Prediction of severe retinopathy of prematurity in 24–30 weeks gestation infants using birth characteristics by Dr. R. E. Zackula and Dr. T. S. Raghuveer [We read with great interest Journal Club publication entitled aghuveer . We are DIGIROP-Birth was based on 6947 infants born 2007–2017 at gestational age (GA) 24–30 weeks included in SWEDROP, the Swedish ROP registry. Of those, 289 (4.2%) had ROPT. From the development group, 94/7041 (1.3%) infants were excluded for missing data or date inconsistencies, 3 had ROPT. GA at birth and sex were similarly distributed in the excluded vs development group, 28.4 (SD 1.8) vs 28.3 (SD 1.9) weeks, and 47.9 vs 45.1% girls.SWEDROP does not include race/ethnicity. A thorough validation of a model is a prerequisite for clinical implementation. If required, the model selection and/or parameter estimates might be re-evaluated for a specific population or clinical setting.Although separately evaluated in our publication, 153/2122 (7.2%) infants had ROPT in the Swedish, German and US validation datasets. Per the PROBAST instrument, validation with ≥100 events is recommended .Reducing the effective sample by 1% (3/292 excluded events) and having no indication of infant selection in the excluded group, biased estimates were not expected. Internal validation including cross-validation and calibration plots, and external validations were affirmative.z-score). Hence, univariable analyses were not required. The model was consecutively extended, starting with GA.DIGIROP-Birth aimed to include few well-known risk factors available for all infants at birth; GA, sex and birth weight (BW) , r = −0.06. Therefore, we did not expect multicollinearity problem.Concern was raised regarding multicollinearity for GA and BW In the DIGIROP-Birth publication the optimal cut-offs were not investigated. We identified cut-offs in our publication for the extended model incorporating ROP progression data (DIGIROP-Screen), proposing a clinical decision support tool . Pre-speWe sincerely encourage and are thankful for all the efforts put on the validations and discussions of our work.


Recently, there is a growing interest in advanced monitoring of the cardio-circulatory system and the brain to get further objective information about the neonate’s condition during the immediate postnatal transition after birth. The aim of the present study was to combine cardiac output (CO) and brain oxygenation monitoring in term neonates after caesarean section in order to analyse the potential influence of CO on cerebral oxygenation during neonatal transition. This was a monocentric, prospective, observational study. For non-invasive cardiac output measurements, the electrical velocimetry (EV) method  was used. The pulse oximeter probe for SpO2 and HR measurements was placed on the right hand or wrist. The cerebral tissue oxygen index (cTOI) was measured using a NIRO-200NX monitor with the near-infrared spectroscopy (NIRS) transducer on the right frontoparietal head. Monitoring started at minute 1 and was continued until minute 15 after birth. At minutes 5, 10, and 15 after birth, mean CO was calculated from six 10 s periods . During the study period, 99 term neonates were enrolled. Data from neonates with uncomplicated transitions were analysed. CO showed a tendency to decrease until minute 10. During the complete observational period, there was no significant correlation between CO and cTOI. The present study was the first to investigate a possible correlation between CO and cerebral oxygenation in term infants during the immediate neonatal transition. In term infants with uncomplicated neonatal transition after caesarean section, CO did not correlate with cerebral oxygenation.The immediate transition from foetus to neonate includes substantial changes, especially concerning the cardiovascular system. Furthermore, the brain is one of the most vulnerable organs to hypoxia during this period. According to current guidelines for postnatal stabilization, the recommended parameters for monitoring are heart rate (HR) and arterial oxygen saturation (SpO Howeverery room . Oxygen ery room . Our stuery room . Furtherery room . The aimThis was a monocentric, prospective, observational study conducted from September 2013 to March 2017 at the Division of Neonatology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz. The study was approved by the Regional Committee on Biomedical Research Ethics (EC number: 25-342 ex 12/13). Informed parental consent was obtained antenatally before neonates were included in the study.Neonates born by caesarean section were included. After the neonates were fully delivered, a stopwatch was started. After cord clamping, which was routinely performed within 30 s, neonates were brought to the resuscitation table and placed under an overhead heater in the supine position. Measurements were performed during the first 15 min after birth. For non-invasive CO measurements, the Aesculon monitor  was used. Before starting the measurement, the skin was cleaned from vernix and the four surface electrodes were placed on the left forehead, left side of the neck, left hemithorax, and left thigh.2 and HR measurements  was placed on the right hand or wrist. The cerebral tissue oxygenation index (cTOI) was measured using a NIRO-200NX monitor . The near-infrared spectroscopy (NIRS) sensor was positioned on the right frontoparietal head and secured with a cohesive conforming bandage .CO was calculated as an average out of six 10 s periods . The data from these 10 s periods were only accepted if the signal quality index (SQI) was ≥80%. The pulse oximeter probe for SpO2 and HR were stored every second, and the sampling rate of cTOI was 2 Hz.Resuscitation was performed according to latest guideline recommendations ,9. We on2 (%) and HR (beats per minute) were analysed using a linear mixed-effects model with a fixed effect for time and a first-order autoregressive covariance structure. Estimated mean scores with 95% confidence intervals (CI) are given for the analysed variables for 5, 10, and 15 min. To analyse possible associations between CO and cerebral oxygenation, correlation analyses (Spearman’s rank correlation coefficient) were performed separately at minutes 5, 10, and 15 after birth. A p-value < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics 26.0.0 .Baseline characteristics are presented as mean ± standard deviation (SD) for normally distributed continuous variables and medians with interquartile range (IQR) when the distribution was skewed. Categorical variables are given with numbers and percentages. Changes in CO (mL/kg/min), cTOI (%), SpODuring the study period, 99 term neonates were enrolled. The demographic and clinical characteristics of the study population are presented in 2 showed a statistically significant increase from minute 5 to 10 after birth. Additionally, SpO2 rose significantly from minute 10 to minute 15, but after considering the number of values, this increase is not relevant for clinical praxis. HR did not change from minute 5 to 10 or 15.The courses of vital parameters at the time points 5, 10, and 15 min after birth are presented in There was no correlation between CO and cTOI during the first 15 min after birth .To our knowledge, this is the first study presenting correlation analyses between CO and cerebral oxygenation in term infants during the immediate neonatal transition. As the brain is a vulnerable organ, it is important to better understand oxygen delivery to the brain during this time. We hypothesized that higher CO would result in higher cerebral oxygenation, as oxygen delivery is dependent on CO and oxygen content. However, in our study population of 99 term infants delivered by caesarean section, we could not observe any significant correlation between CO and cerebral oxygenation.Most published haemodynamic changes during the immediate neonatal transition described an increase in heart rate and a decrease in pulmonary vascular resistance after cord clamping and lung aeration ,13,14,15Compared with echocardiography, EV provides the opportunity to monitor CO continuously and objectively. Additionally, the feasibility of this method has already been proven in the delivery room in term infants after caesarean section , and in Noori et al.  comparedSeveral studies have described lower cerebral oxygenation values in preterm neonates immediately after birth, resulting in cerebral injury in the following days ,12. As aWe recognize several limitations in this study. First, we only included neonates born by caesarean section. Due to technical reasons, not all of the measurements were able to be performed in the delivery room next to the mother. Since all neonates after caesarean section were brought to the resuscitation table and observed by a neonatologist for 10 to 15 min, we only performed measurements on those neonates. We did not include vaginally born neonates to avoid delaying immediate bonding with the mother. Therefore, we do not have any information about cardiac output measurements in vaginally born neonates. Recent studies showed that the mode of delivery might influence haemodynamic parameters and cerebral oxygenation during neonatal transition ,17,18. WThe present work is the first study to investigate a possible correlation between CO and cerebral oxygenation in term infants during immediate neonatal transition. In term infants with uncomplicated neonatal transition after caesarean section, there was no significant correlation between CO and cerebral oxygenation at 5, 10, or 15 min after birth.


