothers wait before they have a second premarital birth.Contrary to the expectation that contraceptive use increases after the first premarital birth  and singSecond, our analysis provides evidence that the incidence of a second premarital birth differs significantly by women’s educational attainment in most countries. In a few countries, we also observed that the timing of a second premarital birth is lower among younger women, those in rural areas, and women who are not literate. This finding contrasts with our hypothesis, considering that lower levels of education and high levels of unemployment place many single mothers in precarious positions, struggling to pay for food, and other necessities critical for the health and well-being of themselves and their first child . AlthougAs families formed outside of marriage continue to increase in size in sub-Saharan African countries, especially in Angola, Sierra Leone, Liberia, South Africa, Namibia, and other countries where a significant proportion of single mothers have had another premarital birth, there is a need to review the situation. Children living in such contexts require high levels of supervision and attention since the mothers are more likely to be young, unlikely to have secondary or higher education, have higher poverty rates, and fewer economic resources than married mothers –18. EvidThough further research is needed to understand why socio-economically disadvantaged single mothers have another premarital birth and rapidly in a few countries, the findings of this study are also relevant for future research on premarital childbearing in sub-Saharan African countries. It is imperative to explore whether different men father the two premarital births. This may particularly be of interest to policymakers in the family planning and HIV prevention programs, as it may reflect the level of women’s susceptibility to sexually transmitted infections in the absence of effective means of contraception, especially condoms. We also anticipate that our study will be followed by future work that seeks to understand how socio-economic disadvantage and social structures, including stigma, serve as facilitators of a second premarital birth.Our study, being one of the first to examine the timing of a second premarital birth, has a few weak points. First is the cross-sectional nature of the data, and as a result, we cannot completely rule out the possibility of a reverse causality whereby low education may result in having another premarital birth, but having a second premarital birth may also contribute to delays in the educational advancement of the single mother especially where premarital childbearing is socially unacceptable and stigmatized. However, there is a very minimal possibility of reverse causality with other study variables like age at first birth, place of residence, and perhaps literacy. Secondly, ensuring that women accurately report the date of their marriage is challenging in any setting and may be especially so in African contexts, where the formalization of unions often involves customs that occur over several months , 48, 49.Overall, our study found a mixed pattern of progression to having a second premarital birth in sub-Saharan Africa. We noted the rapid succession of first premarital births in Angola, Benin, the Republic of Chad, Liberia, Namibia, Nigeria, Sierra Leone, and Uganda, where more than 15% of single mothers have had another child before marriage by the third year. The timing of a second premarital birth differed significantly by educational attainment in most countries while residing in an urban area and being literate was associated with a lower incidence of second premarital birth in a few countries.


Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth outcomes. However, evidence on whole diet that considers complex nutrient and food interaction is rare and conflicting. We aim to elucidate the influence of whole-diet maternal dietary inflammatory potential and quality during periconceptional and antenatal periods on birth outcomes.n = 2 cohorts) and antenatally (n = 7 cohorts). Maternal dietary inflammatory potential and quality were ranked using the energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) index, respectively. Primary outcomes were birth weight and gestational age at birth. Adverse birth outcomes, i.e., low birth weight (LBW), macrosomia, small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm and postterm births were defined according to standard clinical cutoffs. Associations of maternal E-DII and DASH scores with infant birth outcomes were assessed using cohort-specific multivariable regression analyses , maternal height, parity, cigarettes smoking, and alcohol consumption), with subsequent random-effects meta-analyses.We harmonized and pooled individual participant data (IPD) from up to 24,861 mother–child pairs in 7 European mother–offspring cohorts . Maternal diets were assessed preconceptionally  was associated with higher birth weight  and head circumference , longer birth length , and lower risk of delivering LBW  and SGA  infants. Higher maternal prepregnancy E-DII score (more pro-inflammatory diet) was associated with lower birth weight  and shorter birth length , whereas higher pregnancy E-DII score was associated with a shorter birth length  and higher risk of SGA . In male, but not female, infants higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA . No consistent associations were observed for maternal E-DII and DASH scores with gestational age, preterm and postterm birth, or macrosomia and LGA. Limitations of this study were that self-reported dietary data might have increased nondifferential measurement error and that causality cannot be claimed definitely with observational design.Overall, the study mothers had a mean ± SD age of 29.5 ± 4.9 y at delivery and a mean BMI of 23.3 ± 4.2 kg/mIn this cohort study, we observed that maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized IPD. Improving overall maternal dietary pattern based on predefined criteria may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes. In this cohort analysis, Ling-Wei Chen and colleagues explore associations of maternal dietary patterns with offspring birth outcomes. Adverse birth outcomes are associated with higher morbidity and mortality during childhood and a higher risk of noncommunicable diseases in adult life.The Developmental Origins of Health and Diseases (DOHaD) theory posits that maternal periconceptional and intrauterine nutrition can alter the health trajectory of the offspring.Although individual maternal dietary factors have been studied widely, evidence on the impact of whole-diet maternal dietary inflammatory potential and quality on birth outcomes is scarce and conflicting.We investigated whether maternal prepregnancy and antenatal dietary quality and inflammatory potential are associated with birth outcomes in a consortium of 7 European cohorts in 5 countries using harmonized individual participant data from up to 24,861 mother–child pairs.After adjusting for confounders, we found that a low-quality and pro-inflammatory maternal diet during pregnancy is significantly associated with lower offspring birth weight and higher risk of offspring being born small-for-gestational-age (SGA).In male, but not female, infants higher maternal prepregnancy energy-adjusted Dietary Inflammatory Index (E-DII) score was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA.Improving overall maternal dietary quality and reducing dietary inflammatory potential may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes.Policies to ensure availability of affordable healthy foods and programmatic efforts to inform and support women of reproductive age, such as raising awareness of the importance of maternal diet and prenatal and antenatal counseling would help women achieve a healthier diet. Adverse birth outcomes including low birth weight (LBW), macrosomia, and preterm or postterm birth are associated with higher morbidity and mortality during childhood and higher risk of noncommunicable diseases in adult life –4. GlobaThe Developmental Origins of Health and Diseases (DOHaD) theory posits that maternal periconceptional and intrauterine nutrition can alter the health trajectory of the offspring. Several lines of evidence from animal studies , human fDespite the importance of dietary quality and inflammatory potential, limited studies have investigated their relationships with birth outcomes, with inconsistent findings reported ,21. AlthThis study involves 7 mother–offspring cohort studies across 5 European countries within the ALPHABET consortium, formed in 2017 with an overarching aim to investigate the complex interplay between maternal dietary environment, epigenetics, and a range of child health outcomes. These cohorts/longitudinal follow-up from a randomized controlled trial include the Lifeways Cross-Generation Cohort Study  and the Randomised cOntrol trial of LOw glycaemic index diet during pregnancy study  in Ireland, the study on the pre- and early postnatal determinants of child health and development  in France, the Avon Longitudinal Study of Parents and Children  and the Southampton Women’s Survey  in the United Kingdom, the Polish Mother and Child Cohort  in Poland, and The Generation R Study  in the Netherlands. The study design for each cohort has been described in detail elsewhere –30. FollAll studies have been approved by the respective local ethical review committees (listed in n = 5 cohorts) and late pregnancy  .Prepregnancy or antenatal dietary intakes of the study mothers were assessed using validated (except ALSPAC) food frequency questionnaire (FFQ), which have been described in detail