Background: The present study compared baseline characteristics, comorbidities and clinical burden of pre-term infants with type 1 and 2 severe bronchopulmonary dysplasia (BPD) Collaborative classification.Methods: This study was a prospective cohort study of pre-term (<32 weeks) very-low-birth-weight infants. Severe BPD was divided into type 1 severe BPD requiring of ≥30% oxygen and/or non-invasive ventilation at 36 weeks post-menstrual age (PMA), and type 2 severe BPD requiring invasive mechanical ventilation at 36 weeks PMA. Baseline characteristics, comorbidities, and clinical burden were compared between these two types of severe BPD.Results: Of the 1,328 infants included, 983 (74.0%) developed type 1 severe BPD, and 345 (26.0%) developed type 2 severe BPD. Lower birth weight, small for gestational age, lesser maternal pre-mature rupture of membrane, lower 5-min Apgar score, air leak, pulmonary hemorrhage, surgical ligation of patent ductus arteriosus, necrotizing enterocolitis, and late-onset sepsis were significantly associated with type 2 severe BPD. Compared with infants with type 1 severe BPD, infants with type 2 severe BPD had an increased risk of mortality , pulmonary hypertension , and tracheostomy .Conclusions: Our data highlight the substantially greater mortality and clinical burden in infants with type 2 severe BPD than infants with type 1 severe BPD. A comprehensive and multidisciplinary approach is needed for infants with type 2 severe BPD. Bronchopulmonary dysplasia (BPD) is one of the most common chronic morbidities in pre-term infants . BPD is Infants with severe BPD have higher mortality and morbidity than infants with mild or moderate BPD . InfantsTo better define BPD severity, a multi-institution group dedicated to filling knowledge gaps in the care of infants with BPD called the BPD Collaborative recommended that severe BPD be further classified into two phenotypes . InfantsHowever, the baseline characteristics and comorbidities associated with type 2 severe BPD remain understudied given its low incidence. Few reports have focused on perinatal factors that could affect disease severity and variation in the clinical burden within a severe BPD category.In the present study, we identified the baseline characteristics associated with the development of type 2 severe BPD and assessed the clinical burden of type 2 severe BPD in compare to type 1 severe BPD using a large cohort of very-low-birth-weight (VLBW) infants.We performed a cohort study using prospectively collected data from 69 NICUs participating in the Korean Neonatal Network (KNN). The KNN is a nationwide multicenter registry of VLBW infants that collects demographic and clinical data using a standardized operating procedure .+0-31+6 gestational weeks between January 2013 and December 2017. Among these, 274 infants who had major congenital anomalies, 1,140 infants who died or were transferred to other hospitals before the diagnosis of BPD at 36 weeks PMA, and 2,560, 2,203, 937 infants with no, mild, moderate BPD, respectively were excluded. The remaining 1,534 infants had severe BPD, which was defined as the use of supplemental oxygen for at least 28 days plus treatment with ≥30% oxygen and/or positive pressure ventilation at 36 weeks PMA , histological chorioamnionitis, and the use of antenatal corticosteroids. The neonatal data included gestational age (GA), birth weight, sex, small for gestational age (SGA), multiple births, delivery mode, and Apgar scores at 1 and 5 min. The following clinical information was collected: respiratory distress syndrome (RDS), air leak, pulmonary hemorrhage, surgical ligation of patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), late-onset sepsis (LOS), postnatal corticosteroids, pulmonary hypertension, periventricular leukomalacia (PVL), retinopathy of pre-maturity (ROP) requiring treatment, the results of automated auditory brainstem response (AABR) before discharge, duration of invasive mechanical ventilation and non-invasive ventilation, length of NICU admission, and survival to NICU discharge or death. Because the KNN VLBW infant registry only collects data up to 12 months after birth, discharge information for infants who stayed in the NICU beyond 12 months of age were not available and not included in the analysis of discharge information. For surviving infants discharged from the NICU, we collected data on z-scores for weight, height, and head circumference at the time of discharge using Fenton 2013 growth curves  and 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using SPSS version 24.0 . A P < 0.05 was considered statistically significant.Continuous variables are expressed as the means ± standard deviations; categorical variables are expressed as numbers and proportions. Comparisons of continuous variables between the groups were performed using Student's The registration of data in the KNN was approved by the institutional review board of each participating center. Informed consent was obtained from the parents of each infant prior to participation in the KNN registry.+0-31+6 weeks) VLBW infants. Their mean GA was 27+0 ± 2+0 weeks, and their mean birth weight was 893 ± 253 g. Of these 1,328 infants, 983 (74.0%) infants developed type 1 severe BPD, and 345 (26.0%) infants developed type 2 severe BPD.The final study population included 1,328 pre-term (23p = 0.038).The baseline characteristics are presented in Compared to infants with type 1 severe BPD, infants with type 2 severe BPD had a lower birth weight, lower 5-min Apgar score and a higher rate of SGA. Infants who developed type 2 severe BPD also had significantly higher rates of air leak, pulmonary hemorrhage, surgical ligation of PDA, NEC, and LOS .n = 109) of the infants with severe BPD died before discharge, and 0.5% (n = 7) remained in the NICU beyond 12 months of age. Cardiorespiratory failure was the most common cause of death and accounted for 40% of all deaths. The mortality rate during the NICU admission was 1.9% in the type 1 severe BPD group and 26.1% in the type 2 severe BPD group (p < 0.001) for infants with type 2 severe BPD compared to infants with type 1 severe BPD . The odds of PVL  and abnormal AABR results  were also significantly increased in these infants. Regarding the clinical burden, the type 2 severe BPD group was associated with a longer duration of invasive mechanical ventilation and NICU admission, and increased risks of discharge with home oxygen , tracheostomy , and mechanical ventilation . For somatic growth at the time of discharge, the type 2 severe BPD group was associated with lower z-scores for weight, height, and head circumference .The datasets presented in this article are not readily available because the KNN Publication Ethics Policy adheres to the following research data management and access guidelines: All information about patients and participating NICUs is confidential and is only available to individuals who have access for the purposes of the research activities permitted. Access is only allowed for the purpose of collecting data for the first time, and no access for any other purpose is allowed. Requests to access the datasets should be directed to Yun Sil Chang (The registration of data in the KNN was approved by the institutional review board of each participating center. Informed consent was obtained from the parents of each infant prior to participation in the KNN registry. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.H-RK and CC performed the research, analyzed the data, and wrote the manuscript. YJ and CC designed the study. CC reviewed and revised the manuscripts. BK and SK provided suggestions with regard to the content and concept of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Increased level of urate is the strongest risk factor for gout development but since only a minority of hyperuricemics are affected by gout, other pathogenic factors must be considered. Low birth weight is associated with future morbidities causing hyperuricemia, such as diabetes and renal disease. The purpose of this study was to investigate if, and to what extent, maternal and perinatal factors, including birth weight, are associated with future risk of being diagnosed with gout.A population-based retrospective nested case-control registry study based on regional and national health care registers in Sweden. All incident cases of gout born in 1973 and onward who had received ≥1 diagnosis of gout from 2000 through 2019 in the region of western Sweden were included. Up to 5 non-gout controls were matched to each case by age, sex, and county at the year of first gout diagnosis. A range of maternal, gestational, and perinatal factors were analyzed for their potential association to future gout development. This included the health of the mother, gestational length, birth weight, number of siblings, and congenital malformations.p=0.01), 1.33 (1.04 to 1.7) (p=0.02), and 1.75 (1.3 to 2.3) (p<.0001), respectively.Maternal diabetes, any congenital malformation, and being small for gestational age were factors that significantly increased the risk for future gout development, odds ratio (95% CI) 3.1 (1.3 to 7.4) (In this study, maternal diabetes and being small for gestational age increased the risk for future gout development in young adults. As of today, these conditions are becoming more prevalent and may contribute to the ongoing gout epidemic. These results require both confirmation and further delineation of underlying mechanisms. Gout is the most common inflammatory joint disease in the world  as well All individuals born from 1973 and onward who had received ≥1 main or auxiliary diagnosis of gout at a visit to a physician or a hospitalization from 2000 and through 2019 in western Sweden were identified in the healthcare consumption database VEGA. Up to 5 controls, without a gout diagnosis or a prescription of urate-lowering medication (ATC-code M04) during the same time period, were matched to each case by age, sex, and county at the year of first gout diagnosis. Controls were selected from the Swedish national census register.The Western Swedish Health Care Region register (VEGA) was used for the identification of the gout cases. This register contains information about all health care contacts, at both primary and specialized health care units in western Sweden from 2000 onwards. All diagnoses given by physicians are registered according to the Swedish version of the International Classification of Disease (ICD) codes. Since 1997, the 10th version of ICD codes (ICD-10) is used in Sweden.The comparators were identified from the census register.The Swedish Medical Birth Register (MBR) started in 1973. It includes administrative and medical data related to pregnancy, partum, and postpartum neonatal care . It is c2; maternal parity 0 (ref) or ≥1 previous births; season of delivery month January to March (ref), April through June, July through August, and October through December; birth weight <2500 (ref), 2500 to 2999, 3000 to 3499, 3500 to 3999, 4000 to 4499, and ≥4500 g; gestational age ≤258 (ref), 259 to 293, and ≥294 days; birth weight for gestational age small , normal (ref), and large  [All exposure variables regarding perinatal characteristics were retrieved from the MBR for both cases and controls. The variables assessed were age and marital status