Epidermal cysts can rarely occur in internal organs, but epidermal cyst of the urinary bladder is extremely rare with a very low tendency for malignant transformation. This article will guide the physicians to be aware of such rare complex neoplastic combinations to take proper decisions in management and treatment of the patients.A 40-year-old rural male patient with hematuria and urinary frequency presented to a hospital. Ultrasonography reported a cyst and a 2 × 1.5 cm stone in the urinary bladder. Surgery planned to remove the cyst and the stone. During the surgery, a cyst with solid parts and a stone were observed. The cyst had superficial penetrations into the bladder wall, the patient refused to done radical cystectomy, therefore the cyst excised from the bladder and sent for histopathological examination. The histopathological examination confirmed a well differentiated invasive squamous cell carcinoma arising from epidermal cyst with detrusor muscle invasion, staged pT2aNx. After diagnosis the patient received chemotherapy and improved his urinary symptoms. The possibility of further radical cystectomy and radiotherapy in neighboring countries remains open.Urinary bladder cysts associated with stones are uncommon but the occurrence of epidermal cyst in the urinary bladder is an extremely unusual incidence and malignant transformation of this lesion made it even rarer.Despite the rarity of malignant transformation in epidermal cyst and the unknown etiology of its occurrence in the urinary bladder, further clinicopathological and molecular studies are needed to reveal the possible pathogenesis with involved risk factors. •Malignant growth must be considered in a chronic epidermal cyst that displays unusual features.•Epidermal cysts can rarely occur in internal organs.•This is the first case of epidermoid cyst in urinary bladder with malignant transformation.•Both epidermal cyst malignancy and squamous cell carcinoma in the urinary bladder are more common in males than females. The patient is a tobacco addict with no other systemic diseases or family history for malignancy. On physical examination, no other visible abnormality was noted. Ultrasonography reported a cyst with solid areas and a 2 × 1.5 cm stone (vesicolithiasis) in the urinary bladder. Laboratory examinations showed gross hematuria and pyuria. Hemoglobin, kidney function test and liver function test were in normal ranges. Surgery was planned to remove the stone (vesicolithiatomy) and the cyst. During the surgery, a cystic lesion and a stone were observed. The cyst also had solid areas and during resection it showed superficial penetrations into the bladder wall. The cyst was excised and send for histopathological examination. Grossly it was consisting of fragmented gray-white cyst wall tissue, with the largest tissue fragment measures 3 cm in its greatest dimension. The inner surface of cyst wall fragments was tan and flaky in appearance. The entire tissue specimen was submitted for microscopic evaluation. Histologically features showed detrusor muscle of the urinary bladder with associated epidermal cyst lined by keratinized stratified squamous epithelium exhibiting keratin flakes and prominent granular layer . The cys3Ewing in 1942, proposed that epidermal remnants derived from Wolffian ducts in internal organs can be the possible source of EC development Although the etiology of EC transforming into malignancy is unclear, tobacco use, male gender, chronic irritation, trauma and recurrent infection are the triggering factors that have been suggested. Persistent chronic irritation due to chronic inflammation or repeated trauma cause the damage to the lining cells of cyst and the repeated damage and repair process finally could result in dysplastic changes and invasive carcinoma In our case, the middle-aged male patient presented with hematuria and urinary frequency has gone through vesicolithiatomy with removal of the cyst as primary therapeutic interventions. Considering the unknown etiology of EC transforming into malignancy, further clinicopathological and molecular studies are needed to identify the possible pathogenesis with involved risk factors.4EC is rare in internal organs and MT within the cyst is much rarer. In the current case, male gender and chronic irritation of the EC because of bladder stone possibly leads to MT. Malignant growth must be considered in a chronic EC that displays unusual features.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.None declared.Ethical approval was obtained from the Research Ethics Committee of the concerned hospital.JAG and MH diagnosed the case. MH conceived the idea. MH and RS were the major contributors to the writing of the first draft of manuscript. JAG and HAM were major contributors to the critically revising of the manuscript and important intellectual content. All authors read and approved the final manuscript.Not applicable.Jamshid Abdul-Ghafar, MD, PhD.Not commissioned, externally peer-reviewed.The authors report no declarations of interest.