elsewhere –38. IntaMaternal dietary inflammatory potential was scored using the energy-adjusted (using density method) Dietary Inflammatory Index (E-DII), a well-validated literature-derived score derived from the Dietary Inflammatory Index (DII) of which development has been described in detail elsewhere . BrieflyDietary quality was assessed by degree of adherence to the Dietary Approaches to Stop Hypertension (DASH) diet. The harmonization and moderation process for DASH score generation within the ALPHABET consortium has been described elsewhere . In ALPHPrimary outcomes were birth weight and gestational age, both modeled continuously and categorized based on clinical cutoffs as follows: (1) low birth weight ; (2) macrosomia ; (3) preterm birth (delivery at <37 completed weeks of gestation); and (4) postterm birth (delivery at ≥42 completed weeks of gestation) ,44. FurtSecondary outcomes were birth length and head circumference measured at birth. In some cohorts , abdominal circumference and sum of subscapular and triceps skinfolds were also available for investigation.2), maternal age at delivery (in year), maternal education status (study-specific definition of low/medium/high), self-reported maternal birth place/maternal ethnicity (European-born/white or non-European-born/non-white), maternal cigarette smoking (never/ever/current), maternal alcohol intake during pregnancy (yes/no), maternal parity (primiparous/multiparous), and infant sex . These data were originally collected by questionnaires (interviewer- or self-administered) or abstracted from birth records. Data are expressed in different units and categories in different studies, thus we harmonized the covariates across studies through standardizing units and categories for downstream analysis. For example, educational attainment was recategorized based on study-specific definitions of low, medium, and high. In addition, some countries did not allow specific question on “ethnicity” and thus can only be proxied by questions on place of birth. We grouped participants who specifically reported as being of European ancestry and those reported as being born in Europe into 1 group.Important covariates were identified and harmonized for subsequent analyses. These included maternal height (in cm), prepregnancy body mass index  and main outcomes  information. We further excluded participants with implausible energy intakes  to avoid extreme misreporting ,48.I2-statistic  and shorter birth length , whereas higher pregnancy E-DII score was associated with a shorter birth length  and a higher risk of LBW  and SGA . No consistent association was observed between prepregnancy DASH and primary continuous and binary outcomes . However, higher maternal pregnancy DASH score  was associated with higher birth weight , longer birth length , higher head circumference , and lower risk of delivering LBW  and SGA  infants. These were consistently observed for early-pregnancy and late-pregnancy DASH scores. Maternal E-DII and DASH scores were not associated with indicators of excessive fetal growth (macrosomia and LGA). The main results for birth weight and risk of SGA were summarized in the form of forest plots in Figs The associations of maternal prepregnancy and pregnancy E-DII and DASH scores with offspring birth outcomes are documented in P value = 0.042]. In a small subset of studies , higher maternal prepregnancy and late-pregnancy DASH scores were associated with higher offspring abdominal circumference [only 1 study (SWS) included], while higher early-pregnancy DASH score was associated with thicker offspring skinfolds, but these associations should be interpreted with caution due to smaller numbers.In contrast, no consistent associations were observed between maternal E-DII, DASH and gestational age at birth , and risP for quadratic term = 0.007, 0.031, and 0.001, respectively). Upon closer inspection, the influence of higher prepregnancy DASH versus longer birth length seemed to level off at the highest quartile, whereas higher prepregnancy DASH versus higher abdominal circumference and higher early-pregnancy DASH versus lower risk of LBW relationship appeared to level off after the second quartile, as compared with those in lowest quartile . Higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and a higher risk of SGA in male but not female infants  and birth size measures  and a higher risk of delivering SGA infants. Furthermore, we observed interesting sex differences in the associations between maternal dietary inflammatory potential and birth outcomes. To our knowledge, this is hitherto the largest multicenter study confirming that maternal whole diet is associated with birth size .Our results appeared robust across several sensitivity analyses, including in a healthier sample of mothers without pregnancy complications or among full-term infants. In addition, further adjustment for gestational age had minimal influence on effect estimates, implying that the observed relationships between maternal dietary scores and birth size were not mediated through length of gestational duration. However, mutual adjustment of E-DII and DASH appreciably, but not completely, attenuated the associations, suggesting that the associations of general healthy eating with higher birth sizes might not have been mediated completely through lowering maternal inflammation, and other biological mechanisms such as epigenetic programming might be in play.n = 5), the pooled estimate was statistically significant [OR (95% CI) = 0.91 ]. Our results showed more consistent associations between maternal dietary quality and birth size, probably due to more consistent definition of healthy dietary pattern, harmonized covariates derivation, and analysis strategy. In contrast, both previous reviews noted limited but consistent evidence that maternal healthy eating during pregnancy was associated with a lower risk of preterm birth, as opposed to our observed null association between higher DASH score and preterm birth risk. It may be that the prevalence of preterm birth is too low in our study (<5%) or factors other than maternal dietary quality have a greater influence on the risk of preterm birth in developed countries with good access to healthcare. Interestingly, in subgroup analysis of the previous review, the association between maternal healthy eating during pregnancy and lower risk of preterm birth also appeared stronger in non-European versus European studies [There have been recent comprehensive systematic reviews . This could be due to residual clinical and methodological heterogeneity, or that the true effects may vary from study to study—an assumption of our chosen random-effects model. To further reduce heterogeneity, a prospectively planned IPD with harmonized study design should be conducted. Dietary data were self-reported  before the outcomes, which might have increased nondifferential measurement errors that may bias results toward the null. Diet measures are based on FFQs with different degree of detail   having some differences in dietary intakes and sociodemographic characteristics, our study samples can mainly be generalized to white women in developed countries. Despite substantial efforts spent to reduce clinical heterogeneity by harmonizing data across included studies, especially for a harmonized definition of general healthy eating and inflammatory potential, it should be kept in mind that some pooled analyses were associated with high statistical heterogeneity  , which cs, etc.) , and ours, etc.) . While tOur findings may have important clinical and public health implications. For example, a higher maternal dietary quality indicated by higher maternal pregnancy DASH score, scaled to a very plausible 2-SD increase , was associated with a 37 g higher birth weight and a 24% lower risk in delivering SGA infants. Considering the high prevalence of fetal growth restriction, especially in developing countries, and its potential negative impacts on lifelong health, improving overall maternal dietary quality is of utmost importance. Our findings represent a significant contribution to the knowledge base regarding the importance of maternal diet on offspring health outcomes. Better understanding of these relationships may inform revision of existing dietary guidelines or development of new guidelines for optimal nutrition in pregnancy. Policies to ensure availability of affordable healthy foods and programmatic efforts to inform and support women of reproductive age, such as raising awareness of the importance of maternal diet and prenatal and antenatal counseling, would help women achieve a healthier diet.In conclusion, maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized individual participants data. Although confirmation from other sources including randomized controlled trials are needed to establish causality, our results strongly suggest that improving overall maternal dietary pattern based on predefined criteria related to overall quality and inflammatory potential is beneficial for optimal fetal growth.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S11 Table(DOCX)Click here for additional data file.S12 Table(DOCX)Click here for additional data file.S13 Table(DOCX)Click here for additional data file.S14 Table(DOCX)Click here for additional data file.S15 Table(DOCX)Click here for additional data file.S16 Table(DOCX)Click here for additional data file.S17 Table(DOCX)Click here for additional data file.S18 Table(DOCX)Click here for additional data file.S19 Table(DOCX)Click here for additional data file.S20 Table(DOCX)Click here for additional data file.S21 Table(DOCX)Click here for additional data file.S1 PRISMA Checklist(DOCX)Click here for additional data file.