of the mother, maternal smoking and body mass index (BMI) at start of pregnancy, maternal stature and parity, mode of delivery , season of birth, birth weight and gestational age, congenital malformations, number of older siblings, maternal diagnosis of recurrent urinary tract infection, chronic kidney disease, diabetes, epilepsy, asthma/lung disease, inflammatory bowel disease, systemic lupus erythematosus (SLE), and hypertension. The following categorizations were used: age of mother at birth <20 (ref), 20 to 35, and >35 years; maternal stature ≤154 (ref), 155 to 164, 165 to 174, and ≥175 cm; maternal BMI <20 (ref), 20 to 25, 26 to 30, and >30 kg/mnal age) ; and thep values < 0.05 were considered statistically significant. Statistical analyses were performed by using SAS version 9.3 .Continuous variables are presented as mean ± SD or median (25 and 75 percentile). Categorical variables are presented as numbers and percentages. All variables that showed significant association with gout development univariately were included in a multivariate logistic regression except for maternal smoking and BMI at the start of pregnancy due to large proportions of missing data. Furthermore, the two variables birth weight and birth weight for gestational age both showed a significant association to gout but due to great collinearity between them, we chose to only include the latter in the multivariate analysis. Odds ratios (OR) for developing gout were calculated using conditional logistic regression models. Nominal 2, respectively (p=0.01) (Table p=0.0001), while no differences were seen regarding gestational age and number of older siblings  (Table p=0.04) and 1.57 (1.25 to 1.96) (P <0.0001), respectively, but these results are uncertain due to 70 to 80% missing values in both cases and controls  1.98 (1.09–3.8) (d 1.57 1.5 to 1.96p=0.01) (Table p=0.02), while being small for gestational age significantly increased risk for gout, OR (95% CI) 1.77 (1.36 to 2.3) (p<.0001) (Table p=0.018), and specifically, Down’s syndrome showed a great risk increment for gout development, OR (95% CI) 12.9 (4.2 to 39.7) (p<.0001)  2.98 (1.25 to 7.1) ; 1.33 (1.04 to 1.7) (p=0.02); and 1.75 (1.3 to 2.3) (p<.0001), respectively  3.1 (1.3 to 7.4)  . Today, The Barker hypothesis, proposed by Barker and colleagues more than three decades ago, states that intrauterine starvation leads to changed fetal developmental programming, abnormal organogenesis, LBW, and through this an increased risk for cardiovascular disease, diabetes, obesity , and endThere are no previous reports on any associations between congenital malformations and future gout. However, malformation is a wide term and spans from missing a toe to advanced genetic disturbances such as Down syndrome. The association for future gout to Down syndrome in this study (based on few exposed subjects) has not been described earlier except for some case reports. A possible underlying mechanism could be the increased frequency of the metabolic syndrome in individuals with trisomy 21, such as dyslipidemia, diabetes, and obesity . Down syWe found no association between number of older siblings and risk for gout and neither did Wallace et al in their study from 1967 . Having What is a typical gout patient? It may differ around the world but in western Sweden, it is a male aged 65 or above with multiple comorbidities. In the current study, data on perinatal factors was retrieved from the MBR which started in 1973 which rendered our oldest cases of gout 46 years of age. Thus, it is not possible to generalize these findings to the whole gout population, and studies are needed both to confirm our results in subjects with onset of gout at a younger age and with extended analyses in higher age groups.Some possible limitations in our study should be acknowledged. First, the identification of the patients with gout was based on ICD codes, which may have led to some misclassification bias. However, in previous validation studies, the ICD-coded definition of gout was found to have a high positive predictive value for fulfilling the various classification criteria for gout , 28. SecThere are some strengths to our study. First, it is population based including all gout cases in western Sweden born in 1973 and later which reduces the risk of selection bias. Second, patients were identified from both primary and specialized health care, which covers all the different phenotypes of gout, from mild to severe disease. Third, our data was retrieved from independent national compulsory registers with prospectively collected data.We suggest that maternal diabetes and small for gestational age are perinatal factors that increase the risk for future gout development in young adults. Since these factors are increasing in occurrence, they may contribute to the ongoing gout epidemic and thus require both confirmation and further delineation of underlying mechanisms.


We explored the circumstances of and motivators for repeat adolescent birth in Eastern Uganda.First birth before 18 years has declined in Uganda unlike Between January and March 2020, we conducted a qualitative study involving 70 individual in-depth interviews with purposively selected respondents - 20-25-year-old women with and without repeat adolescent birth, their partners, and parents, in the communities of Teso sub-region. We conducted latent content analysis.Four major themes emerged: poverty, vulnerability, domestic violence, and demotivators. Sub-themes identified under poverty were: “limited provisions”, “peasantry”, “large families”, “dropping out of school”, “alcohol abuse”, and “broken family structure”. Vulnerability included “marital entrapment” and “partner coercion”. Demotivators included: “abandonment”, “stern warning”, “objection to marriage”, and “empowerment”. Extreme poverty resulted in inadequate provision of basic needs leading to unprotected sexual activity in a bid to secure financial support. Following the first birth, more than three quarters of the women with repeat adolescent birth reported increased economic distress that forced them to remain in unwanted marriage/union, often characterized by partner coercion, despite wanting to delay that repeat birth. Women without repeat adolescent birth avoided a second birth by empowerment through: an economic activity, contraception use, and resumption of schooling.Repeat adolescent birth in Uganda is premised around attempts to address the economic distress precipitated by first birth. Many women want to delay that repeat birth but the challenges robbed them of their reproductive autonomy. Beyond efforts to prevent first birth, programs need to address economic empowerment, ensure contraceptive access, and school re-integration for adolescent mothers in order to prevent shortly-spaced repeat births. In the last 30 years, the proportion of adolescents (10–19 years) in Uganda having a first live birth before age 18 years has declined. However, among these, the proportion who proceed to have another live birth before age 20 years (=repeat adolescent birth) has not declined. We therefore set out to find out what motivated or were the circumstance under which these adolescent girls had repeat adolescent birth. We answered this question by interviewing people in Eastern Uganda: 1) women age 20–25 years who had first birth before age 18 years; those with and without history of repeat adolescent birth, 2) the parents with girls who had first birth before 18 years, 3) partners to women with repeat adolescent birth, and 4) community leaders.We found that the financial challenges that had escalated following the first birth was responsible for the events or decisions that culminated into a repeat adolescent birth. In an attempt to find a solution to the financial challenges, the adolescent girls end up in unwanted unions with men and ultimately lost their power to decide on whether or not to get pregnant again. Many wanted to have this repeat birth later but were robbed of the opportunity to do so. The study findings suggest that beyond helping adolescent girls prevent the first birth, they need to be supported with economic empowerment activities, improved contraception services, and re-integration in school. The father, who usually controlled all the resources at home, unilaterally determined ‘what and when’ to give them for their basic needs.Women with repeat adolescent birth reported multiple vulnerabilities including marital entrapment and partner coercion that culminated in the repeat birth.“… they said ‘there is no problem she will first remain there, even if she dies, we shall also come and do what we shall do’. So, I then had to remain living there … I still had to stay because I didn’t want to take the burden to my people …” . However, four out of the five rural and two out of the six urban parents interviewed  stated that they did not force the girls into marriage but only wanted the man responsible cater for their daughter during the pregnancy and pay a ‘fine’ to compensate for their investment in their daughter. Despite the parents saying this, the women with repeat adolescent birth stated that their parents pursued dowry payment following the first birth. Nearly all of these women said they had to remain in the union due to lack of an alternative and they feared that the dissolution of the marriage would burden their families to return the dowry. Once in a union and under the expectation to bear more children, the women found themselves unable to prevent the repeat adolescent birth. As a woman from the rural residence stated,“… you know as someone has married you, so you cannot go and just stay in someone’s place like that! Someone will want what? (pause) Children!”At the point of first pregnancy of a minor, almost all the women and the parents reported that, families usually settled for dialogue involving payment of a fine in the form of cows and money by the perpetuator instead of prosecuting them for defilement, as dictated by the law. The law enforcers reportedly encouraged families to negotiate and settle matters out of court. Parents who had tried to take the legal action were often frustrated by the police corruption. Most of the women from both residences reported being forced to go and live with the man during or shortly after the payment negotiations, in a transfer of financial responsibility for the pregnancy. The women stated that their birth families did not want them at home with the pregnancy; they were considered a burden.