After stratification for conception mode, this association remained in IVF/ICSI pregnancies with frozen embryo transfer , but not in IVF/ICSI pregnancies with fresh embryo transfer and natural pregnancies. Homocysteine was not associated with longitudinal measurements of head growth in first trimester, nor with second and third trimester fetal growth. Homocysteine in the highest quartile (7.3–14.9 µmol/L) as opposed to the lowest (2.5–5.2 µmol/L) was associated with reduced birth weight in natural pregnancies only . In conclusion, high maternal homocysteine within the reference range is negatively associated with first trimester embryonic growth and birth weight, and the effects of homocysteine are dependent on conception mode.Homocysteine is a marker for derangements in one-carbon metabolism. Elevated homocysteine may represent a causal link between poor maternal nutrition and impaired embryonic and fetal development. We sought to investigate associations between reference range maternal homocysteine and embryonic and fetal growth. We enrolled 1060 singleton pregnancies  pregnancies) from November 2010 to December 2020. Embryonic and fetal body and head growth was assessed throughout pregnancy using three-dimensional ultrasound scans and virtual reality techniques. Homocysteine was negatively associated with first trimester embryonic growth in the included population (crown-rump length B −0.023 mm, 95% CI −0.038,−0.007,  Derange12. A high blood concentration of homocysteine is recognized as a sensitive marker for general folate deficiency [One-carbon metabolism is composed of the interlinked folate and methionine cycles, and the transsulfuration pathway, which support essential biological processes including cell multiplication, differentiation, and epigenetic programming . Clinicaficiency ,5.Elevated homocysteine levels are known to impair female fertility and preimplantation embryo development. Studies report that elevated homocysteine impairs gamete quality, decreases fertilization success, and alters epigenetic processes in the preimplantation embryo ,6. It isBesides birth weight, only a few studies address the association between maternal homocysteine and prenatal development. Parisi et al. reported that high homocysteine levels are associated with delayed embryonic development (Carnegie stages) , togetheWe were the first to hypothesize that maternal homocysteine is associated with neural tube defects ,15 and cThis study is embedded in the Rotterdam Periconception Cohort (Predict Study), a prospective tertiary hospital-based birth cohort study at the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Center, Rotterdam, The Netherlands. This is an ongoing study initiated in 2009, with the aim of investigating the association between parental periconception health and its impact on reproduction, pregnancy, and neonatal outcomes . The stuBetween November 2010 and December 2020, pregnant women in early first-trimester (<11 weeks of gestation) were eligible for enrolment, provided they (and their partner) had at least reached the age of 18 years, and could read and speak the Dutch language. In naturally conceived pregnancies, gestational age (GA) was calculated from the first day of the last menstrual period of a regular menstrual cycle. For IVF and ICSI pregnancies, GA was calculated from 14 days before the conception date for fresh embryo transfers and 14 days before the fictitious conception date for cryopreserved embryo transfers, adjusted for the age of the embryo at transfer. For pregnancies achieved via IUI, GA was calculated from 14 days before the insemination date. GA was considered unreliable in cases with an unknown last menstrual period or an irregular menstrual cycle (<21 or >35 days). Information on women and their partners was obtained via extensive self-reported questionnaires given at the time of enrolment (<11 weeks of gestation), covering details such as age, anthropometrics, family history, medical history, education, lifestyle behavior, and habits (from 4 weeks before to 8 weeks after conception). Based on Statistics Netherlands, education level was classified as ‘low’ for primary/lower vocational/intermediate secondary school, ‘intermediate’ for higher secondary/intermediate vocational school, and ‘high’ for higher vocational school/university . The con12. Homocysteine was measured until December 2020, whereas folate and vitamin B12 were measured until December 2016, due to a change in study protocol. In vitro quantitative determination of total L-homocysteine in human serum was performed using an HCYS assay with a Cobas 8000 system, and in vitro quantitative determination of human serum folate and vitamin B12 was performed using the Elecsys Folate III and Elecsys Vitamin B12 II assays with a Cobas 8000 system by Cobas® Roche Diagnostics. Protocols are publicly available online on www.diagnostics.roche.com (accessed on 20 December 2021).At the time of enrolment (<11 weeks of gestation), one venous blood sample from both women and their partners was collected for the determination of biomarkers of one-carbon metabolism: serum homocysteine, folate, and vitamin BTo measure embryonic and fetal growth parameters, ultrasound scans were obtained from all women in the first, second, and third trimesters of pregnancy, and neonatal birth weight was obtained from medical records.n = 118), measurements of head size (head volume (HV), biparietal diameter (BPD), occipitofrontal diameter (OFD), head circumference (HC), and cerebellar size (transcerebellar diameter (TCD)) were performed using an offline 3D software  [Longitudinal transvaginal three-dimensional (3D) ultrasound scans were performed from enrolment to the end of the first trimester of pregnancy with a maximum of 6 scans per pregnancy. 3D ultrasound examinations were performed using a 6–12 MHz transvaginal probe of the Voluson E8 or E10 system . 3D ultrasound images were stored as Cartesian volumes and analyzed by virtual reality (VR) systems and V-Scope software . The VR systems used in the current study were the BARCO I-Space (until 2019) and Desktop VR system (since 2014), which all use the identical in-house developed software program V-Scope ,22. The Systems) ,24. Suchn = 269) [In a subpopulation of the Predict Study (included population n = 269) , longitun = 269) ,28,29,30Additional second trimester measurements of fetal biometry were obtained from medical records and included a single time-point measure of BPD, HC, TCD, AC, FL, and EFW. These measurements were performed during the standard fetal anomaly scan, with a mean of 20 weeks of gestation, according to the ISUOG practice guidelines .Birth at <37 weeks of gestation was defined as preterm birth, and neonatal birth weight of ≤2500 g as low birth weight. Hoftiezer percentiles were calculated according to the publication of Hoftiezer et al. . Neonatet-test with unpaired samples was used to compare continuous variables, Fisher’s exact test for dichotomous categorical variables, and Chi-square test for polychotomous categorical variables. Non-parametric data were log10-transformed to obtain parametric data. Associations were performed with univariate linear regression for continuous exposure and outcome variables, and with binary logistic regression for continuous exposure variables and outcome dichotomous categorical variables.The Student’s In subanalyses, homocysteine was divided into categories, as the