This cohort study examines the association between preterm birth and psychotropic drug prescriptions during adolescence and young adulthood. Do adolescents and young adults who were born preterm receive more prescriptions of psychotropic drugs compared with those who were born full term?In this cohort study in Norway of 505 030 individuals followed up from ages 10 to 23 years, all degrees of preterm birth were associated with higher rates of prescription of psychotropic drugs during adolescence and young adulthood compared with those born at term.These findings provide further evidence for increased risk of mental health impairment among individuals born preterm. Individuals born preterm have increased risk of mental health impairment compared with individuals born at term. The associations between preterm birth and attention-deficit/hyperactivity disorder and autism are well established; for depression, anxiety, psychotic and bipolar disorder, studies show divergent results.To compare the prescription of psychotropic drugs in adolescence and young adulthood between those born preterm and those born at term.This cohort study used registry data to identify all Norwegians born after 23 weeks of completed gestation between 1989 and 1998. Included individuals were those without registered birth defects, alive at age 10 years, and with available maternal data. Individuals were followed up from 2004 to 2016. Psychotropic drug prescriptions received from age 10 to 23 years were compared between preterm groups and peers born at term. Individuals were compared with their siblings to control for shared family confounding. Data analyses were performed from August 2018 through February 2020.(GA) was categorized in 4 groups: extremely preterm , very preterm , moderately or late preterm , and full term .Gestational age at birth Prescriptions of psychotropic drugs  among preterm groups were compared with prescriptions among peers born at term and among siblings.Among 505 030 individuals , 762 individuals (0.2%) were extremely preterm, 2907 individuals (0.6%) were very preterm, 25 988 individuals (5.1%) were moderately or late preterm, and 475 373 individuals (94.1%) were full term. Individuals born preterm had increased risk of psychotropic drug prescription, with a dose-response association between GA and prescription. The extremely preterm group had higher rates of prescription for all drug types compared with peers born at term, with odds ratios from 1.7  for antidepressants to 2.7  for psychostimulants. The elevated odds of prescription of all types were less pronounced in the moderately to late preterm group, including odds ratios of 1.1  for antidepressants and 1.2  for psychostimulants. The increases in odds were smaller in the sibling comparison, and increases were not significant for several groups. For example, the OR for any prescription in the sibling analysis was 1.8  in the very preterm group and 1.0  in the moderately or late preterm group.This cohort study found higher rates of prescription of psychotropic drugs throughout adolescence and young adulthood among individuals with all degrees of preterm birth compared with those born at term. These results provide further evidence for an increased risk of mental health impairment among individuals born preterm and suggest that this is not restricted to the most preterm groups. While children born preterm have an increased risk of attention deficit hyperactivity disorder (ADHD) and autism,20 there is still uncertainty as to whether they have an increased risk of depression and anxiety24 or psychotic and bipolar disorders,25 with studies finding divergent results.Children born preterm have an increased risk of neurodevelopmental and cognitive impairment8 However, to our knowledge, a minority of the studies in this field have targeted adolescence, a period during which many mental health difficulties emerge.26The increased risk of mental health impairment among children born preterm is found throughout their lifespan, from childhood through adolescence and into adulthood.30 and explore how associations for the different drug types varied by age and sex.The aim of this study was to assess the association between individuals’ degree of preterm birth and prescriptions of psychotropic drugs during adolescence and into young adulthood. Additionally, we wanted to assess associations within sibling groups to reduce confounding due to factors shared within familiesSTROBE) reporting guideline for cohort studies.This cohort study was assessed and approved by the Regional Committees for Medical and Health Research Ethics (REC) and the Norwegian Data Protection Authority. A waiver of informed consent was granted by REC because of the difficulty of obtaining consent owing to population size. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (31 Norwegian Prescription Database (NORPD),32 and Statistics Norway.33 We included all Norwegians who were born from 1989 through 1998, had a gestational age (GA) of from 23 weeks to less than 45 weeks, had a birthweight greater than 400 g, had no registered congenital birth defects, were alive at age 10 years, and had registered maternal variables. We excluded individuals for whom the size of the discrepancy between birth weight and gestational age suggested that it was most likely associated with errors in registrations. The MBRN includes virtually all births in the country and provides information on maternal and neonatal health, education, and demographic characteristics at birth. The information was linked using a unique personal identification number, and siblings were identified using the unique identification number for each mother, provided by Statistics Norway. Information from the NORPD, established in 2004, provided a continuously updated listing of all prescribed drugs dispensed by pharmacies. Data from Statistics Norway provided dates of emigration and death.This study was based on a registry data linkage among the Medical Birth Registry of Norway (MBRN),All study participants were followed up with annual assessments from 2004 through 2016. Participants were followed up from age 10 years until the year of emigration, death, or 24th birthday, whichever occurred first.We measured GA by completed weeks of gestation at birth, as recorded in the MBRN according to the mother’s last menstrual period. We categorized GA into 4 groups: extremely preterm , very preterm , moderately or late preterm , and full term .34 In addition to recording specific prescriptions for each drug type for individuals, we recorded if individuals were prescribed any of the 5 types. Prescription status  was recorded each year during follow-up according to age for each of the 5 types of psychotropic drugs and for any prescription. Based on these annual registrations, we also constructed measures of prescription vs no prescription for each of the drug groups for the entire follow-up period , early adolescence , and late adolescence or early adulthood .Outcomes were receiving psychotropic drug prescriptions during follow-up period, per data collected from the NORPD. We defined 5 categories of psychotropic drugs, classified according to the Anatomical Therapeutic Chemical (ATC) system  per year; DDD is an international standardized unity for drug consumption and is defined as the assumed mean maintenance dose per day for a drug used for its main indication among adults.z score for birth weight using Marsal et al’s fetal growth standards35 and identified individuals with birth weights more than 6 SDs less than mean z score or more than 3 SDs greater than mean z score by gestational age. Maternal variables, including parity and relationship status, were also collected from NMBR. Maternal age, country of birth, and highest education attained at the time of the child’s birth were obtained from Statistics Norway. Details of covariates are presented in eTable 2 in the We included covariates considered as potential confounders in the association between gestational age and mental health. Child variables collected from the NMBR included sex, birth year, birth weight, and multiple birth status. We created a In the population sample, we used logistic regression models to compare psychotropic drug prescription from age 10 to 23 years in each of the preterm groups with prescription in the term group during the follow-up period. All analyses were repeated for each of the 5 drug types and for any drug in unadjusted models and models adjusted for participant’s sex, year of birth, multiple birth status, and birthweight z score and mothers’ parity, relationship status, age in years and age in years squared, educational level, and country of birth. Analyses were repeated for male and female participants separately and using alternative outcomes of early prescription  and late prescription . Further adjustment for confounding by parental or family factors was done by comparing drug prescription vs no prescription within maternal sibling groups using conditional logistic regression analyses. All maternal siblings were eligible for the sibling comparison analysis, but only sibling groups differing in both exposure and outcome status were used in the calculation of estimates.To study the development from ages 10 to 23 years, repeated measurements of psychotropic drug prescription at each age (in years) were compared between each of the preterm groups and the term group using logistic regression with general estimating equation models. All models were stratified by sex and adjusted for participant’s year of birth and multiple birth status and mothers’ parity, relationship status, age in years and age in years squared, educational level, and country of birth. Estimates from these models were used to calculate annual percentages with drug prescription for each gestational age group at 3-year age intervals from age 10 to 23 years.We performed sensitivity analyses to explore whether exclusion of individuals who died before age 10 years or exclusion of birth defects were associated with changes in our outcome estimates.We performed all analyses using STATA statistical software version 15.1 (StataCorp), and precision was evaluated with 95% CIs, where estimates within this interval could be described as compatible with data given