“… actually, what I thought was that when I get another child, he would now settle down and that is what drove me to get a second child … I thought by doing that, he will be convinced and he opens up his mind to know that am now ready to be a wife and he stays with me but [pause]...but I realized that men are not trusted and they will never talk the truth …”Most of the women with repeat adolescent birth stated that they personally decided to have another child as either a means of: securing their relationship with the partner (new partner or the one responsible for both first and repeat birth), increasing her family size or, simply fulfilling the expectation of producing more children. This was more common among the rural residents. As stated by a woman from rural residence, she thought a second birth would help stabilize their relationship,“… it is also good for you to have your children. Sometimes, they help you … like now that elder one you can send her that go and do for me something like this like that … .”Another woman from rural residence said it was good to have your children as they are a source of help,“..I feel bad but I have nothing to do because I want to see my sisters push with their studies otherwise I would have left that man long time ago but I look at my sisters and wonder how they can survive; we are orphans and our mother is not able to support them so I have to stand in the gap because there is none who can be there for them … I had to push myself into marriage”.The ability to channel financial resources from the relationship to support their birth families also motivated longer union tenures and therefore the repeat pregnancy, as reported by eight out of the 17 women with a history of single parent  families. For the women from urban settings, the support was mainly to ensure continued schooling for their siblings whereas those in rural areas aimed at getting bride-price paid; this would be used for support. This selflessness was a motivator to stay in the union and ultimately the repeat pregnancy. As a woman- a half orphan- from an urban area narrated,“… so I thought that it was better for me to go for marriage and I see how to help my brothers on the side of cows maybe they would purchase some piece of land somewhere where they would also settle.”Whereas another orphan from the rural area narrated,“… .my friends would also tell me to get a boyfriend … .I wanted to stop suffering..” Among women from rural residence, seven out of the 18 reported being influenced by peers who had already given birth to get into relationships and subsequently bear children. In the urban area, peer influence to get into union as a solution to the poverty and violence was at the point of first pregnancy and following this, their peers began avoiding them.“… She said I should stop so that I can conceive because I cannot stay with the man when I don’t have a child; that it is a child that makes a man to love you!”.Unfortunately, this man also abandoned her as soon as she had the repeat adolescent birth.These women reported that their peers and older women in the community put them under pressure to have the first birth and following this, to have more births as soon as possible in order to have time to concentrate on raising their children. The fear of failure to attract other suitors was used to compel them to accept unwelcome partners or to cement the relationship by having more children. As an example, a woman with repeat adolescent birth from rural residence stated that, following abandonment by the first partner, her own mother encouraged her to stop contraception and get pregnant for the second partner to accelerate the decision on marriage. She said,Regarding the partners interviewed, four out of the seven stated that they were already in a union and more children were expected out of the union. They however acknowledged the value of spaced childbirth and were considering starting a contraceptive method. Two partners said they had already encouraged the woman to use contraception.“… and then he got me when I had put the injection [points at implant site in arm] for family planning and he then told me that we should remove that injection and when I refused, he started to beat me and took me to the hospital and removed it!”Nine out of twenty eight of the women in the rural and urban areas reported that the fathers of the first birth forced them to have the repeat adolescent birth. Most of these women had opted to use contraception following first birth but were coerced by the partners  to stop contraception and conceive again. The partners threatened to end the relationship and financial support. As a woman in the urban area state,“… he started quarreling that am not giving him a child, it seems am barren and that is how I got pregnant but I did not intend to get a second child because my first child was still not well …”Some new partners, demanded a child as a condition for continued financial support and perhaps marriage. These women reported that much as they did not want a second child soon, they did not want to risk losing this opportunity. As a woman in the urban area stated,For two women, the repeat birth was a result of rape by men they were acquainted with. One got married to the perpetrator and opted to have more births. The other reported that the perpetrator ridiculed her as a prostitute – due to first birth. None of these women sought legal redress because they perceived that no one would believe them since they had already given birth.“… the words when you are in someone else’s home someone who is different and not your mother, the person favors giving you harsh words … there is so much abusing like that to the extent that my aunty told me that ‘you people are like dogs. It wasn’t me who told your mother to pass on’ …” .Many rural residence women (9 out of 18) opted for marriage and ultimately, more childbearing, as a means of escape from the domestic violence at their birth home in forms including: deprivation of food, physical abuse, verbal abuse, and excessive manual labor/child abuse from their parents or guardians. They said that they could not even think of returning into the abusive homes. Women from broken family structures faced more violence compared to those who were living with both parents. As a rural woman who was orphaned reports,“… When he [the father] is sober the stay would be good but the moment he drinks, things would change; he would start barking and chasing us...”Among the women from rural residence with parents having extreme alcohol consumption, violence got worse when the parents were drunk. As one woman from rural residence narrated;“… I have gone through a lot and it has made me stay without getting another child; problems that I have experienced right from the time I got pregnant... I vow not to repeat the same mistake I did!”.From the interviews with women without repeat adolescent birth and parents to women without repeat adolescent births, we identified four demotivators for repeat adolescent birth: partner abandonment, stern warning, objection to marriage, and empowerment. A common feature was the endurance of more hardships following the birth than prior to the pregnancy. As an example, a woman from rural residence stated,“… No he doesn’t help me at all! Not even a call to find out how the child is doing. Nothing!...”.Nearly all of the women, irrespective of the residence, reported abandonment by the man as soon as the pregnancy was pronounced. The women and parents reported that the men who had initially been deceiving them with ‘financial support to bridge the gap in their basic needs’ suddenly abandoned them by either denying the pregnancy or escaping from the area. Some returned later and accepted responsibility for the pregnancy. The few women who had been sent off to be with the man until they gave birth returned back to their birth families due to physical violence from the men. The men were reported not to cater for the children either and in situations where they tried, it followed use of force/threats, was sporadic, and meagre. The women reported that this lack of partner support for the child put a lot of emotional and financial strain on them because their own families, on most occasions, could not afford to meet the child’s needs either. The women echoed that they had come to the realization that their future had been ruined and these men; they had nothing to offer them. As an urban woman stated,I told her … for her to have another child in my home was not acceptable! Not when she is still with me!...”.‘ … The women from both rural and urban residence, stated that their parents expressed great disappointment in them and gave them stern warnings not to get pregnant again while still at home. The women reported that this reaction was a source of great emotional and psychological trauma for them. This was exacerbated by negative social labelling and feedback from the community members; that they were spoilt girls who would ruin others. Almost all the parents of women without repeat adolescent birth, irrespective of residence, stated that they sternly warned and counselled their daughters against having another birth. As one father from the urban residence stated,Eight of the fifteen the women without repeat adolescent birth reported that their parents had initially chased them out of home and only allowed back on condition they did not conceive again. In the interim, they had to live with either the man responsible or his relatives. This category of stern parents went on to support the girls with either economic activities or schooling while catering for the child.All except two women without repeat adolescent birth reported that they were not in a union nor had their families coerced them into it. Those who had initially been sent to be with the partner returned shortly after giving birth. They said that their parents gave them a chance to opt out. A few women reported that their parents actually rejected the option of marriage, citing their young age, contrary to the advice from other community members.The above challenges and reactions shaped the strong personal resolve by women to prevent a repeat adolescent birth with the following empowerment actions taken in isolation or in combination, irrespective of residence: 1) empowerment of the woman through an economic activity, 2) contraception use, and 3) school resumption.Nine of the fifteen women without repeat adolescent births, irrespective of residence, reported getting start-up capital from either parent shortly after giving birth; they started an economic activity. The parents reported that they opted to do this to reduce girls’ dependency on men for financial support. The activities were such as: setting up a road-side stall to sell tomatoes, making cassava chips, and brewing alcohol, etc. These activities, the women said, though relatively low yielding (generating 5000 shillings/ two United States Dollars daily), delivered significant financial independence and insulation against the demand for sexual favors in exchange for very little money. As an urban woman acknowledged support from her mother,“… I then started to fry chips [cassava] … My mother first gave me 10,000/= [approximately 3 United States Dollars], then with that 10,000/= I bought cassava for 5,000/= and then I bought cooking oil two half liters. And then I realized that it started adding up until my money increased … and then some I also would take it to the savings group.”Majority of the women without repeat adolescent (10 out of 15) reported that they used modern contraceptive methods to deliberately delay another pregnancy within an active sexual lifestyle, that continued even while living with their parents. They acknowledged that it was not easy to completely avoid having sex. This was most common among women engaged in their own economic activities. Although some parents reported that they suspected that their daughters were using contraception, it was not discussed with them. They were happy that their daughters had managed to find a solution.The women without repeat adolescent birth also reported awareness of men’s use of deception to acquire sexual favours without carrying responsibility for the pregnancy and subsequent child support. Some, mainly urban-based women, supported by a few parents, opted to retain control of the situation even in scenarios where a partner was against contraception.In almost all the scenarios of adolescent pregnancy by learners, the schools immediately expelled the girls. A few of the women reported that their parents excused their having given birth and promptly supported resumption of schooling or acquisition of technical skills (most commonly tailoring and hairdressing) from vocational institutions. They resumed school shortly after giving birth. In these instances, the families took charge of looking after the infant. These opportunities were most common in the urban settings. As a father from the urban area narrated,“… I wanted my daughter to go back to school … So we thought it would not be good to simply leave her, so we took her for a tailoring course.”