literature shows that the effect of homocysteine levels on neonatal birth weight is not linear. Homocysteine was divided into fourths with equal number of pregnancies per quartile: Q1 2.5–5.2 µmol/L, Q2 5.3–6.0 µmol/L, Q3 6.1–7.2 µmol/L, Q4 7.3–14.9 µmol/L, and Q1 was used as reference category.Linear mixed models were used to analyze associations between longitudinal measurements and maternal homocysteine, adjusting for confounders and assuming the effect of homocysteine was constant over gestation. For all analyses, confounders were chosen based on the literature: (Model 1) adjustment for GA and (Model 2) adjustment for GA, conception mode, parity, folic acid supplement use, alcohol use, smoking, maternal BMI, maternal age, and fetal sex. All analyses were stratified by conception mode.p < 0.05. All analyses were executed in IBM SPSS Statistics for Windows (version 25), and R (version 4.1.1).For all analyses, statistical significance was defined as A total of 1060 pregnancies were included in the study, of which 555 (52%) were natural pregnancies and 505 (48%) were conceived by IVF/ICSI, according to the inclusion and exclusion criteria described in p = 0.02). Homocysteine was positively associated with maternal BMI , p = 0.01), with the odds of being a smoker , p = 0.01), and with being nulliparous , p = 0.01). Maternal homocysteine showed an inverse association with maternal and paternal vitamin B12 , p < 0.01 and B −0.06 , p = 0.03 respectively), maternal and paternal serum folate , p < 0.01 and B −0.06 , p = 0.04 respectively), and there was a positive association with paternal homocysteine , p = 0.01).In the included population, women conceiving naturally were more likely to have higher homocysteine levels than women pregnant after IVF/ICSI , In the included population, the mean GA for CRL and EV was 9 + 6 weeks (69 days). CRL and EV did not differ between natural and IVF/ICSI pregnancies. Linear mixed effect models showed that homocysteine was negatively associated with growth trajectories of CRL and EV in the included overall population . The negIn the subpopulation including 118 pregnancies, embryonic BPD, OFD, HV, HC, and TCD at 9 and 11 weeks of gestation did not differ between natural and IVF/ICSI pregnancies. Linear mixed effect models showed that maternal homocysteine was not associated with longitudinal embryonic head growth .p = 0.03). Linear regression showed that homocysteine was not associated with second trimester fetal growth . These measurements did not differ significantly between conception modes. Associations between homocysteine and longitudinal fetal BPD, HC, TCD, AC, and EFW were not significant, except for FL in IVF/ICSI pregnancies .In the included population, the mean GA at birth was 39 + 1 weeks, and the average birth weight was 3286 g. Birth weight did not differ between natural and IVF/ICSI pregnancies. Linear regression showed that homocysteine was not associated with birth weight but was negatively associated with Hoftiezer percentiles in natural pregnancies . The dirThe present study sought to investigate the association between maternal first trimester homocysteine levels, within the standard reference range, and longitudinal embryonic and fetal growth from the sixth week of gestation until birth, based on mode of conception. We demonstrated that maternal homocysteine is negatively associated with embryonic growth  during the first trimester, specifically in IVF/ICSI pregnancies with frozen embryo transfer. Embryonic head growth was not affected by maternal homocysteine levels. Homocysteine was not associated with second and third trimester fetal growth. Levels of homocysteine in the highest quartile were associated with reduced birth weight and Hoftiezer percentiles in natural pregnancies only.12 deficiency [Homocysteine is an important biological and clinical marker of one-carbon metabolism. It is well recognized that high homocysteine levels are indicative of folate and/or vitamin Bficiency , and thificiency ,34,35. Wficiency . We repoficiency . In lineDeficiencies of one-carbon substrates and co-factors during the periconceptional period are involved in alterations of the embryo’s genetic and epigenetic landscape, which negatively impact prenatal and early postnatal offspring growth . ElevateOne-carbon metabolism is also involved in brain development and neural programming, and derangements of the pathway increase the short-term risk of embryonic neural tube-related defects and long-term childhood behavior, cognition, and autism spectrum disorders . As repoFirst trimester embryonic growth is associated with second and third trimester fetal growth, and consequently with neonatal weight at birth ; therefoThis study adds to the current debate on homocysteine and birth weight. Elevated homocysteine is associated with SGA neonates, preterm birth, and low neonatal birth weight ,48,49,50Despite selecting women with a ‘healthy’ reference range of homocysteine, we found that there was still a negative association with embryonic growth during the first trimester. This observation may be due to epigenetic regulation of embryonic development; cell lineage specification and tissue patterning are predominant during the first trimester, under the influence of one-carbon metabolism . SimilarAdditionally, we confirm that conception mode is a strong determinant of the effects homocysteine exerts on first trimester embryonic growth and neonatal birth weight. Embryos from IVF/ICSI pregnancies with frozen embryo transfer appear to be most sensitive to the negative effects of homocysteine during the first trimester, whereas embryos from natural pregnancies were most vulnerable to negative effects at birth. This may suggest that ART treatment factors specific to the in vitro culture environment, and/or freezing/thawing procedures, may influence the way the embryo responds to the surrounding maternal environment during development. ART treatment may alter the embryo’s epigenome, which therefore responds differently to the influence of homocysteine during pregnancy.This study is the first to analyze, longitudinally, embryonic, and fetal growth from the first trimester until birth. Detection of early pregnancy intrauterine growth is currently advantageous, as the majority of studies include birth as the earliest measurable time point. With this approach, we were able to keep track of offspring development throughout pregnancy, knowing that growth patterns are GA-dependent. All included longitudinal measurements have previously shown to have excellent inter- and intra-observer reproducibility . The samThe study design is a tertiary cohort, which includes a high-risk population that may introduce bias in the results and reduce external validity. A population-based cohort may avoid such interferences . MoreoveReduced embryonic and fetal growth is a sign of disturbed development and can lead to adverse postnatal growth patterns and development with long-lasting effects during the life course ,54. For Future research should investigate the role of homocysteine in women undergoing ART treatment to identify which factors related to fertility or the ART treatment itself influence the embryo’s response to maternal one-carbon metabolism. Lastly, during pregnancy, the reference range of homocysteine should be redefined or adapted, as high levels of homocysteine within the current reference range appear to negatively impact prenatal growth.