the model assumptions. Analyses of data were performed from August 2018 through February 2020.Among 505 030 individuals included in the analyses  , 762 indCompared with individuals born at full term, individuals born preterm had significantly higher odds of prescription for all the psychotropic drug groups at ages 10 to 23 years , increasResults for drug prescription during age periods 10 to 16 years and 17 to 23 years for male and female participants separately  received aripiprazole, olanzapine, or quetiapine at high doses , the odds of such prescription were increased for the extremely preterm group  compared with the full-term group. There were too few individuals for sibling comparison.Sensitivity analyses found that 1313 children (37.9%) among 3467 children in the original population sample (before exclusion) who died before age 10 years were born preterm; 1210 of them (92.2%) died before age 1 year  recent studies have found an increased psychiatric morbidity in adolescence and adulthood, including hospital admissions for psychiatric disorders and psychiatric diagnoses.12 found associations between GA and ADHD and autism, but after adjusting with sibling analyses, the increases in risks were smaller for bipolar and psychotic disorder and there was no significant increase in risks for suicide or receipt of social welfare benefits. Lindström et al18 also found an unchanged association between GA and use of drugs for ADHD when comparing siblings. This is consistent with our findings, which suggest that many of the mental and social conditions found in the preterm population, with the exception of ADHD, could be associated with confounding factors in the environment or genetics, especially for the later preterm groups. There is evidence suggesting that children born preterm from households with low socioeconomic status are at greater risk for mental health impairment.11 This association has been a subject of debate, and a possible explanation for our findings might be that confounding factors play an increasing role with increasing GA. The findings in prescription of psychotropic drugs from ages 10 to 23 years in this study add detail and nuance to existing knowledge. We have not been able to find other similar studies of how the increased use of psychotropic medication for children born preterm varies by drug type, sex, and age. Of particular interest was the prominent increase in prescriptions from ages 16 to 18 years and 19 to 21 years found among female participants born extremely preterm .Similar to the results from other studies, our findings suggest that there may be different mechanisms associated with different types of conditions. D’onofrio et alStrengths of our study include the study design, with a large, naturally selected population distributed across all gestational ages, with the possibility to follow up all participants using high-quality registry data, along with the opportunity to study the population over several years and across participants’ youth. Using sibling design made it possible to adjust for confounding factors shared by siblings.38 The method based on menstrual period has been shown to be associated with overestimations of the true gestational age by 2 or 3 days. However, we consider such misclassification as nondifferential, which would most likely bias the results from the population analyses toward the null.This cohort study has several limitations. In our registry data, term date was determined based on the mothers last menstrual period, which is a less exact method than using ultrasound measurement.39Prescriptions of a psychotropic drug provides little information about specific psychiatric diagnoses. However, we consider it a sensitive measure of mental health difficulties.40 Random measurement error in the assessment of gestational age may thus be increased when comparing siblings and may lead to an attenuation of estimates in the sibling comparison. However, we consider error in the measurement of gestational age a minor issue owing to standardized procedures and registration.Even if sibling comparison may be an effective way of accounting for unmeasured confounding associated with family background, it has been suggested that this approach may increase selection bias and measurement error.We had no knowledge of diagnoses other than perinatal conditions, which makes it difficult to rule out confounding from other comorbid conditions present at birth but diagnosed later.Additionally, these findings may primarily be valid only for survivors, because only those alive at age 10 years were followed. Individuals born preterm were overrepresented among those who died, and we expect that if survival were greater among these individuals, the prescription of psychotropic medication found in our study would also have increased.This cohort study found that the prescription of psychotropic drugs was higher among adolescents and young adults who were born preterm compared with those born at term. Children born preterm have increased mental and social risks in adolescent and young adult years. This increased risk may be largely associated with factors involving genetics and childhood environment for the later preterm groups. Trajectories established during adolescence are associated with later mental health status and lifetime opportunities, and this period could thus be an important target for health-promoting measures and preventive measures for this group.


Associations of fruit and vegetable consumption before and during pregnancy with birth weight of new-borns and the risk of low birth weight (LBW) remain unclear.Between July 2013 and March 2017, we recruited 23,406 pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). Fruit and vegetable consumption before and during pregnancy was calculated using food frequency questionnaires. Information regarding birth weight was obtained from medical records, and LBW was defined as < 2500 g. We used a multivariable linear regression model and a multivariate logistic regression model to assess associations between fruit and vegetable consumption and birth weight/risk of LBW.In total, 17,610 women were included in the analysis. Mean birth weight was 3061.8 ± 354.1 g, and 5.4% of the new-borns had LBW. Compared to women in the lowest quartile of fruit consumption between pre- and early pregnancy, women in the highest quartile had heavier new-borns  and lower risk of LBW . Women in the highest quartile of fruit consumption from early to mid-pregnancy also had heavier new-borns , and they tended to have lower risk of LBW . Results of analysing the association between changes in fruit consumption from pre- to mid-pregnancy and birth outcomes revealed that women with continuous high fruit consumption from pre- to mid-pregnancy had heavier new-borns , but they did not have lower risk of LBW . Associations involving vegetable consumption and birth weight/risk of LBW were not observed.Fruit consumption before and during pregnancy was positively associated with birth weight of new-borns and negatively associated with risk of LBW. Low birth weight LBW, < 2500 g) contributes to approximately 80% of neonatal deaths worldwide , 2. Surv500 g conDietary habits before and during pregnancy are one of the major factors related to birth weight of new-borns , 9. In pn = 115), and using simple questions that asked whether fruits/vegetables were consumed at least once a day or not. Among the remaining nine studies, six suggested that fruit and/or vegetable consumption during pregnancy is positively associated with birth weight of new-borns [To our knowledge, 10 previous studies have investigated associations between fruit and vegetable consumption, before or during pregnancy, and birth weight. Only one study researched fruit and vegetable consumption before pregnancy . The resew-borns , 18–22. ew-borns –25. Addiew-borns , 27. HowThis study aimed to clarify associations involving fruit and vegetable consumption before and during pregnancy, and birth weight of new-borns/risk of LBW. Moreover, we analysed associations between changes in fruit and vegetable consumption before and during pregnancy and birth weight of new-borns/risk of LBW to clarify the appropriate period of fruit and vegetable consumption before and during pregnancy.n = 353), women who participated in the survey for the second or third time (n = 909), women who suffered abortions (n = 357), and women who experienced multiple births (n = 316), were excluded. New-borns who were not full-term at birth , women for whom there were no data corresponding to the first food frequency questionnaire (FFQ) (n = 1064) and the second FFQ (n = 310) were also excluded. Among the remaining participants, new-borns whose birth weight data were missing (n = 7), new-borns who exhibited extreme birth weight values , women who had extreme height values , women who had extreme pre-pregnancy weight values , were excluded. We also excluded women who had extreme energy consumption values identified in the first and second FFQs , and women who had missing data (10%) corresponding to the first or second FFQ (n = 328 and 222). Finally, 17,610 mother-newborn pairs were included in the analysis . The TMM BirThree Cohort Study is a prospective cohort study based in Miyagi Prefecture, Japan. Detailed information regarding the TMM BirThree Cohort Study has been reported elsewhere , 29. In ths n = 36, were eThe first and second FFQs were used to evaluate dietary consumption during two different time periods. We defined early pregnancy as 0 to 13 weeks of gestation, and mid-pregnancy as 14 to 27 weeks of gestation. The first FFQ was given in early pregnancy and queried the frequency and amount of food items and beverages over the past year to evaluate dietary consumption from pre- to early pregnancy. The second FFQ was given in mid-pregnancy and identified the frequency and quantity of food items and beverages consumed since the first FFQ was answered so as to evaluate dietary consumption from early to mid-pregnancy. Average response periods of the first and second FFQs were 20.2 ± 7.4 weeks and 28.3 ± 5.4 weeks of gestation, respectively. Frequency and amount of 130 food items and beverages consumption were evaluated through each FFQ. The first and second FFQs involved 10 