.In this paper, we explored the circumstances and motivators for repeat adolescent birth in Soroti and Katakwi districts in Teso sub-region, Eastern Uganda. Individual in-depth interviews were conducted among: women age 20–25 years with and without repeat adolescent birth, parents to women with and without repeat adolescent birth, and partners to women with repeat adolescent birth. We found that repeat adolescent birth was largely driven by attempts, among both rural and urban adolescent women, to escape from family-related socio-economic challenges through developing financially supportive sexual relationships and marriages. However, the hardships which were present at first pregnancy, for many, only got worse following first birth. Below we discuss four key findings.First, rampant household poverty compromised the provision of basic needs for the girls and led to interrupted school attendance. This situation was compounded by the large family sizes, parental alcohol abuse, broken families, and domestic violence. Largely, the adolescents had first pregnancy while still at school and dropped out once confirmed pregnant. Previous quantitative studies in Uganda and other LMICs affirmed that adolescent first pregnancy and birth, occurred mainly in situations of: economic deprivation, broken family structures, domestic violence, and cultures that promote early marriage and bride-price payment , 12, 43.Second, majority of the respondents reported being trapped in marriage/union and ultimately further childbearing in an effort to: get financial support, secure the relationship, meet the demands of the spouse or new partner, and meet the cultural expectations of bearing more children, despite preferring to delay the second order birth. For those who were rejected by the father of the first child, they had to get another partner shortly after giving birth. Therefore, while the first birth was described as unintended, the following pregnancy was largely intended, albeit not always. Along with this was partner coercion including physical violence in case the woman tried to avoid a repeat adolescent birth using contraception. Once married, adolescent girls get trapped; they lose individual power over their fertility decisions and resign into further childbirths. It can therefore be argued that marriage diminishes the power adolescent girls could have had if they had not been married; their agency is taken over by the men. The younger the adolescent girl, the more vulnerable she is due to for example, low economic empowerment and developing decision-making ability . PatriarThird, adolescent girls who were empowered through: starting an economic activity, contraception use, and continuing with schooling or acquisition of vocational skills, did not have a repeat adolescent birth. These girls had resolved to avoid the repeat adolescent birth for reasons including: abandonment by the partner, stern warning with counselling from parents and objection to marriage. These results align with previous findings that repeat adolescent pregnancy can be delayed or averted by provision of viable alternatives such as: school continuation, economic activity, parental support, and contraception use , 55. ThiLastly, a few women made personal pragmatic decisions to bear more children. This finding that some of the women made individual decisions to have the repeat birth for reasons, such as a desire to have more children, aligns with previous findings that not all the repeat births are unwanted, but rather, adolescent girls make pragmatic decisions whether to or not to have another pregnancy/birth , 37. TheThis study was the first in Uganda, a LMIC, to explain repeat adolescent birth. We triangulated findings from different respondents - parents to the women and partners - beyond the women themselves unlike previous qualitative studies that interviewed only the women. This gave a more comprehensive view of the motivators and circumstances for repeat adolescent births. Further, we conducted our study using a community sample of rural and urban residents unlike other qualitative studies that used an institutionally drawn sample that potentially introduced a challenge regarding transferability. We do acknowledge that this study involved recall of information and the time lapse may have affected precise recollection of all events.Additionally, the sensitive nature of the topic might have inclined respondents to provide socially desirable responses. During the interviews, four women with repeat adolescent birth broke down while narrating how the births happened. The interviewers allowed them to recompose and only proceeded when they signaled that they were comfortable to continue with the interview. They declined our offer to provide a counsellor, confirming their desire to share their testimonies to help other girls.Nonetheless, this initial inquiry is a major step towards understanding repeat adolescent birth following first birth < 18 years of age in a LMIC.The principal investigator, DA, is a medical doctor with specialized training in Obstetrics/Gynaecology and Public Health. Having worked as a clinician, health program implementer, and reproductive health advisor to the Ministry of Health, this technical background may have affected the interpretation of findings. To safeguard against this, qualitative inquiry was conducted with a multidisciplinary team that included social scientists; LA & SM.Our findings suggest that escalation of economic distress following first birth was the overarching reason for repeat adolescent births. Along with domestic violence, broken family structures and cultural norms promoting early marriage, it provided grounds for sexual exploitation of the girls and concession of their fertility control decisions in an effort to get financial support. Adolescent mothers who were supported by their birth families through school continuation or an economic activity (with or without contraception use) avoided a repeat adolescent birth.Our study results suggest the need to: alleviate household poverty and eradicate domestic violence; implement a school continuation policy or provide alternative forms of education for adolescent mothers; strengthen legislation against early marriage; and offer contraception services at each contact with the adolescent girls, including during postnatal care and childhood vaccination clinics which first-time adolescent mothers frequent. Beyond focusing on preventing index adolescent pregnancy, programs need to specifically place emphasis on preventing repeat adolescent pregnancy.We suggest future studies explore appropriate approaches to advance economic empowerment of adolescent mothers, delivery of contraception services to vulnerable adolescents such as those in marriage, and implementation of a school continuation policy, in LMIC settings.


Qualitative studies about the abnormalities appreciated on routine magnetic resonance imaging (MRI) sequences in prematurely born adults are lacking. This article aimed at filling this knowledge gap by (1) qualitatively describing routine imaging findings in prematurely born adults, (2) evaluating measures for routine image interpretation and (3) investigating the impact of perinatal variables related to premature birth.In this study two board-certified radiologists assessed T1-weighted and FLAIR-weighted images of 100 prematurely born adults born very preterm (VP <32 weeks) and/or at very low birth weight (VLBW <1500 g) and 106 controls born at full term (FT) (mean age 26.8 ± 0.7 years). The number of white matter lesions (WML) was counted according to localization. Lateral ventricle volume (LVV) was evaluated subjectively and by measurements of Evans’ index (EI) and frontal-occipital-horn ratio (FOHR). Freesurfer-based volumetry served as reference standard. Miscellaneous incidental findings were noted as free text.The LVV was increased in 24.7% of VP/VLBW individuals and significantly larger than in FT controls. This was best identified by measurement of FOHR (AUC = 0.928). Ventricular enlargement was predicted by low gestational age  and presence of neonatal intracranial hemorrhage . The numbers of deep and periventricular WML were increased while subcortical WMLs were not.Enlargement of the LVV and deep and periventricular WMLs are typical sequelae of premature birth that can be appreciated on routine brain MRI. To increase sensitivity of abnormal LVV detection, measurement of FOHR seems feasible in clinical practice.The online version of this article (10.1007/s00062-020-00901-6) contains supplementary material, which is available to authorized users. Premature birth, defined as birth earlier than 37 gestational weeks, is estimated to have a prevalence of 11% worldwide and survival of preterm infants is increasing . EspeciaPremature birth has been shown to be associated with an increased risk of white matter injury (WMI), either by relatively rare hemorrhagic or more commonly by nonhemorrhagic complications . PerinatTo date, there is a paucity of data regarding typical MRI findings in prematurely born adults that can be appreciated on routine sequences; however, this information will help the correct interpretation of presumably incidental findings. The purpose of this study was to qualitatively describe incidental findings with an emphasis on FLAIR-hyperintense PWML and ventricular enlargement in a large cohort of prematurely born adults and controls born at full term (FT). These findings were correlated with parameters of premature birth and it was established how to best measure ventricular size in order to identify ventriculomegaly in young adults in clinical practice. The impact of perinatal variables of premature birth on these findings was investigated and practical implications of the results in different diagnostic scenarios for the radiologist are discussed.n = 145) and the Department of Radiology, University Hospital Bonn (n = 67).The participants examined in this study are part of the Bavarian Longitudinal Study, a geographically defined, whole population sample of neonatal at-risk children and healthy full-term controls who were followed from birth until adulthood , 19. AllGestational age (GA) was estimated from maternal reports on the first day of the last menstrual period and serial ultrasounds during pregnancy. In cases where the 2 measurements differed by