After controlling for biological, demographic, and social factors, a significant decrease in birth weight was found for primiparous women of the age group ≥30 years and multiparous women aged ≥35 years compared to the age group of 25–29 years. The lowest neonatal birth weight was observed in the case of women aged ≥45 years. Confounders did not affect birth weight Z-scores among primiparous women, whereas among multiparous women, together with educational factors, they reversed Z-scores from positive to negative values. The lower birth weight of neonates was overall associated with lower maternal education. Conclusions: Regardless of parity, advanced maternal age is strongly associated with a decreased neonatal birth weight, implying complications in early pregnancy and the antenatal period as well as obstetric complications. Counseling to support women’s family planning decisions and improving women’s education during their reproductive age may help to alleviate unfavorable newborn outcomes.Background: Despite numerous studies of women having children later in life, evidence of the relationship between maternal factors and newborn outcomes in Central and Eastern European countries is limited. This study aimed to examine the association between maternal age, biological determinants, including parity and sex of the newborn, demographic and social background, and birth weight in 3.8 million singleton live births in Poland. Methods: The effect of maternal age on birth weight (in grams and Z-scores) adjusted for confounders was assessed using Generalized Linear Models. Results: The mean (±SD) birth weights of neonates born to primiparous women and multiparous women were 3356.3 ± 524.9 g and 3422.7 ± 538.6 g, respectively, which corresponded to a Z-score of −0.07 ± 0.96 and 0.14 ± 1.00, respectively ( Birth weight is a critical parameter for assessing neonatal health and a predictor of newborn growth and survival . NeonataStudies on newborn health conducted in developed countries ,7,8 and So far, studies have not focused much on explaining the causes of differences in birth weight in Poland, which is the largest country in Central and Eastern Europe, with an annual number of live births of around 400,000. Research on the Polish population has analyzed the association of respiratory distress syndrome in preterm infants with social and demographic factors of mothers  and chanThe aim of this study was to examine the associations between maternal characteristics, such as age, biological determinants , demographic and social background , and birth weight in 3.8 million singleton live births in Poland, using data collected from the Polish Birth Registry.In this retrospective study, we used the data collected from the Central Statistical Office (CSO) in Poland on live births based on 3,918,344 individual records. Cases of live births registered from 2008 to 2017 were included in the study. Because the reports are based on birth certificates and the Polish law requires each birth to be registered, the records covered every birth in the analyzed decade. Data of live births were transferred from obstetric and newborn medical records in each hospital using a standardized document for the entire country . IndividThe primary outcome of interest was birth weight, which was recorded in grams and measured directly at birth. Birth weight converted into Z-scores was calculated separately for subgroups defined by sex and gestational age (with 1-week precision) by subtracting the group using standard deviations . To deteMaternal age was stratified into the following age groups: 20–24, 25–29, 30–34, 35–39, 40–44, and ≥45 years, with the range of 25–29 years considered as reference. Based on the number of previous live births, parity was stratified into primiparity and multiparity. The biological variable of the mothers was gestational age, which was defined as preterm (<37 full weeks), term (37–41 full weeks), and post-term (≥42 full weeks). Stillbirth in any previous gestation was defined as fetal death after the 22nd week of gestation .Previous studies focusing on maternal age and birth weight indicated that demographic and social factors had a potential impact on newborn outcomes ,23,24. DThe potential individual mediating factors included maternal characteristics, which were obtained from the data available from the Polish Central Statistical Office and were used as confounding factors as appropriate. We assumed that multiple births may significantly influence the association between maternal age and birth weight  and thatTo analyze the relationships between newborn outcomes (newborn weight by sex) and maternal factors, Generalized Linear Models with continuous dependent variables were used . Covariance matrices of the models were determined using model-based estimators . The influence of maternal age on the birth weight of neonates was estimated as a linear and quadratic trend.Results for birth weight were presented as the coefficients (β) of the regression models with 95% confidence intervals (CIs), which should be interpreted as estimated differences in birth weight in grams between particular maternal age category and reference age category. Regression models for birth weight Z-scores, including maternal age groups, were presented using expected values of the dependent variable as birth weight Z-scores with 95% confidence intervals (CIs). Independent factors were identified and analyzed by univariate regression, and multivariate regression analyses, taking into account the possible confounding factors. Four models were constructed to investigate the associations between maternal variables and birth weight by sex of newborns: model 1 included only maternal age; model 2 was adjusted for biological factors ; model 3 included those variables analyzed in model 2 as well as demographic factors ; and model 4 additionally included education, an important social factor. All the analyses were conducted including stratification for parity and sex of neonates according to the approach reported elsewhere ,29,30.® SPSS® Statistics for Windows, Version 26.0 .Statistical hypotheses were verified at a significance level of 0.05. All calculations were performed in IBMDuring 2008–2017, a total of 3,657,583 singleton live births were recorded, of which 1,883,367 were boys (51.5%). A total of 1,742,641 births (47.6%) were recorded among primiparous women. The maternal and newborn characteristics analyzed in the study are presented in p ≤ 0.001). A stepwise decrease of birth weight was observed in the case of neonates born to primiparous women aged over 25–29 years and in multiparous women aged above 30–34 years. The lowest birth weight of neonates was observed for mothers ≥ 45 years of age . The results differed significantly by sex of newborns (p ≤ 0.001), with boys having a higher birth weight than girls   .p ≤ 0.001), but in mothers above 34 years of age, the differences were insignificant . On the other hand, for multiparous women, the total Z-score had a positive value (0.14 ± 1.00), except in the case of the age group 20–24 years, for which the Z-score was found to be negative (−0.02 ± 1.00). A similar trend was found for boys and girls, i.e., negative Z-scores for primiparous women and positive values for multiparous ones, except for those aged 20–24 years. The highest mean and median Z-scores were found for primiparous mothers aged 25–29 years old (−0.05 ± 0.95) and multiparous mothers aged 30–34 years old (0.18 ± 0.99). A significant difference in Z-scores between boys and girls was found for mothers in the age groups 20–24, 25–29, and 30–34 years (nificant .p ≤ 0.001). The inclusion of educational level in model 4 led to a significant increase in the difference in birth weight among primiparous women aged 20–24 years in comparison to the referenced age group. For primiparous women aged 29 years and older, the negative difference in birth weight (β) continued to systematically increase, and for mothers with most advanced age (≥45 years), the significant difference in β was −131.0 in boys, and −192.3 g in girls. For multiparous women, models 1–3 showed a distinct positive difference in the birth weight of girls born to those aged 30–34 years vs. the reference group. Significant positive differences in the birth weight of boys were found for the same maternal age in models 2 and 3. A continuous decrease in newborn birth weight was observed for multiparous women above 34 years of age. After adjustment for confounders, in those aged ≥45 years, the significant decrease of β value in boys and girls was −99.4 and −101.9 g, respectively  were negative for both sexes and all mother age groups, compared with the reference age group 25–29 years  led to a shift of birth weight Z-scores from positive to negative for the majority of the multiparous women. Regardless of parity, the educational factor was strongly associated with a decreased Z-score for the birth weight compared with other confounders .p ≤ 0.001). Furthermore, the differences in birth weight were found to be more pronounced among multiparous women compared to primiparous ones. Among primiparous women, the difference in newborn birth weight between mothers with low vs. high levels of education was significant, and was on average −140.5 g in boys and −144.3 g in girls, whereas among multiparous women it was on average −236.1 and −223.0 g, respectively. Smaller differences in newborn birth weight were found between mothers with a low vs. medium level of education . The smallest differences in newborn birth weight were found between mothers with a medium vs. high level of education .Our study showed that AMA had a significant impact on newborn birth weight. A stepwise decrease of birth weight was observed for primiparous women from the age group 25–29 years to the age group ≥45 years (from 3373.1 to 3106.9 g), and for multiparous women who were older than 30–34 years . The associations between maternal age and birth weight were linear and also an