response options: “constitutionally unable to eat it”, “never or less than once a month”, “from one to three times a month”, “once or twice a week”, “three or four times a week”, “five or six times a week”, “once a day”, “two or three times a day”, “from four to six times a day”, and “seven or more times a day”. Portion sizes were defined, and the amounts were answered with response options as follows: “less than half”, “the same”, and “more than one and a half times”. Frequency and amount of food items and beverages were converted into average daily consumption by multiplying frequency and quantity. Those items included 18 fruit portions  and 26 vegetable items . Total fruit and vegetable consumption were identified by summing responses to fruit and vegetable consumption queries. Fruit and vegetable consumption were included in the analysis as continuous or categorical values which were divided into quartiles. Total energy and nutrient consumption were calculated using the Standard Tables of Food Composition in Japan (Fifth Revised and Enlarged Edition 2005) . Also, wBirth weight of new-borns and LBW were used as outcome variables. Information concerning birth weight (g) was obtained from birth records. LBW was defined as birth weight < 2500 g .2) was calculated by dividing pre-pregnancy weight (kg) by the square of height (m2). BMI values were divided into three categories . Information on cigarette smoking , alcohol consumption , folic acid supplementation during early pregnancy (yes/no) was gathered from the questionnaire during early pregnancy. Information concerning household income  was gathered from the questionnaire during mid-pregnancy. Maternal educational attainment data  were gathered a year after birth. Total meat, fish, grain, potato, beans, and dairy product consumption were identified by the same method as for fruit and vegetable consumption and were divided into quartiles. Changes in dietary consumption of these food products were also characterised, and confounders were imputed by multivariate imputation methods by chained equations (MICE) assuming missing data as random [Confounders considered to affect exposures and outcomes were selected from previous reports , 18–22. s random . For theP <  0.05 was considered statistically significant. Statistical analyses were performed using R, v.3.6.0.Continuous variables were expressed as means ± standard deviation (SD), and categorical variables were indicated as frequencies and percentages. Association between fruit and vegetable consumption and birth weight of new-borns were evaluated by multivariable linear regression analysis to calculate regression coefficients and 95% confidence intervals (95% CI) per quartile. Also, associations involving fruit and vegetable consumption and risk of LBW were evaluated by multivariate logistic regression analysis to calculate odds ratio (OR) and 95% CI per quartiles. Associations between changes in fruit and vegetable consumption from pre-pregnancy to mid-pregnancy and birth weight of new-borns/risk of LBW were also analysed by multivariable linear regression analysis/multivariate logistic regression analysis. We used the crude model and the multivariable model adjusted confounders. First quartile and category A were used as a reference group. 2), 72.8% were normal weight (18.5 ≤ BMI < 25.0 kg/m2), 12.6% of women were overweight (BMI ≥ 25.0 kg/m2), and 1.4% of data was missing. Approximately half of the participants were experiencing their first birth. The number of missing data points regarding maternal educational attainment was large (n = 6120) because that information was gathered a year after birth. Totally 16.1% of the participants smoked when they became pregnant. A large proportion of women (19.8%) drank alcohol and around half (56.2%) took folic acid supplements during pregnancy. Dietary consumption from early to mid-pregnancy was lower than from pre- to early pregnancy except for dairy product consumption. Mean birth weight was 3061.8 ± 354.1 g and 5.4% of the new-borns were categorised as LBW. Focusing on protein, fat, and carbohydrate consumption, women with high fruit consumption had high carbohydrate consumption, and women with high vegetable consumption had high protein and fat consumption  and multivariable models (P = 0.01)  Table . In contWomen who had high fruit consumption only from pre- to early pregnancy (Category C) and women who had high fruit consumption from pre- to mid-pregnancy (Category D) more often had heavier babies, compared to women who had low fruit consumption from pre- to mid-pregnancy (Category A) Table . Above aWomen who had high fruit consumption only from pre- to early pregnancy (Category C) had a low risk of LBW, compared to women who had low fruit consumption from pre- to mid-pregnancy in the crude model (Category A) Table . In the We found that fruit consumption from pre- to mid-pregnancy was positively associated with birth weight and negatively associated with the risk of LBW. Also, continuous high fruit consumption from pre- to mid-pregnancy resulted in increased birth weight of new-borns and partly decreased risk of LBW.In this study, women with continuous high fruit consumption from pre- to mid-pregnancy (Category D) had new-borns with higher birth weights compared to women in other categories. This result indicated that continuous fruit consumption from pre-pregnancy positively affected birth weight. The importance of dietary consumption before pregnancy in terms of birth outcomes is gradually becoming clearer , whereasThis study revealed that women with high fruit consumption also had high carbohydrate consumption compared to women with high vegetable consumption Table S-S4. In aThe results of this study do not deny the effects of vegetable consumption before and during pregnancy on birth weight. One of the reasons for the absence of any association between vegetable consumption and birth weight of new-borns/risk of LBW may have been insufficient vegetable consumption. The average vegetable consumption in the highest quartile from pre- to early pregnancy 278.6 g/d) and that from early to mid-pregnancy 258.1 g/d) were less than the recommended target value for vegetable consumption in Japan (350 g/d) . This ma78.6 g/d 8.1 g/d wRegarding fruits, the differences in average consumption from pre- to early pregnancy and that from early to mid-pregnancy between the lowest and highest quartiles were 290.88 g/d and 270.53 g/d, respectively Table S, S3. TheFruit consumption from pre- to early pregnancy and that from early to mid-pregnancy was associated with 16.9 g and 10.3 g heavier birth weight per quartile increase, respectively. These results imply that the weight birth differences between the highest and the lowest quartile were approximately 50 g and 30 g. The difference in birth weight of 20 g may be related to the fact that fruit consumption from early to mid-pregnancy were associated with new-born birth weight but not with LBW risk. This may be due to the information lost by converting continuous variable of birth weight to categorical variable of LBW risk.In the present study, fruit consumption from early to mid-pregnancy was negatively associated with preterm birth risk Table S. This maThis study had several limitations. First, dietary consumption may have included measurement errors because each such consumption was calculated from self-reported FFQ data. Second, dietary consumption before pregnancy and early pregnancy could not be distinguished because the results of the first FFQ were calculated from dietary consumption reported for the past year from early pregnancy. However, the first FFQ largely reflected consumption before pregnancy because that questionnaire was given at early pregnancy and queried the frequency of dietary item consumption over the past year. Third, women with high fruit or vegetable consumption may maintain healthy lifestyle behaviours, and such behaviours may have been confounding. To rule out this effect, information regarding identified confounders, which were gathered from previous reports in the literature, was used to adjust the multivariable model. Fourth, the first and second FFQs were modified versions of an FFQ used in the Japan Public Health Center-Based study (JPHC study) –40. We aNevertheless, one of the major strengths of this study is that it investigated not only consumption during pregnancy but also that before pregnancy using two FFQs conducted at different periods. It was possible to evaluate changes in fruit and vegetable consumption before and during pregnancy and birth weight of new-borns. Moreover, this study was based on TMM BirThree Cohort Study, which was a prospective birth cohort design with a large sample size. Further, the data concerning birth weight were collected from reliable clinical birth records.The present study highlighted the association between high fruit consumption before and during pregnancy with increased birth weight of new-borns and decreased risk of LBW. Increasing the amount of fruit consumed by women with otherwise low fruit intake may contribute to increasing the birth weight of new-borns and preventing LBW. Also, the identified associations involving vegetable consumption before and during pregnancy and birth weight/risk of LBW cannot be denied by the results of this study. Further quantitative observational studies of fruit and vegetable consumption from before to during pregnancy are ultimately necessary to confirm the effect of continuous fruit and vegetable consumption on birth weight of new-borns and risk of LBW.Additional file 1: Table S1. Characteristics of participants by fruit consumption from pre- to early pregnancy. Table S2. Characteristics of participants by vegetable consumption from pre- to early pregnancy. Table S3. Characteristics of participants by fruit consumption from early to mid-pregnancy. Table S4. Characteristics of participants by vegetable consumption from early to mid-pregnancy. Table S5. Energy-adjusted nutrient consumption from pre- to mid-pregnancy and new-born birth weight. Table S6. Fruit consumption from pre- to mid-pregnancy and new-born birth weight adjusted by nutrient consumption. Table S7. Energy-adjusted fruit and vegetable consumption from pre- to mid-pregnancy and preterm birth risk.