more than 2 weeks, clinical assessment at birth with the Dubowitz method was applied . Maternap = 0.11). For FLAIR sequences fast spin echo acquisition was used based on the variable refocusing 35° flip angle sweep technique [The MRI examinations were performed at both sites on either a Philips Achieva 3T or a Philips Ingenia 3T  system using 8‑channel SENSE head-coils. Subject distribution among scanners and sequence specifications are given in Table S1. Across all scanners, sequence parameters were kept identical for T1 and FLAIR sequences. Scanners were checked regularly to provide optimal scanning conditions. The MRI physicists at the University Hospital Bonn and Klinikum rechts der Isar regularly scanned imaging phantoms, to ensure within-scanner signal stability over time. Signal-to-noise ratio (SNR) was not significantly different between scanners  = 1.84, echnique .Two board-certified radiologists with 6 years experience evaluated FLAIR and T1-weighted images blinded to birth status. Supratentorial hyperintense lesions on FLAIR-weighted imaging were counted separately depending on their localization . Subcortical localization was defined as a distance <3 mm from the cerebral cortex, periventricular localization was defined by direct contact with the ventricular surface. Examples of periventricular, deep white matter and subcortical FLAIR hyperintense lesions are shown in Fig. http://surfer.nmr.mgh.harvard.edu) and volumes of subcortical structures were extracted [In order to obtain fully automated and volumetric measures as a reference standard, T1-weighted scans of all participants were analyzed with the Freesurfer image analysis suite v6.0, which is documented and freely available for download online (xtracted . The LVV2-test (sex). Logistic regression analysis was used to determine predictors of abnormal LVV, linear regression analysis was used to determine predictors of absolute LVV. Pearson correlation analysis was used to investigate the relationship between PVH grade and LVV. Interrater reliability for categorical variables was tested using Cohen’s kappa. Intraclass correlation coefficients were calculated to assess interrater reliability regarding flair lesion count for consistency from a 2-way mixed model. Statistical computations were performed with the SPSS software package . Statistical significance was set at p < 0.05.Statistical differences regarding the patient groups were tested by Student’s t‑test  and χThe study was carried out in accordance with the Declaration of Helsinki and was approved by the local institutional review boards (#153/10). Written consent was obtained from all participants. All study participants received travel expenses and a small payment for participation.p = 0.152), sex (p = 0.937), and maternal age (p = 0.868). By design, VP/VLBW subjects had significantly lower GA (p < 0.001) and lower BW (p < 0.001) and were hospitalized for a longer time after birth (p < 0.001).Group demographic and clinical background variables are shown in Table Of 100 premature-born adults, 16 were diagnosed with intracranial hemorrhage (ICH) in the neonatal period (PVH grade 1: 5 (31.3%), grade 2: 7 (43.8%), grade 3: 3 (18.8%), grade 4: 1 (6.3%)).p < 0.001). The LVV was also higher in premature-born adults if sides were considered separately  and if LVV was divided by total intracranial volume (TIV) . In VLBW/VP individuals, LVV of 22 out of 87 (25.3%) were 2 standard deviations above the mean LVV in controls normalized to TIV and thus considered abnormal. The rate of abnormal LVV was 5.1% (5 out of 99) for FT individuals (p < 0.001). Premature birth was associated with an increased risk of adult ventricular enlargement , while sex was not a significant predictor of ventricular enlargement . Binary logistic regression analyses in prematurely born adults revealed that both GA at birth and presence of PVH at birth were significant predictors of abnormal adult LV enlargement , while BW and sex were not significant . In prematurely born individuals who were diagnosed with PVH during the neonatal period, grading of PVH neither predicted absolute adult LVV  nor abnormal LVV .Automated lateral ventricle volumetry was successful in 186 of 206 cases and showed increased volumes for premature-born individuals .Subjective classification of LVV was abnormal in 25 out of 100 (25.0%) prematurely born individuals and in 2 out of 106 (1.9%) control individuals for reader 1 and in 16 out of 100 (16.0%) prematurely born individuals and in 2 out of 106 (1.9%) control individuals for reader 2. Cross-table analysis with the volumetric definition of abnormal LVV revealed a sensitivity and specificity of 55.6% and 93.8% and a positive and negative predictive value of 0.60 and 0.93, respectively for reader 1 and a sensitivity and specificity of 44.4% and 96.9% and a positive and negative predictive value of 0.71 and 0.91, respectively for reader 2. Interrater reliability was moderate  and 0.880 (p < 0.001) for FOHR and EI, respectively. Youden’s J was calculated to identify the optimal cut-off for identifying abnormal LVV for both measures, leading to a value of 0.37 for FOHR and 0.27 for EI. These values were associated with sensitivities of 96.3% and 77.8% and specificities of 73.8% and 81.9% for FOHR and EI, respectively. The ROC curve is shown in Fig. The ROC analysis revealed AUC of 0.928 (p = 0.259), 31 individuals (15.0%) were positive for periventricular FLAIR lesions , 49 individuals (23.8%) were positive for deep white matter FLAIR lesions  and 84 individuals (40.8%) were positive for subcortical FLAIR lesions . Detailed information on the distribution of periventricular, deep white matter, and subcortical FLAIR lesions can be found in Table The FLAIR lesions were counted by two board-certified radiologists independently. Intraclass correlation coefficient (ICC) showed good to excellent agreement  ; Tornwaldt cysts were seen in 4 cases  and 2 individuals showed a pituitary intermediate lobe cyst . Arachnoidal cysts were seen in two FT subjects in retrocerebellar and anterior temporal pole localizations. Partially empty sella was diagnosed in three subjects . One FT subject showed a cerebellar developmental venous anomaly. One FT subject was diagnosed with megacisterna magna. Ecchordosis physaliphora was diagnosed in one VP/VLBW patient. One VP/VLBW individual showed widening of the cerebellar foliae consistent with cerebellar hypoplasia without involvement of the vermis. One VP/VLBW subject was diagnosed with a Chiari I malformation and associated long-segment syringomyelia of the cervical spine.Suspicious FLAIR hyperintense mass lesions were found in three subjects  located in the right and left pulvinar, and the left parietal lobe. One FT patient showed a 9 mm meningioma adjacent to the left occipital pole. A 9 mm subependymal mass in the lateral ventricle found in one VP/VLBW subject, suggesting disturbed neuronal migration.This study qualitatively analyzed incidental findings in a large cohort of prematurely born adults and found increased rates of ventricular enlargement as well as an increased number of FLAIR hyperintense white matter lesions specifically located in the deep white matter. Significant predictors for abnormal lateral ventricle enlargement were low gestational age and history of periventricular hemorrhage in the neonatal period.A previous study on a rather small subset of the present cohort investigated how well the neuroradiologist can distinguish between prematurely born adults and adults born at full-term . They coVentriculomegaly is a mostly idiopathic and unspecific neuroradiological imaging finding potentially indicating either hydrocephalus or parenchymal atrophy. These two etiologies can be reliably distinguished by midsagittal morphological changes such as stretching and displacement of the corpus callosum, widening of the third ventricular recessus, and decreased mamillopontine distance . We confPremature birth has been found to have an impact on the white matter either by causing direct damage and tissue necrosis or by inhibiting the development of pre-oligodendrocytes and subsequent altered axonal maturation , 10, 11.Despite the rather sizable study cohort, its size is too small to deduct frequencies of rare incidental findings. One prematurely born individual exhibited a subependymal remnant of neuronal tissue. This is likely related to premature birth, since the neuronal migration period extends well into the third trimester and thus coincides with preterm birth . We obseWe have described increased rates of incidental findings on routine MRI after premature birth and think that this could have implications for radiological reporting in two distinct scenarios. Either the radiologist knows that a patient was born prematurely or it is unknown. If the radiologist knows, ventricular enlargement or increased periventricular or DWM punctate white matter lesion load can be interpreted as long-term sequelae of preterm birth and alternative explanations such as hypertension and/or chronic inflammatory CNS disease become less likely. If the radiologist is not aware of the patient’s birth history (which will be the case most of the times), findings such as ventricular enlargement or a certain distribution of PWMLs in periventricular or deep white matter locations should prompt thorough history taking before making a diagnosis.Some points should be carefully considered when interpreting the results. The current sample is biased to VP/VLBW adults with less severe neonatal complications. Individuals with more severe birth complications and/or severe lasting impairments in the initial BLS sample were more likely to drop out of this study covering more than two and a half decades from the neonatal period until adulthood and to be excluded in initial screening for MRI due to exclusion criteria for MRI. This selection towards less serious cases should be kept in mind when interpreting the results.Unfortunately, no structured physical examinations were performed at the 26-year follow-up visit, so that direct information about clinically evident findings is limited; however, due to the previously mentioned selection bias towards less severe cases and through the exclusion criteria for MRI participation as mentioned in the Material and Methods section , it seems justified that the analyzed imaging features in fact constitute incidental findings.Unfortunately, no sequence to detect blood degradation products (T2* weighted or susceptibility weighted imaging) was included in the study protocol owing to the overall study design. We consider it a strength of our study that a relevant impact of patient age on MRI findings at the time of the scan is excluded because all participants had approximately the same age of 26 years.Structural brain abnormalities visible on routine brain MRI sequences are commonly found in prematurely born adults. Prematurity at birth, in particular low GA and history of PVH is associated with ventricular enlargement, which could be best assessed by measuring the FOHR. The total number of PWML was not increased in prematurely born adults, however, the increased rate of deep white matter PWML suggested spatially distinct vulnerability of the white matter after premature birth.Flow chart diagram of study participants and MRI sequence parameter settings.