inverse U-shaped curve and persisted even after adjusting for biological, demographic, and social characteristics of the mothers. In the multivariate model including the educational factor, an increasing trend of newborn birth weight was observed only for primiparous mothers in the age group 20–24 years. The estimated birth weight Z-scores were negative for primiparous women. Confounding factors did not change the results. However, in the case of multiparous women, the Z-score was generally positive, but after adjusting for education the values changed to negative. Parity was a factor associated with birth weight; for primiparous women, the mean birth weight for each maternal age group was significantly lower in comparison to multiparous women. Additionally, differences in birth weight were found in relation to the sex of the neonates: the weight at birth was about 4% greater in boys than in girls.The associations between maternal age and birth weight were found to be highly specific for each maternal age group—linear and nonlinear . The findings were observed to be similar for multiparous and primiparous mothers, both in unadjusted analyses and after adjustment for confounders. Newborns of the AMA group had a significantly lower birth weight compared to those of mothers of the age group 20–24 years. These results are in line with those reported by studies conducted in high-, middle-, and low-income countries, despite the use of different estimation methods ,7,8.Although we could not identify the mechanisms underlying the observed associations, some explanations can be given. For example, in the case of the AMA group, biological conditions, particularly those associated with the reproductive system, i.e., the body aging processes, are associated with stepwise functional involution, accelerated placental aging, and detrimental changes in nutrient transport and vascular functions. In addition, AMA is associated with an increased risk of chronic diseases, including hypertension and diabetes, which usually result in impaired placental function and in utero undernutrition of the fetus ,8,31.Adverse newborn outcomes such as lower birth weight (commonly observed among older mothers) are associated with both short- and long-term consequences, including neonatal health problems in later life. Low birth weight has been identified as a predictor of mortality among preterm newborns, owing to an increased risk of bronchopulmonary dysplasia and necrotizing enterocolitis ,32. It hImportantly, the results of our study also showed that parity was strongly associated with birth weight, while a greater newborn birth weight observed in the case of multiparous mothers had a rather biological etiology. It seems that the volume of the uterus increases following the first pregnancy, along with an increase in the capacity of uterine and placental blood flow, which subsequently leads to better fetal growth . In the The biological characteristics of the mother had a significant impact on the association between maternal age and birth weight. Model 2 analyzed in the present study showed that a shorter gestational age was strongly associated with a reduced birth weight compared to crude model 1. This result was also confirmed by previous studies ,37, whicThe results of this study showed that lower maternal education was associated, at least partly, with inequalities in newborn outcomes. Regardless of parity, the Z-scores reflected the most evident deficits in newborn birth weight after adjusting for the educational factor, and in the case of multiparous women, the values shifted from positive to negative. This may have been due to the lower education level of multiparous women whose primary-to-secondary education ratio was greater compared to primiparous women (58.6% vs. 47.2%). Contrastingly, among multiparous women aged 30–39 years, the Z-scores were not fully consistent with those of the other age groups, which may be due to a higher proportion of births observed among mothers in the age group 30–39 with a higher level of education. The significant influence of differences in maternal educational level on newborn outcomes has also been highlighted in some studies ,38,39, wAlong with maternal factors liable to inequalities, fetal sex was another significant factor producing potential inequality in newborn outcomes. Compared to girls, the birth weight of boys was higher by 131.0 g among primiparous mothers and 140.9 g among multiparous women. These data are consistent with the findings of other investigators, who demonstrated that the mean difference in birth weight between boys and girls ranged from 111 to 184 g ,40. BirtThis study is the first to report the results of birth weight using Z-scores in five-year maternal age groups encompassing parity. Only a few published reports have shown changes in birth weight using Z-scores concerning mothers’ age in a national sample but without division based on parity . MoreoveSeveral limitations should be addressed when interpreting the findings of this study. The results obtained are averaged for the entire neonatal population and should not be interpreted as an individual risk. However, the analysis of the complete live birth dataset revealed a clear trend toward lower birth weight, especially in the case of older and less educated mothers. We could not adjust the findings for smoking and antenatal care, both of which were associated with adverse neonatal outcomes ,44. UnfoRegardless of parity, advanced maternal age was strongly associated with decreased neonatal birth weight, implying complications in early pregnancy and the antenatal period as well as obstetric complications. The findings of this study may have clinical significance and may be useful in preconception and pregnancy counseling to support women’s family planning decisions, particularly the consequences of maternity delay. The usefulness of the data obtained in this study may confer a key role for public health by providing an opportunity to inform about the health needs of mothers and children. The finding of birth weight inequalities related to maternal education emphasizes the importance of social policies aimed at improving women’s education during their reproductive age to alleviate unfavorable newborn outcomes.


Epidermoid cysts are small, solitary, and slow-growing lesions that rarely appear in the perineum and mostly arise because of trauma. This study examined a huge perineal epidermoid cyst that slowly grew over eight years in a premenopausal woman. Ultrasonography showed that the hemorrhage in the cyst was a semisolid hypoechoic mass, which mimicked endometrioma, and was tentatively diagnosed as scar endometriosis in the perineum after vaginal delivery. This case study highlights the importance of wide surgical excision and histopathologic diagnosis, even with typical ultrasonography and surgical findings. An epidermoid cyst is a cutaneous or subcutaneous mass that occurs due to the implantation of epidermal elements in the dermis . It usuaA 44-year-old woman was referred for a perineal lump that she experienced for eight years since her last vaginal delivery. No other gynecological symptoms, such as dysmenorrhea and chronic pelvic pain, were reported. Initially, the lump was a painless, peanut-sized mass. It slowly grew to the size of a man’s fist, but its size did not change during the menstrual cycle. The movable gray mid-perineal mass measured 8 cm × 8 cm × 6 cm and was soft without tenderness . Trans-lAn epidermoid cyst is a common, benign intradermal or subcutaneous tumor that slowly arises and grows from the invagination of the keratinizing squamous epithelium ,2. It usThe epidermoid cyst on the female external genitalia is mostly localized on the clitoris following circumcision for cultural or ethnic reasons ,9. ClitoEpidermoid cysts can occur in vulvar lesions, the labia majora, and the labia minora, and large cases without trauma history were usually reported. An 11-cm epidermoid cyst in the labia majora was reported in a 17-year-old girl without trauma history who complained of a painful and palpable mass . In addiRarely, an epidermoid cyst can occur in the perineum, between the vestibule and anus. The vast majority of cysts are less than 1 cm in diameter and mostly occur because of exposure to trauma, including vaginal delivery. One study reported a case of a 4-cm perineal epidermoid cyst in a 28-year-old woman who complained of a tender vaginal mass on the episiotomy site 10 years after vaginal delivery was reported . In thisDiagnostic imaging tools in the previously reported epidermoid cyst cases consisted of ultrasonography and MRI. The epidermoid cyst’s ultrasonographic appearances vary because the cyst’s contents are diverse, ranging from hypoechoic to hyperechoic lesions. Turkay et al.  depictedThe characteristics of MRI also depend on the composition of the cyst. Thus, variable signal intensity and enhancement of the T1 and T2 values can be seen . These uThe perineal tumor, along with Bartholin’s cyst, lipomas, endometrioma, post-traumatic hematoma, malignant tumors, liposarcomas, and endometrioma-originating clear cell carcinomas, should be considered during differential diagnosis ,19,20,21For the clinical presentation of the perineal epidermoid cyst, various demonstrations were reported. Some epidermoid cyst cases can be asymptomatic, while, in other cases, the only symptom is a gradual increase in size ,22,23. ISome cases accompany complications, and Nigam et al.  reportedThis epidermoid cyst of the perineum is the largest one known in current literature. It is necessary to consider epidermoid cysts when a painless, slow-growing perineal mass, especially in a patient with a history of perineal trauma , is encountered. Therefore, a pathological diagnosis should be emphasized even in cases that show the characteristic clinical manifestations of typical hypoechoic, semisolid masses on ultrasonography with thick, chocolate-colored liquid, as seen in this case.