Gram-positive bacteria and considered as a last resort in the case of ineffective use of other antigens. While due to the occurrence of adverse reactions, the application of vancomycin is strictly limited. We will conduct a meta-analysis to summarize adverse reactions of vancomycin in humans.Vancomycin is effective against To collect comprehensive randomized controlled trials (RCTs), the following electronic databases will be searched: PubMed, Embase, Web of Science, Cochrane Library, the China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database. The range of publication time will be from the inception of the database to August 2020 without language limitation. Two reviewers will independently conduct selection of studies, data extraction and management, and assessment of risk of bias. Any disagreement will be resolved by discussion with the third reviewer. Review Manager 5.3  will be used for meta-analysis. The Cochrane risk of bias tool will be used to assess the risk of bias.This study will synthesize the data from the present eligible high quality RCTs to explore the incidence of adverse reactions such as hypersensitivity reactions, nephrotoxicity, ototoxicity, phlebitis, and agranulocytosis.This meta-analysis will provide systematic evidence for adverse reactions of vancomycin in humans.INPLASY202080094 It is effective against Gram-positive bacteria by disrupting cell wall synthesis and has been approved for clinical use for more than 60 years.,3 It is commonly used for methicillin-resistant Staphylococcus aureus (MRSA), ampicillin-resistant enterococci and Gram-positive organisms in patients allergic to penicillin.–6 Vancomycin is usually given by intravenous drip. In the treatment of Clostridium difficile-associated disease, vancomycin is taken orally.,8 Because of the strong bactericidal effect, Vancomycin is often considered as a last resort in the case of ineffective use of other antigens. While due to the occurrence of adverse reactions, the application of vancomycin is strictly limited.Vancomycin is a glycopeptide antibiotic isolated from the fermentation broth of  The major effects of vancomycin-induced hypersensitivity reactions are vasodilatation, bronchoconstriction, capillary permeability increase, autonomic nervous system activation, and mucosal hypersecretion.,13 One study showed that after vancomycin intravenously, 7%–17% of patients infected with MRSA presented nephrotoxicity. The dose, duration, and plasma concentration of vancomycin are all closely related to the incidence of nephrotoxicity. Cases of hearing loss may be related to vancomycin because the drug damages auditory branch of the eighth cranial nerve directly. Furthermore, some minor adverse reactions such as reversible neutropenia, reversible agranulocytosis, gastrointestinal symptoms, and pseudomembranous colitis should not be ignored.,18The main adverse reactions of vancomycin include hypersensitivity reactions, nephrotoxicity, ototoxicity, and so on. The most common manifestations of hypersensitivity reaction are hypersensitivity macular cutaneous rashes and anaphylaxis.Up to now, no meta-analysis has been performed on the adverse reactions of vancomycin. In view of this, we have an opportunity to evaluate adverse reactions of vancomycin in humans comprehensively. Therefore, we will conduct a meta-analysis to summarize adverse reactions of vancomycin in humans.22.1This study has been registered on INPLASY (INPLASY202080094). This meta-analysis will be performed according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist.2.22.2.1Only randomized controlled trials (RCTs) on clinical application of vancomycin will be considered without language limitation. Case reports, reviews, non-RCTs, and animal experiments will be excluded.2.2.2Participants who received vancomycin therapy will be included without restrictions of age, gender, and race.2.2.3In the experimental group, patients were given vancomycin with no limitations of administration routes, frequency, and treatment period.In the control group, no limitations were applied to the control treatments. However, studies used the combination of vancomycin and other treatments will not be included.2.2.4The incidence of adverse reactions  will be designated as the outcomes.2.3The following electronic databases will be searched: PubMed, Embase, Web of Science, Cochrane Library, the China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database. The range of publication time will be from the inception of the database to August 2020 without language limitation. The detailed search strategy of PubMed is shown in Table 2.4EndNote 7.0 (Thomson Reuters) will be used to manage all retrieved citations. After removing duplicates, 2 reviewers will independently scan titles and abstracts to eliminate all irrelevant records. Then, the remaining records will be read by full texts in further assessing the inclusion of the study. Any confusion over inclusion criteria will be resolved by discussion with the third reviewer. A PRISMA flow diagram will be designed to illustrate the details of study selection.2.5After selection, 2 reviewers will independently conduct data extraction. Any confusion will be resolved by discussion with the third reviewer. If some important information is missing, we will contact original authors by email to request detailed information about the research. The general information will be extracted, including first author's name, country of publication, year of publication, title of journal, study design, patient information, experimental, and control intervention , and specific details about adverse events (symptoms and number of persons experiencing an adverse reaction).2.6Risk of bias of the selected studies will be assessed by the Cochrane risk of bias assessment tool. This tool covers 7 aspects: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. A bias value of “high”, “unclear”, or “low” was given for each item. These 7 items were assessed independently by 2 reviews. Any divergences will be resolved by discussion with the third reviewer.2.72.7.12 test. The I2 value > 50% means significant heterogeneity, and the random effects model will be used. Otherwise, the I2 value ≤ 50% means minor heterogeneity, and the fixed effects model will be utilized. If significant heterogeneity still exists after subgroup analysis, meta-analysis will not be pooled, and descriptive summary will be reported.Review Manager 5.3  will be used for data synthesis. Odds ratio will be used for dichotomous outcomes with 95% confidence interval. Heterogeneity will be examined using the I2.7.2Subgroup analysis will be performed to check the potential heterogeneity and inconsistency based on the different participant characteristics, administration routes, and dose of vancomycin, control methods, and outcome measurements.2.7.3Sensitivity analysis will be conducted to check the robustness and reliability of pooled outcome results by excluding low-quality studies and small studies.2.7.4,21Publication bias will be assessed with funnel plot and Egger regression test if sufficient trials  are included.3To our knowledge, this is the first meta-analysis to conduct a comprehensive literature search and provide a systematic synthesis of current published data to summarize adverse reactions of vancomycin in humans. We will search 7 electronic literature databases to avoid missing any potential eligible studies, and apply rigorous methodology to examine studies reporting the adverse reaction outcomes of vancomycin for patients. The results of this study will provide helpful evidence for clinical practice and patients, future research, as well health related policy makers.Conceptualization: Yang Peng, Chen-yang Li, Zhi-ling Yang.Data curation: Yang Peng, Zhi-ling Yang.Formal analysis: Yang Peng, Chen-yang Li, Zhi-ling Yang, Wei Shi.Funding acquisition: Chen-yang Li.Investigation: Chen-yang Li, Wei Shi.Methodology: Yang Peng, Chen-yang Li.Project administration: Zhi-ling Yang.Resources: Yang Peng, Chen-yang Li, Zhi-ling Yang.Software: Zhi-ling Yang, Wei Shi.Supervision: Yang Peng, Zhi-ling Yang.Validation: Chen-yang Li.Visualization: Zhi-ling Yang, Wei Shi.Writing – original draft: Yang Peng, Chen-yang Li.Writing – review & editing: Zhi-ling Yang, Wei Shi.