Excessive birth weight is associated with maternal and neonatal complications. However, ultrasonically estimated large for gestational age  predicts these complications poorly.To determine whether a maternal serum metabolite ratio developed for fetal growth restriction (FGR) is predictive of birth weight across the whole range, including LGA at birth.Metabolites were measured using ultrahigh performance liquid chromatography-tandem mass spectroscopy. The 4-metabolite ratio was previously derived from an analysis of FGR cases and a random subcohort from the Pregnancy Outcome Prediction study. Here, we evaluated its relationship at 36 weeks of gestational age (wkGA) with birth weight in the subcohort (n = 281). External validation in the Born in Bradford (BiB) study (n = 2366) used the metabolite ratio at 24 to 28 wkGA.P = 6.7 × 10−5]. The ratio was also inversely associated with birth weight z score . Analysis in the BiB cohort confirmed that the ratio at 24 to 28 wkGA predicted LGA  and was inversely associated with birth weight z score .The inverse of the metabolite ratio at 36 wkGA predicted LGA at term [the area under the receiver operating characteristic curve (AUROCC) = 0.82, 95% CI 0.73 to 0.91, A metabolite ratio which is strongly predictive of FGR is equally predictive of LGA birth weight and is inversely associated with birth weight across the whole range. A high absolute birth weight, independent of gestational age, is called macrosomia and is usually defined as >4000 g . MacrosoThe current approach to ultrasound scanning to detect LGA in pregnancy is to target women at high risk—for example, those with diabetes mellitus or who have a symphyseal-fundal height above the upper limit of the normal range for gestational age . The observations in the Cochrane review indicate that screening the whole population for LGA and offering earlier induction of labor to screen positive women could decrease maternal and neonatal morbidity. However, low risk women necessarily have a lower prior risk of complications and in many cases where the baby is thought to be LGA by ultrasound, the result is a false positive. Modeling has demonstrated that very large numbers of low-risk women need to have intervention to prevent relatively small numbers of adverse events .It has been suggested that combining ultrasonic EFW with maternal biochemical markers could improve diagnostic effectiveness . We haveThe overall approach of the study was (1) to analyze the metabolite ratio and its components measured at 36 wkGA in relation to LGA and birth weight z score at term in the Pregnancy Outcome Prediction (POP) study, (2) to externally validate the POP study results in 24 to 28 wkGA samples from 2 independent subgroups of the Born in Bradford (BiB) study in relation to subsequent LGA and birth weight z score, and (3) to repeat the POP study analysis using measurements from 28 wkGA and the same definitions to allow a direct comparison with the validation results from the BiB study.The POP study was a prospective cohort study of unselected nulliparous women with a singleton pregnancy attending the Rosie Hospital, Cambridge, UK, between January 2008 and July 2012, and it has been previously described in detail ,7. In brWe previously analyzed serial maternal serum samples  using a case cohort analysis in the POP study ; howeverWe wrote a prospective analysis plan for external validation of the metabolite ratio and its components at 24 to 28 wkGA in relation to subsequent delivery of LGA infant and birth weight as a continuous z score in the BiB study [Supplemental Panel 1 ]. The BiThe primary analysis of the POP study used the 36 wkGA serum sample, as the focus of the study was predicting large babies at term, and 36 wkGA was the latest gestational sampling point in the POP study. The BiB study only had a single gestational time point of blood sampling, which was at 24 to 28 wkGA. Hence, we repeated the POP study analysis using the 28 wkGA metabolite ratio to compare associations between the two cohorts. When we compared data from the POP and BiB studies, the same modified definition of LGA was employed in the POP study to allow a direct comparison between the cohorts (see following discussion).In the POP study, nonfasting maternal serum samples were analyzed, whereas in the BiB study, fasting plasma samples were analyzed. Metabolomic measurements were performed by Metabolon  using ultrahigh performance liquid chromatography-tandem mass spectroscopy as the platform. The details have been described previously ,18. In bThe 4-metabolite ratio [(A × B)/(C × D)], its numerator and denominator, and the 4 individual metabolites were used as exposures in the present analysis. The 4 individual metabolites were (A) 1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1), (B) 1,5-anhydroglucitol , (C) 5alpha-androstan-3alpha,17alpha-diol disulfate, and (D) N1,N12-diacetylspermine. The main outcomes were (1) birth weight >90th percentile (LGA) and (2) birth weight z score for gestational age and fetal sex using the UK 1990 reference  and the 95% CI. The metabolite ratio was originally developed to be positively associated with FGR. Consequently, the direction of association with LGA should be in the opposite direction; hence, the inverse of the ratio was used to calculate the AUROCC. The associations between each exposure and LGA were also analyzed using logistic regression, and associations were expressed as the odds ratio (OR) and the 95% CI for a 1 SD increase in the given exposure.  Panel 1 ]. StatisThe random sample of the POP study cohort included 313 participants. Of these, 11 had preexisting or gestational diabetes and 21 did not have the metabolite measurements available at 36 wkGA, leaving 281 eligible participants. This group included 15 LGA cases and 266 noncases [Supplemental Figure 1 ]. With tP-value between the ratio measured at 36 wkGA and fetal sex was 0.20 when the outcome was LGA and 0.66 when the outcome was birth weight z score.Despite the small numbers, all 4 metabolites at 36 wkGA were associated with the risk of delivering an LGA infant . As antiP = 1.3 × 10−9). The ratio was also predictive of LGA . Interestingly, when the 2 BiB subgroups were analyzed separately, the association with birth weight was weaker in the first sub-group compared with the second  . However, there was strong evidence for an association between the metabolite ratio and the risk of LGA in BiB subgroup 2   . Similarto 0.72)  and 3.Analysis of 28 wkGA samples in the POP study demonstrated that a 1 SD increase in the log-transformed metabolite ratio was associated with a −0.22 SD (95% CI −0.12 to −0.32) change in birth weight z score. Moreover, using the same modified definition of LGA , the 28 wkGA measurement of the ratio was also associated with LGA in the POP study . Hence, the point estimates for BiB subgroup 2 were within the 95% CI of the POP study values relating to the 28 wkGA blood sample, whereas those of subgroup 1 fell outside this range.P-values, are also unlikely to have occurred by the play of chance. The associations with both birth weight z score and the risk of delivering an LGA infant were also validated in a separate group of cases and controls from the BiB study, another pregnancy cohort. Validation was observed despite the fact that the BiB cohort was highly dissimilar from the POP study  and employed different sample types (fasting plasma vs nonfasting serum). We conclude that there is strong evidence to indicate that the metabolite ratio is predictive of fetal growth across the whole range of fetal size. Hence, it may offer clinically useful prediction of LGA, as well as of FGR.The main finding of the present study was that a metabolite ratio, which we had previously described as a predictor for FGR , was alsThe clinical importance of the current work is that this test has potential for use as a screening test in combination with ultrasound. Screening all pregnant women with ultrasound is not currently recommended due to lack of direct evidence that it is clinically and economically effective . One of The biological plausibility of associations between each of the metabolites and fetal growth has previously been discussed . HoweverA relative weakness of the present study is that the gestational age of collection of blood in BiB was at a much earlier stage in pregnancy (24-28 wkGA) than that for the main analyses in the POP study (36 wkGA). We addressed this by comparing the associations with the POP study sample collected at 28 wkGA. However, we anticipate that the ultimate clinical application relating to screening for LGA will take place near term, as the main intervention is earlier term delivery. Ideally, external validation would also have involved analysis of samples at around 36 wkGA. Analysis of the BiB data confirmed the presence of associations with both birth weight z score and with the risk of delivering an LGA infant. The associations were generally weaker, but external validation results are often weaker than those found in the discovery sample (a phenomenon known as “winner’s curse”). However, a further complexity is that the strength of association differed comparing the 2 subgroups of the BiB study. This inconsistency is difficult to explain, given the similarity between the 2 subgroups and given that we observed consistent associations between the 2 subgroups when we analyzed FGR. It may be explained partly by the method for quantifying metabolites in the samples. The metabolomics platform employed in both studies was a discovery platform and the method did not include isotopically labeled standard but rather calculated relative concentrations. More consistent results might be achieved when all metabolites are quantified by the actual molar concentration, and this is an area for future study, as well as being a necessary step for clinical development of the assay.P-value of 0.062 but an AUROCC of 0.68. The likelihood that these values are consistent with a true association with LGA is supported by the observation that the metabolite was strongly associated with the birth weight z score. We overcame the limitation of small numbers by choosing a larger cohort with a mixed parity for validation. The total number of LGA infants included in the analysis from the BiB study was 86 (the proportion of LGA was 4%), and therefore there was much less uncertainty in the estimation of the associations between LGA and the metabolites. The potential impact of fasting on the metabolite ratio could not be directly assessed in the present analysis, and this could be an area for future study. Another interesting area for further study would be to examine the association between the ratio and birth weight related long-term childhood health conditions.Among the women included in the analysis from the POP study (n = 281), the proportion of LGA was about 5%, and the number of women delivering an LGA infant was low (n = 15). This was partly due to the deliberate exclusion of diabetic women and partly because nulliparous women deliver smaller infants on average. For example, with these numbers, estimation of the association between 5alpha-androstan-3alpha,17alpha-diol disulfate and LGA resulted in a Although our validation cohort consisted of ~50% women of Pakistani ethnicity, there were small proportions of other ethnic groups such as black Africans in both POP and BiB study cohorts. Therefore, further external validation is needed to assess the generalizability of our results in other ethnic groups.The analyses adjusted for maternal characteristics in the POP study demonstrated that the observed associations were robust. Moreover, self-reported smoking had a high sensitivity and very high specificity against maternal serum cotinine N-oxide levels. Hence, we do not believe that the results are likely to be affected by the self-report of maternal variables.We were not able to perform an analysis of fully customized birth weight percentiles in the BiB study. However, the utility of customization is not universally accepted. For example, 1 of the largest studies in fetal growth in the last 10 years (InterGrowth 21st) does not support customization , and theTo conclude, we have shown than a recently described metabolite ratio which is predictive for FGR is also associated with birth weight across the whole range, including LGA. The ratio has the potential to improve the prediction of LGA over the current methods. Further studies using a quantitative version of the assay and tested in late pregnancy in other populations would strengthen the case for the ratio’s potential clinical utility in this context.