The first birth is the most significant events in a woman's life that indicates the beginning of undertaking the intensive responsibilities of motherhood and childcare. Age at first birth has health, economic and social consequences and implications. But little has been known on the time to first birth and its determinants in Ethiopia. Therefore, this research is planned to address this issue.To assess the time to first birth and its determinants among married female youths in Ethiopia, 2020.https://www.dhsprogram.com). Survival analysis of time to first birth was done based on EDHS 2016 data among 2597 weighted study subjects. The data was extracted using STATA version 14.0. Kaplan Meier’s survival and Log rank test were used to compare survival experiences of respondents using categorical variables. Proportional hazard assumption was checked and was not violated. Cox proportional hazard model was applied, hazard ratio with 95% CI was computed and variables with p value < 0.05 in the multivariable analysis were taken as significant determinants.The data was accessed freely through . The significant determinants of time to first birth are place of residence ,Religion ,being protestant ], age at first sex [first sex < 15 years ] and first sex between 15 and 17 years , age at first marriage , marriage between 15 and 17 , unmet need for family planning In this study, the median age at first birth was 18 years. This show, about 50% of study participants give birth for the first time before their 18th birth day. This age is the ideal age for schooling and to do other personal development activities. Therefore giving birth before 18 year will limit female youths from attending school and performing personal development activities in addition to health and demographic consequences of early child bearing. The first birth is one of the most significant event in a woman’s life, which can affect the welfare of women, men, and children indicating the beginning of undertaking the intensive responsibilities of motherhood and childcare . Girls iScholars say that the best time to get pregnant is between late 20 s and early 30 s. This age range is associated with the best outcomes for both the mother and her baby . One stuFertility patterns in the world have changed dramatically producing a world with very diverse child bearing patterns after the international conference on population and development (ICPD) in 1994, . Sub-SahNearly 16 million adolescent girls between 15 and 19 give birth each year which accounts roughly 11% of all births worldwide; 95% occur in developing countries .Ethiopia is the second most populous country in Africa and is characterized by high population growth of 2.5% annually . The ferDelaying pregnancy and child bearing among young women may contribute to higher school attainment, which might translate into better human capital outcomes for their children . First bWomen’s fertility level is affected by different factors such as availability of effective birth control methods, age at marriage, age at first sexual intercourse, religious beliefs, acceptability of abortion, infant mortality rate, educational and career development opportunities, economic factors and urbanization –27.Ethiopia has national adolescent and youth health strategy to address the sexual and reproductive related issues including preventing early child bearing  but earlFew available literatures on this issue mainly focus on either teenagers or all reproductive women regardless of their marital status. The current study focuses on youths who were given little attention by the previous researchers and being married also enabled to address factors related to their husbands. Updated knowledge using nationally representative data could provide useful information for policy makers to implement future interventions for controlling the total fertility rate and reduce the health, demographic and socioeconomic consequences of first child bearing at early age.Therefore, the objective of this research project was to determine time to first birth and to identify its determinants among ever married youth females.https://www.dhsprogram.com). The data extraction period was from 1st June to 1st July. Weighted sample was 2597. About 2597 participants were involved after weighting.The study was conducted in Ethiopia using the 2016 Ethiopian demographic and health survey data. In Ethiopia according to the EDHS 2016 report, the median age at first marriage and first sexual intercourse were 17.1 years and 16.6 years respectively, the maternal mortality ratio was 412 per 100,000 live births, skilled delivery coverage was 28%, the contraceptive prevalence among married women and a fertility rate was 36% and 4.46 respectively and Sexually active unmarried women accounts 58% [, use of contraceptives, age at first sex and age at first marriage), behavioral factors , media related factors (media exposure and hearing family planning messages on mass medias) and husband related factors .The dependent variable in this study was the time (age in years) at first birth. Whereas the independent variables were Socio-demographic and economic factors , reproductive factors  from her birth to give her first birth.A total of 2597 respondents were included in this study. All sampling procedures are available at the EDHS reports of each year. But to highlight the sampling procedures and step of data extraction we use the following diagram Fig. .Fig. 1ScSurvival analysis was used to identify the determinants of age at first birth.All procedures of Ethiopian Demographic and health survey were performed based on the international ethical guideline of the DHS program  and the p value = 0.0900). As stated above the data source for this study was the EDHS data which has hierarchical nature (that means youths in the same cluster may have similar characteristics than youths in another cluster). As a result, we have checked the presence or absence of between cluster variability/ heterogeneity by fitting frailty model (random effect Cox regression model) and the theta value at the null model was insignificant . It indicates that there is no unobserved heterogeneity between clusters. Multicollinearity was also checked and the maximum variance inflation factor (VIF) was 2.62 for age at first marriage and the mean VIF was 1.67. This shows that no multicollinearity between covariates. Variables which were associated with the outcome variable in the bivariable analysis at p value < 0.25 were entered into a multi-variable analysis. The cutoff point for the significant association was p value < 0.05 at 95% confidence interval.The data for this study were extracted from EDHS 2016 individual (women) record folder using STATAversion14software. The extracted data was recorded, cleaned using frequency; listing and sorting to identify any missed values. Kaplan Meier's survival was used to estimate the time of first birth and used to compare survival experiences among categories across time. A log-rank test was used to compare survival experiences between two or more groups and to show the statistical significance of the observed difference in the Kaplan Meier's survival plot. The PH assumption was checked both graphically and using global test. A global test based on Schoenfeld residuals found that all of the covariates and the full model satisfied the proportional hazard assumption  data is unique because the outcome of interest is not only whether or not an event occurred, but also when that event occurred. Logistic and linear regression is not suited to be able to include both the event and time aspects as the outcome in the model. These regression methods also are not equipped to handle censoring, a special type of missing data that occurs in time-to-event analyses when subjects do not experience the event of interest during the follow-up time .In this study the weighted sample size