The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and “mood disorder” construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression , bipolar disorder , and mood disorder  in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents. Birth by cesarean section is a life-saving surgical procedure in cases with maternal-fetal complications. Nevertheless, the increasing number of cesarean sections performed in several countries worldwide has encouraged the study of their consequences on the offspring's mental health . Recent Studies have shown that cesarean birth is associated with alterations in the child's intestinal bacterial microbiome, loss of benefits resulting from exposure to delivery-induced hormonal and immunological physiological changes, and neurodevelopmental disorders –6. TheDepression and bipolar disorders are mood disorders with complex and poorly understood multifactorial etiology that result from a combination of genetic, environmental, psychological, and physiological factors. Depression is characterized by loss of interest or pleasure in activities and sad mood during most of the day, as well as changes in sleep, appetite, concentration, psychomotricity, among others. Bipolar mood disorder is characterized by mood or affection pathological alterations, which may vary from hypomania or mania (extreme elation) to severe depression. Such disorders can begin even in childhood or adolescence and persist into adulthood, causing adverse psychosocial and neurobiological consequences , which aIn a Finnish case-control study, Chudal et al.  investigIn addition to the lack of consensus in the literature on this topic, there has been an increasing trend of cesarean section procedures worldwide. Even a slight increase in the risk of mood disorder development due to cesarean birth ,14,19 coThis was a longitudinal study with data collected from a birth cohort study in the city of São Luís, MA, Brazil. The cohort was initiated in 1997/98 as part of the RPS research consortium with the project entitled “Determinants along the life cycle of obesity, precursors of chronic diseases, human capital and mental health: a contribution of Brazilian birth cohorts to SUS [Brazilian healthcare system]”, carried out by the Federal University of Maranhão, the Ribeirão Preto Medical School at University of São Paulo, and the Federal University of Pelotas.This study used data from adolescents who were born in the city of São Luís, MA, in 1997, of both sexes, in public and private maternity hospitals and hospitals with maternity services  and who http://sinasc.saude.gov.br/); second, volunteers were recruited in schools, universities, and on social media, with a final study population of 1831 adolescents. Thus, the sample evaluated in the third phase of the study was composed of 684 adolescents from the original cohort and 1831 added in 2016, totaling 2515 individuals. Of these, after exclusion of unreported perinatal data and forceps birth delivery entries, the final sample of the present study was 1603 adolescents. More details on the methodology of this study can be found in Simões et al. , low birth weight , preterm birth , mother's age , parity , mother's schooling , marital status , and maternal smoking during pregnancy . The delivery type was the main explanatory independent variable used dichotomously.This study used information collected through structured interviews with adolescents on sociodemographic, economic, and life-style aspects during the third phase of the study, when they were 18/19 years of age. The following variables were obtained: sex , self-reported skin color , currently studying , religion or cult , divorced parents , current family income in minimum wages , and adolescent's current smoking habit . The use of alcoholic beverages by the adolescents was classified as low- or high-risk through the Alcohol Use Disorder Identification Test (AUDIT) .The outcome variables of this study were depressive disorder, bipolar disorder, and the “mood disorder” construct in adolescents. This construct was formed from the following variables: current or recurrent major depressive episode (depressive disorder) and episode of hypomania or mania (bipolar disorder), which were evaluated through the M.I.N.I.  questionnaire, which can be used by clinicians after training. The M.I.N.I. was applied by two clinical psychologists who were trained previously. An adolescent who presented at least one of these episodes was diagnosed with a mood disorder. The outcome variables were dichotomized  for statistical analysis.The M.I.N.I questionnaire is a brief standardized diagnostic interview compatible with the diagnostic criteria of DSM IV  and the International Classification of Diseases, 10th revision (CID-10). It is a validated diagnostic instrument designed to assess current and previous mental disorders with satisfactory reliability indexes. The M.I.N.I questionnaire can be used in clinical practice and research .directed when all edges are represented by a single arrow, assuming that causality flows in only one direction, and is acyclic when no connection between variables forms a closed circuit (http://www.dagitty.net/) was used to create the graphic model . DAGs are diagrams that encode qualitative hypotheses on causal processes provided by data through non-parametric structural equation models. A graph is  circuit . The Dagic model .After creation of the DAG , the pro® (http://www.project-redcap.org) into Excel spreadsheets for analysis in the Stata/MP 14.0® Program . Categorical variables are described as absolute and relative frequencies.The data were exported from REDcapThe hypothesis of this study was that cesarean birth is associated with depression, bipolar disorder, or mood disorder in adolescence. A graphical and counterfactual approach was used to test the hypothesis using a propensity score weighting estimation method, which is the conditional probability of receiving the treatment (born by cesarean section) as a function of exposure predictor variables . Hence, One of the assumptions for causal inference is interchangeability, a condition required for a balanced distribution of adjustment variables between exposed and non-exposed groups to avoid selection bias . Interch® Program was used to determine the average treatment effect (ATE) on the population using the minimal adjustment of variables suggested by the DAG. The ATE calculation was possible because there was a good common support zone between the exposed and non-exposed groups. As observed in the boxplot graph shown in The teffects ipw package of the Stata/MP 14.0A total of 1603 adolescents were evaluated in 2016 and 50.2% were males, 62.4% self-reported having brown/mixed skin color, and 59.9% had a family income between 1 and 4 minimum wages. As for the use of psychoactive substances, 91.7% of the adolescents did not smoke and 19.0% had high-risk alcohol consumption behavior. About perinatal characteristics of adolescents, 43.7% were born by cesarean delivery, 8.9% had low-birth weight, and 10.4% had preterm birth. At birth, 71% of the adolescents' mothers were aged between 20 and 34 years, 53.5% had completed high school, and 79.9% of them had a partner. Other perinatal, sociodemographic, and economic characteristics of adolescents and maternal socioeconomic conditions are shown in Depressive disorder, bipolar disorder, and mood disorder were identified in 7.4, 9.7, and 15.2% of adolescents, respectively. There was no significant association between these mental conditions and the delivery type  .Adjustment variables  were well-balanced after weighting with propensity score, indicating a good interchangeability between the exposed (born by cesarean section) and unexposed groups. For these variables, a weighted value of less than 0.1 was obtained for the difference between the standardized means, while variance ratios ranged between 0.8 and 1.2 .As seen in The ATE calculation indicated no significant difference in the presence of depressive disorder, bipolar disorder, and mood disorder among adolescents of both sexes born by cesarean section .Studies have addressed the association between cesarean birth and the development of mood disorders, such as depression and bipolar disorder, which are conditions with complex etiology yet to be completely understood ,14,19,33There was no association between cesarean birth and the development of depression and bipolar disorder in adolescents of both sexes. Nevertheless, a case-control study  carried out in Finland by Chudal et al.  reportedIn a cohort study in Sweden n=6,260), O'Neill et al.  found a 60, O'NeiChudal et al.  and O'NeIn addition to formal medical indications, elective caesarean sections may be required by mothers who are anxious, depressed, have dysfunctional personality traits, or low social support. Such characteristics may contribute to an increased risk of development of mood disorders in the offspring due to hereditary and behavioral genetic factors in the family environment ,38. In cThe strengths of this study include the graphical and counterfactual approach with a propensity score weighting estimation method and a DAG theoretical model, which enabled the adjustment for the common causes of exposure and outcome. The M.I.N.I questionnaire, used to verify the presence of mood disorders in adolescents, is a validated and reliable tool for diagnostic purposes . No studThe limitations of this study comprise the retrospective collection of perinatal data, which may have led to measurement bias (memory) and lack of information on mood disorders among adolescents' relatives and the lack of differentiation between elective and emergency cesarean birth.The overall increase in the rate of cesarean sections is worrisome and has encouraged research into the possible consequences of delivery procedure on early determinants of physical and mental health in adulthood . Our stu