In schizophrenia, impaired psychomotor speed is a common symptom predicting worse functional outcome. Inflammation causes changes in white matter integrity, which may lead to reduced psychomotor speed. Therefore, we wanted to investigate if peripheral inflammation assessed with cytokines affected performance on psychomotor speed in patients with a spectrum of psychotic disorders.The current study is a prospective cohort study, including participants from a pragmatic, randomised controlled trial comparing three atypical antipsychotics in patients with a spectrum of psychotic disorders. For the purposes of this sub-study, we analysed drug treatment groups collectively. Psychomotor speed was assessed at baseline, and at weeks 6, 12, 26 and 52 of follow-up, using the neuropsychological tests trail making test (TMT) A and B, and symbol coding. Serum concentration of the following cytokines were measured: interleukin (IL)-β, IL-2, IL-4, IL-6, IL-10, IL12 p70, IL-17a, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Blood samples were collected at baseline and after 1, 3, 6, 12, 26, 39 and 52 weeks. We analysed the effect of cytokines levels on psychomotor speed over time in linear mixed effects models.In our linear mixed effects models controlling for possible confounders, IFN-γ had a significant negative effect on TMT-A and symbol coding performance. None of the other tests for psychomotor speed were significantly associated with cytokines. Overall psychomotor speed performance increased significantly across the study period while cytokine levels remained stable.Our study indicates a negative association between IFN-γ and psychomotor speed, which might be of importance when understanding the mechanisms behind psychomotor deviations in psychotic disorders. •The cytokine interferon (IFN) – γ is related to psychomotor speed in patients with psychotic disorders.•For majority of cytokines, we found no significant association with psychomotor speed.•Cytokines remained stable during the study period of 52 weeks. In patiIn general, psychomotor speed is associated with reduced white matter integrity in magnetic resonance imaging (MRI) studies of healthy volunteers and patients with schizophrenia . This reThe possible link between psychomotor speed and inflammation is of particular interest when studying patients with psychosis. There is increasing evidence for a linkage between psychosis and inflammation . NotablyA few previous studies on psychotic disorders identified an association between reduced psychomotor speed and cytokines such as interleukin (IL) -6 and tumor necrosis factor (TNF) -α . However22.1The current study is a prospective cohort study with participants from the BeStInTro study, a pragmatic, randomised controlled trial (RCT) comparing three different atypical antipsychotics in the treatment of schizophrenia spectrum disorders. The primary outcome results from this study are recently published in Lancet Psychiatry . The folThree treatment centers in Norway and one in Austria participated in collecting the data between Oct 20, 2011, to Dec 30, 2016. Inclusion criteria were age ≥18 years and a psychosis spectrum disorder (ICD-10 diagnosis F20-29) with active psychotic symptoms. Active psychosis was defined as a score ≥4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: Delusions (P1), Hallucinatory behavior (P3), Grandiosity (P5), Suspiciousness/persecution (P6) or Unusual thought content (G9) . ExclusiClinicalTrials.gov (NCT01446328).All patients gave written informed consent prior to inclusion. The study was approved by the Regional Committees for Medical and Health Research Ethics and the Norwegian Medicines Agency in Norway, and the Ethikkommission der Medizinische Universität Innsbruck and the Austrian Federal Office for Safety in Health Care in Austria. This work was carried out in accordance with the Declaration of Helsinki. The study is registered at 2.22). Participants underwent testing with Trail Making Tests A (TMT-A) and B (TMT-B)  and converted to ICD-10 diagnoses in line with Norwegian clinical guidelines. Sociodemographic data were recorded at baseline. We assessed alcohol and drug abuse with the two scales the Clinical Alcohol Use Scale and Clinical Drug Use Scale . At base (TMT-B) , at base (TMT-B) . All raw2.3Fasting-state blood samples were collected between 8 and 10 a.m. Before centrifugation at 3300 rpm for 10 min, the blood was left to clot at room temperature for 20–120 min. The aliquoted serum was frozen at -40 °C and stored at -80 °C. Cytokine analyses were conducted with a Multiplex immunoassay ). The following cytokines were analysed: IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 p70, IL-17a, interferon (IFN)–γ and TNF-α. The panel was performed in accordance with the manufacturers' instructions, but we substituted the universal assay buffer with 1X phosphate buffer saline (PBS) with 0.10% tween in order to improve fluorescence intensities. Using the manufacturers’ recommendations for sample dilutions and standard curve concentrations, all samples and standards were assayed in duplicates. A Luminex 200  was used for measuring the fluorescence intensities, and two lots of reagents with similar upper and lower detection limits (ULOQ/LLOQ) were used for all samples (21 plates).The detection limit was defined as the lowest detected value within the standard curve. Samples below the detection limits were set to half of the detection limits. Summarizing all visits, the number of samples and percentage under the detection limit was as follows: IL-1β: 229 (30.1%), IL-2: 41 (5.4%), IL-4: 162 (21.3%), IL-6: 239 (31.4%), IL-10: 74 (9.7%), IL-12 p70: 171 (26.3%), IL-17a: 40 (6.1%), IFN-γ: 158 (20.8%) and TNF-α: 146 (19.2%). Mean inter- and intra-assay coefficients of variation (CV) are given in 2.4www.R-project.org). The level of significance was set at p ≤ 0.05 and all analyses were two-tailed. We evaluated data normality with Shapiro-Wilk normality test and evaluation of the QQ-plots. TMT-A, TMT-B and symbol coding t-scores were close to normally distributed. All cytokine values were heavily right skewed, and thus log transformed cytokine values were used in the statistical analyses. We assessed associations between demographic variables, cytokines, and tests for psychomotor speed with Pearson's correlation for continuous variables, and with Mann Whitney U test or t-test  for dichotomous variables.Statistical analyses were performed using R version 3.6.2 for Windows , but not symbol coding . In addition, IL-4 was associated with TMT-A  and TMT-B . None of the other tested cytokines were significantly related to TMT-A or TMT-B . In thes4Our findings indicate that higher levels of IFN-γ had a significant negative effect upon psychomotor speed (assessed by TMT-A and symbol coding) in patients with a spectrum of psychotic disorders. No other cytokines were significantly associated with psychomotor speed. In addition, we found that although patients improved significantly on tests for psychomotor speed during the study period of 52 weeks, the tested cytokines remained stable without any significant changes.To our knowledge, this was the first study to include IFN-γ when investigating the association between inflammatory markers and psychomotor speed in patients with severe mental disorders. Therefore, it is difficult to find studies that are directly comparable with the finding regarding IFN-γ and psychomotor speed in our study. However, previous studies have found an association between performance on tests for psychomotor speed  and other pro-inflammatory cytokines in schizophrenia patients . AdditioOf the three tests for psychomotor speed, only TMT-A and symbol coding were significantly associated with a cytokine. Although all three tests included in this study measure psychomotor speed to some extent, they differentiate in whether they assess other cognitive domains as well. More specifically, TMT-A tests psychomotor speed and visuospatial abilities, whereas TMT-B also draws on higher cognitive abilities including working memory . The symAfter sensitivity analyses excluding patients with delusional disorder and acute transient psychosis, IFN-γ was still associated with TMT-A, but not symbol coding. In these analyses we lost some statistical power, and this might explain the loss of a significant association between IFN-γ and symbol coding. In addition, we found an association between IL-4 and the two tests TMT-A and TMT-B. Although false positive findings are more probable when performing additional statistical tests, the spectrum of schizophrenia patients might represent a different entity. Regarding blood levels of cytokines, a meta-analysis concluded that certain cytokines are trait markers , and thaIn general, IL-4 represents a different part of the immune system than IFN-γ  Whereas The majority of tested cytokines were not significantly associated with psychomotor speed in our study. This finding was somewhat surprising as it is contrary to a few previous studies which found an association between several cytokines and psychomotor speed in schizophrenia patients . Still, Interferons are potent cytokines with a major antiviral function . IFN-α iOn a neurobiological level, reduced psychomotor speed is associated with reduced white matter integrity in several parts of the brain, such as corpus callosum and basal ganglia . Such reWhen considering the pathophysiological mechanisms behind altered psychomotor activity, the basal ganglia need to be mentioned. In patients with schizophrenia, Yang et al. found an association between psychomotor slowing and basal ganglia activity . FollowiIn the current study, cytokines remained stable throughout the entire observational period of 52 weeks. Several studies have shown that some cytokines change from acute states of schizophrenia to more chronic phases . Still, In contrast to the cytokines remaining stable, patients improved significantly on tests for psychomotor speed during the study period. This in line with other studies demonstrating that schizophrenia patients treated with antipsychotics improve on overall cognitive performance , and psyThere are several limitations that need to be considered in this study. Only IFN-γ was significantly associated with psychomotor speed in the main analyses, and it is largely unclear why none of the other cytokines were associated with psychomotor speed. Considering a few previous studies on the topic, we expected to find an association between psychomotor speed and several inflammatory cytokines. However, as all tests for psychomotor speed changed significantly during the study period, it should have been possible to detect a relation with cytokines if present. The study was not powered for testing associations between cytokines and psychomotor speed and the lack of associations for other cytokines than IFN-γ may be a type II error. Even though correction for treatment groups did not have any effect on the main findings, we do not know from this study if antipsychotics in general influence the association between psychomotor speed and cytokines.However, the study also has several strengths. Importantly, we used a hypothesis driven approach. An extensive panel of cytokines representing different immune responses were included. Regarding psychomotor speed, we included three validated and well-established neuropsychological tests. Although none of these tests are the gold standard for psychomotor speed, they are all considered sound measures of psychomotor speed. When measuring neuropsychological tests repeatedly, improved scores can be a result of practice effects. However, the tests included in this study is proven relatively stable to such effects . As alreIn conclusions, our findings suggest an association between IFN-γ and psychomotor speed over time. Future studies should elaborate this association further, including both a wide range of inflammatory markers and several tests for psychomotor speed.10.13039/501100005416The Research Council of Norway (grant number 213727), the 10.13039/501100004257Western Norway Regional Health Trust (grant number 911679) and the participating not-for-profit hospitals and universities. The funding sources had no role in study design, data collection, analysis and interpretation of data, writing of the paper or in the decision to publish.This work was publicly funded entirely by None.