H-benzo[e][1]benzofuran), is a terpene furan with a pleasant odor and unique olfactive and fixative properties. The current state of the fragrance industry uses ambrafuran materials entirely from synthetic or semisynthetic sources. However, natural compounds with the potential to be converted to ambergris-like odorants have been extracted from several different types of plants. Here we review plant terpenoids suitable as starting materials for the semisyntheses of ambrafuran or intermediates, such as ambradiol, that can be used in biocatalytic transformations to yield ambrafuran.Ambergris, an excretion product of sperm whales, has been a valued agent in the formulation of perfumes. The composition of ambergris consists of two major components: 40–46% cholestanol type steroids and approximately 25–45% of a triterpenoid known as ambrein. Ambergris undergoes oxidative decomposition in the environment to result in odorous compounds, such as ambraoxide, methylambraoxide, and ambracetal. Its oxidized form, ambrafuran (IUPAC name: 3a,6,6,9a-tetramethyl-2,4,5,5a,7,8,9,9b-octahydro-1 Physeter macrocephalus L.) [1]benzofuran, regarded as the prototype of all ambergris odorants. Synonyms include ambroxide (AmbroxTM)/ambraoxide, methylambraoxide, ambracetal, amberlyn, ambronide, and (−)-norlabdane oxide . In. In47]. nt triol . To avoioduction .Much research has been dedicated to improving the chemical synthesis described above, as evidenced by the number of reports focused on the synthesis of ambrafuran from sclareol ,50,51,52Ambrafuran is the leading fragrance compound owing to its fixative properties and animalic fragrance note characteristic . The demEscherichia coli [Hyphozyma roseoniger (Moesziomyces antarcticus), was used in the first step to transform sclareol into ambradiol. The obtained ambradiol was subsequently converted to (−)-ambrafuran using a zeolite-based cyclization procedure.Evidently, the use of sclareol is the most established precursor for ambrafuran synthesis , and, inhia coli  for subshia coli . The filCurrently, there is on-going research on biocatalytic routes for ambrafuran and ambergris-like odorants as a substitute for the chemical routes ,42,55,56


Paratubal cysts are generally small but there are rare cases of large paratubal cyst and this case is one of them. Here we report a case of a young female with complains of abdominal fullness since 3 months. On examination, a huge mass (25 × 25 cm) extending from symphysis pubis upto xiphisternum was noted. Ultrasongraphy showed a cystic mass of 27 × 27 cm. Intraoperatively, the cyst was paratubal. It was drained with the help of veress needle and laparoscopic cystectomy was done. A large adnexal cyst extending above umbilicus is traditionally managed by laparotomy. But with the advent of laparoscopy, even a huge cyst can be managed by laparoscopy. These are incidental findings during ultrasonography or operation and are rarely symptomatic. Generally, they are less than 8 cm in size.Laparoscopy is the gold standard in the treatment of benign adnexal mass. But when the cyst is large then due to chance of malignancy and also space constraint, many surgeons prefer laparotomy over laparoscopy. Here we report a case of a huge paratubal cyst which was managed by laparoscopy.A 25-year-old female came with complain of abdominal fullness since 3-4 months and sensation of mass per abdomen since 12 days. She was unmarried with a regular menstrual cycle and was not sexually active. As per patient, she had joined weight loss classes for 2 months, during which she had a visible weight loss of her arms and thighs but the abdominal fullness did not decrease and only then she noticed a mass in her abdomen. She does not have any other complaints. She had no significant medical or surgical history.On examination, general condition was fair, huge abdominopelvic mass of around 32 weeks size (25 × 25 cm) extending from the symphysis pubis to 5 cm below xiphisternum and occupying the whole abdomen. The mass was cystic with smooth surface, freely mobile and lower margin could be felt.Ultrasonography showed a cystic lesion of 27 × 27 cm in pelvis. Computed tomography  showed aTumor markers-Cancer antigen-125 (CA-125): 29 IU/L, Carcinoembryonic antigen (CEA): 2.5 IU/l, Alpha feto protein (AFP): 2.85 IU/l, Lactate dehydrogenase (LDH): 174 IU/l were normal.With the preop diagnosis of ovarian tumor, laparoscopic cystectomy was planned under general anesthesia.Bowel preparation and antibiotic prophylaxis was given one day before operation theatre. Intraoperatively, there was challenge in inserting the primary trocar as the mass occupied the umbilical as well as left hypochondrium regions so drainage of cyst was done with veress needle and around 3 liters of serous fluid was drained. Primary trocar insertion in the palmer's point was done along with two 5 mm secondary port in right and left iliac fossa under vision. Pneumoperitoneum of 12-15 mmHg was created. A 30-degree scope was placed through by palmer's point.Intraoperatively, paratubal cyst was extending from the mesenteric border of the uterine surface upto the fimbria of the right tube, the cyst had glistening smooth surface and did not have any solid growth. The right tube was stretched over the mass and intact, right ovary was hypertrophied but normal looking. Uterus, left tube and left ovary were normal. There was no ascites, peritoneal, or omental growth .Remaining 2 litre fluid from the cyst was aspirated. Cystectomy of right-sided paratubal cyst was done by dissection and counter traction. The right tube and ovary were preserved. There was no need for suture placement. Hemostasis was secured with cautery. Due to the large size of the cyst, there was difficulty in handling the mass intraoperatively and also in retrieving the specimen. For the retrieval of the mass, the incision in the right secondary port was extended and 10 mm port was created.After removing the mass, peritoneal washing was done. Total time taken for the surgery was 120 minutes.On the cut section, the cyst was 20 × 18 cm and had a smooth glistening surface without any solid mass, surface excrescences, or papillary projection. On the cut section, it was uniloculated cyst with a smooth inner surface. She had no post-operative complications and hospital stay was 48 hours.Histopathology report showed cyst wall lined by intact cuboidal to low columnar epithelium with stratifications and ciliated cells at places. Subepithelium has fibrocollagenous tissue with lymphomononuclear infiltrate suggesting Serous cystadenoma. The patient had been followed up till 1 year and there were no recurrences.2 The literature states many ways of managing such huge cyst-like open Hasson's technique for trocar insertion and laparoscopically aspirating the cyst as done by Thakur A.3 Ates O has inserted nephrostomy catheter in the cyst under ultrasonography guidance and aspirated the content of the cyst completely so that there is no intraperitoneal spillage of the cyst.4This case was special to us as it is the first time that we have performed laparoscopy for such a huge mass in our hospital. In our setting, mass of >24 weeks size is generally managed by laparotomy but taking into consideration, the young age of patient and benign characteristics noted in imaging and tumor markers, we decided to perform a laparoscopy to provide her treatment with least morbidity and minimal scar. The additional advantage was to lessen post-operative adhesions so that her chance of fertility is not hampered. Moreover, this is the largest paratubal cyst reported in literature in Nepal which was managed laparoscopically. In our case, we have decompressed the cyst by drainage of the cyst via veress needle, similar to that done by Nagle and Magos.4The largest cyst managed laparoscopically was by Alobaid where he has removed an ovarian cyst measuring 42 cm in a 20-year-old female. In this case, the abdomen was opened by Hasson method and drainage of the cyst was done laparoscopically by suction and irrigation.5 In this case, the cyst was decompressed by a mini-laparotomy incision given in umbilicus and then extirpation of cyst was done laparoscopically.Dolan in 2006 removed an ovarian cyst measuring 40 × 30 cm in 16 years old.6The largest paraovarian cyst is reported by Letourneur in 19-year old which was 36 × 25 cm in size and was managed by laparoscopy and minimal suprapubic laparotomy.There are chances of upgrading of stage of cancer due to spillage during the process of aspiration or by seeding of the cancer cells in the port but in this case, we did calculate the Risk of malignancy index (RMI) score and were quite confident that it was a benign cyst.7Paratubal/fimbrial/paraovarian cyst are seen in 4% of women and comprises 10% of all adnexal masses. Paratubal cyst are a remnant of Wolffian duct or Mullerian duct. The cyst occurring from the remnant of Mullerian duct tends to lie close to broad ligament but those from Wolffian duct tend to occur more commonly near the fimbriated end of fallopian tube.1 They are usually found in the third or fourth decade of life.Most of the time, these cysts are small in size around 1 to 8 cm in size and do not cause trouble but sometimes they can be large and lead to complications like cyst rupture, torsion, or intracystic hemorrhage.6For the evaluation of the adnexal cyst, ultrasonography is done which shows “split sign” i.e., there is dissociation of the cyst from the ovary when pushing the probe indicating paratubal/paraovarian cyst but such sign was not present in our case. Demonstration of normal ovary, separate from the cyst is an important finding. However, it was not present in our case.Though large cyst are challenging to the surgeon due to the limited space and technical difficulty but with careful planning, laparoscopy for a huge cyst is not impractical. Laparoscopic cystectomy of large cyst after decompression of cyst seems to be applicable treatment modality in the background of benign characteristics in tumor marker and imaging.