Ni-CODH is classified into distinct phylogenetic clades, A–G, with possibly distinct cellular roles. However, the types of Ni-CODH clade used by organisms in different microbiomes are unknown. Here, we conducted a metagenomic survey of a protein database to determine the relationship between the phylogeny and biome distribution of Ni-CODHs. Clustering and phylogenetic analyses showed that the metagenome assembly-derived Ni-CODH sequences were distributed in ~ 60% Ni-CODH clusters and in all Ni-CODH clades. We also identified a novel Ni-CODH clade, clade H. Biome mapping on the Ni-CODH phylogenetic tree revealed that Ni-CODHs of almost all the clades were found in natural aquatic environmental and engineered samples, whereas those of specific subclades were found only in host-associated samples. These results are comparable with our finding that the diversity in the phylum-level taxonomy of host-associated Ni-CODH owners is statistically different from those of the other biomes. Our findings suggest that while Ni-CODH is a ubiquitous enzyme produced across diverse microbiomes, its distribution in each clade is biased and mainly affected by the distinct composition of microbiomes.Ni-containing carbon monoxide dehydrogenase (Ni-CODH) plays an important role in the CO/COThe online version contains supplementary material available at 10.1007/s00792-022-01259-y. If the clustering criterion is precisely selected, each cluster would be composed of sequences from closely related species or single species, except for some horizontally transferred cases. In our study, ~ 94% and ~ 78% of the Ni-CODH clusters consisted of sequences from a single genus and species, respectively, even though horizontal gene transfers have been reported . The compositions of the Ni-CODH clades in the subcategorized biomes were similar within each major category, except for the “engineered” category . Overall, with the few exceptions, the results using subcategorized biomes were similar to those using the three major categories, indicating that the distribution patterns of the distinct clades of the Ni-CODHs were restricted by the major biome categories.The subcategorized biomes see “ mapped oory Fig. D. In theFinally, to gain insight into the factors underpinning the restricted Ni-CODH distribution, we analyzed the relationships between biome distribution and genomic information of Ni-CODHs. In particular, we focused on taxonomy of the Ni-CODH-bearing prokaryotes and function of genes located near the Ni-CODH genes, possibly as gene clusters, since these two appeared to be related to the Ni-CODH phylogeny  as follows Fig. A: FirmicConversely, the composition patterns of neighboring gene-functions  were similar among the three major biome categories, although slight differences were observed Fig. B. The frNi-CODH is a key enzyme for energy conservation and carbon fixation with CO, a mysterious but ubiquitous microbial metabolite Supplementary file2 (XLSX 728 KB)Below is the link to the electronic supplementary material.


This study uses machine learning and population data to analyze major determinants of preterm birth including depression and particulate matter. Retrospective cohort data came from Korea National Health Insurance Service claims data for 405,586 women who were aged 25–40 years and gave births for the first time after a singleton pregnancy during 2015–2017. The dependent variable was preterm birth during 2015–2017 and 90 independent variables were included . Random forest variable importance was used to identify major determinants of preterm birth including depression and particulate matter. Based on random forest variable importance, the top 40 determinants of preterm birth during 2015–2017 included socioeconomic status, age, proton pump inhibitor, benzodiazepine, tricyclic antidepressant, sleeping pills, progesterone, gastroesophageal reflux disease (GERD) for the years 2002–2014, particulate matter for the months January–December 2014, region, myoma uteri, diabetes for the years 2013–2014 and depression for the years 2011–2014. In conclusion, preterm birth has strong associations with depression and particulate matter. What is really needed for effective prenatal care is strong intervention for particulate matters together with active counseling and medication for common depressive symptoms (neglected by pregnant women). Preterm birth is a major part of disease burden for newborns and children on the globe ,2,3,4. EMoreover, emerging literature requests due attention to the significant effects of depression and air pollution on preterm birth ,13,14,15https://www.nhis.or.kr/static/html/wbd/g/a/wbdga0401.html, accessed on 15 March 2021). This retrospective study was approved by the Institutional Review Board (IRB) of Korea University Anam Hospital on 5 November 2018 (2018AN0365). Informed consent was waived by the Institutional Review Board (IRB) given that data were deidentified.Retrospective cohort data for this study came from Korea National Health Insurance Service claims data for 405,586 women, aged 25–40 years who gave birth for the first time after a singleton pregnancy during 2015–2017. South Korea runs a compulsory, universal health insurance service program and Korea National Health Insurance Service claims data cover most health events of all citizens residing in Korea  for each of the months January–December 2014; (3) disease information (no vs. yes) for each of the years 2002–2014, i.e., depression, diabetes, gastroesophageal reflux disease (GERD), hypertension and periodontitis; (4) medication history (no vs. yes) in 2014, i.e., benzodiazepine, calcium channel blocker, nitrate, progesterone, proton pump inhibitor, sleeping pills and tricyclic antidepressant; (5) obstetric information (no vs. yes) in 2014 such as in vitro fertilization, myoma uteri and prior cone. The 65 disease variables were denoted as Depression_2002, …, Depression_2014, Diabetes_2002, …, Diabetes_2014, GERD_2002, …, GERD_2014, Hypertension_2002, …, Hypertension_2014, and Periodontitis_2002, …, Periodontitis_2014. The disease information and the medication history were screened from ICD-10 and ATC codes, respectively (PM_2014_01 (2014 January), …, PM_2014_12 (December 2014) and its monthly average at a district level was obtained from [The dependent variable was preterm labor and birth during 2015–2017 (birth between 20 weeks and 0 day and 36 weeks and 6 days of gestation). Four categories of preterm labor and birth were defined based on ICD-10 Code: (1) PTB 1—preterm birth with premature rupture of membranes (PROM) only; (2) PTB 2—preterm labor and birth without PROM; (3) PTB 3—PTB 1, PTB 2 or both; (4) PTB 4—PTB 3 or other indicated preterm birth . This vaectively . Indeed,Logistic regression, the random forest and the artificial neural network were applied and compared for the prediction of preterm birth . Data on10 in Korea’s seven metropolitan areas for the year 2014 were 56 (January), 50 (February), 52 (March), 52 (April), 64 (May), 44 (June), 39 (July), 30 (August), 33 (September), 35 (October), 44 (November) and 42 (December) in terms of 10−6 g/m3, respectively. In terms of accuracy, the random forest was similar with logistic regression and the artificial neural network , PM_2014_12 (6th), PM_2014_02 (7th), PM_2014_11 (8th), PM_2014_09 (10th), PM_2014_06 (11th), PM_2014_10 (12th), PM_2014_01 (13th), PM_2014_07 (14th), PM_2014_05 (15th), PM_2014_03 (17th), PM_2014_04 (18th). These findings were similar with those of undersampling in PM_2014_08) increases by 1 × 10−6 g/m3 in the table. In a similar vein, the odds of PTB 4 will be greater by 12.2% for those with depression in 2010 than those without it in the table.Based on random forest variable importance, top-40 determinants of preterm birth during 2015–2017 included socioeconomic status, age, proton pump inhibitor, benzodiazepine, tricyclic antidepressant, sleeping pills, progesterone, GERD for the years 2002–2014, particulate matter for the months January2014–December 2014, region, myoma uteri, diabetes for the years 2013–2014 and depression for the years 2011–2014. These values were the averages for PTB 1, PTB 2, PTB 3 and PTB 4 . Several researchers focus on behavioral, infectious, neuroendocrine and neuroinflammatory mechanisms between depression and preterm birth . Other rFirstly, this study did not examine possible mediating effects among variables. Secondly, this study adopted the binary category of preterm birth as no vs. yes (birth between 20 weeks and 0 day and 36 weeks and 6 days of gestation). But preterm birth can have multiple categories and it will be a good topic for future study to compare different predictors for various categories of preterm birth, e.g., extremely preterm (less than 28 (or 24) weeks), very preterm (28–32 (or 24–32) weeks), moderate to late preterm (32–37 weeks) [Preterm birth has strong associations with depression and particulate matter. What is really needed for effective prenatal care is strong intervention for particulate matters together with active counseling and medication for common depressive symptoms (neglected by pregnant women).