was 2597 ever married female youths. Among these respondents 2224 (85.6%) were from the rural residency. One thousand sixty four 41.0%) of the respondents were orthodox. When we see their economics status, 1157 (44.5%) of respondents were in the poor economic class. Eight hundred seventy-three (33.6%) of respondents have no formal education  of the study participants were not using contraceptive methods. Majority of the study participants, 1257 (48.40%) had their first sex between 15 and 17 years old inclusive. Great proportion of participants, 1156 (44.50%) have married between their 15 and 17 years inclusive  have no media exposure and 1922 (74.00%) have not heard family planning messages on mass medias. Among the study participants, 851 32.80%) and 353 (13.60%) had alcohol drinking and chat chewing history respectively  give birth for the first time during the follow up time. Among the respondents who gave birth, 107 (5.90%) give birth before their 15th birth day, 1251 (69.10%) between their 15 and 19 years old inclusive and 451 (24.90%) after 20 years old. About 788 (30.30%) individuals didn’t give birth (they are censored) during the follow up period. The total follow-up time contributed by all study participants was 50,016-person years. The overall median survival time was 18 years (IQR = 17–20). The median survival time varies by respondents’ characteristics. For example, median survival time for urban was 20 years and for rural, it was 18 years. By wealth index, median time for poor, middle and riches were 17.5, 18 and 19.5 respectively. By education, the median age ranges from 17 years for no formal education to 23 years for higher education. The minimum and maximum follow up time for mothers to have first birth was 12 and 24 years respectively , five variables  were significantly associated with the timing of the first birth at p < 0.05 with 95% confidence interval  when compared to urban residents keeping others constant.Religion also affects timing of first birth. The hazard of first birth at earlier age among Muslims was increased by 57% , among protestant it was increased by 73%  when compared to orthodox keeping others constant.Youths who have started sex < 15 years have 68% increased hazard of first birth  and those who started sex between 15 and 17 have 54% increased hazard of first birth  at earlier age than individuals who started sex at age ≥ 18 years keeping others constant.Youths who have married < 15 years have 6.52 times increased hazard of first birth  and those who have married between 15 and 17 have 2.63 times increased hazard of first birth  at earlier age than individuals who married at age ≥ 18 years keeping others constant.Having unmet need for family planning increases the hazard of first birth at earlier age by 1.23 times  when compared to those who have met need keeping others constant Table .Baseline hazard distribution.This study assessed the time to first birth and its determinants among ever married female youths. The finding showed that the median age at first birth was 18 (IQR = 17–20) years and the determinants of time to first birth among the study participants were residence, religion, age at first sex, age at first marriage, unmet need for family planning, and hearing family planning messages on mass medias.In this study the median age at first birth was 18 (IQR = 17–20) years. This finding was in line with finding from Swaziland , NigeriaHowever, our finding was lower than the findings from different countries in which the median age at first birth was 22.6 years in Egypt , 21.4 yeAccording to our finding, residence was one of the determinants for the median time to first birth. Rural youths have shorter survival than urban. This finding is similar to findings in Nigeria , in SwazAge at marriage was also positively associated with age at first childbirth. Female youths who have married early had first child birth earlier than those who have delayed marriage. This finding is in agreement with findings from Nigeria  and BangThis study also shows that age at first sexual intercourse has a significant effect on age at first birth. A woman who starts having sexual intercourse at earlier age have the first child at an earlier age compared to a woman who started sex lately. This is in line with findings from Uganda  and SwazThis study also shows a difference in age at first births along religious affiliations. Among religious affiliations, being Protestant and being Muslim affiliated were found to shorten the survival time of first birth as compared to Orthodox. Regarding to being Muslims, similar findings were documented in Bangladesh  and NigeAnother determinant of timing of first birth was unmet need for family planning. Having unmet need for family planning shortens the timing of first birth when compared to those who have met need. This finding is in line with findings from Nigeria , 44 and The findings of this study implies that future researchers, policy makers and program managers should focus on the unmet need, age at marriage, age at first sex and the contraceptive uses and their associated factors among of rural female youths to prevent early child bearing and its societal, health and demographic consequences.The main strength of this research is using nationally representative data and it is generalizable to all Ethiopian married youths. But since the source of the data was self-report, the accuracy of the data could be affected by recall bias. Using secondary data limit the researcher to measure all possible predictors like peer related and cultural related factors.In this study, the median age at first birth was 18 years. This show, about 50% of study participants give birth for the first time before their 18th birth day. This age is the ideal age for schooling and to do other personal development activities. Therefore giving birth before 18 year will limit female youths from attending school and performing personal development activities in addition to health and demographic consequences of early child bearing. This finding is comparable with developing countries and lower than the global and developed countries. The timing of first birth in Ethiopia was mainly influenced by socio-demographic and reproductive related factors.Continuing enforcing the legal age of marriageExpanding youth friendly service for all communities maintaining the quality of the services to reduce unmet need for family planning.Better to strictly implementing the national adolescents and youths sexual and reproductive health strategies.Designing curriculum consisting comprehensive sexual health education in schools to help adolescents and youths delaying sexual initiation and empowering them to delay age of marriage.Better to do prospective follow up study to assure the cause and effect or temporal relationship between outcome variable and explanatory variables.


Are signs of insufficient brain oxygenation before, during, and immediately after birth, known as birth asphyxia, associated with white matter abnormalities in adult patients with schizophrenia and bipolar disorder compared with healthy control participants?In this case-control study of 850 adult patients and healthy individuals with birth registry and diffusion-weighted imaging data, measures of birth asphyxia were significantly associated with lower fractional anisotropy and higher radial diffusivity in the posterior limb of the internal capsule in the patients with bipolar disorder and schizophrenia but not in the control group.White matter abnormalities in the posterior limb of the internal capsule could suggest early changes or impeded brain development because of an increased susceptibility to birth asphyxia in patients, which is not present in healthy adults. This case-control study examines the association between birth asphyxia and white matter abnormalities in adult patients with schizophrenia and bipolar disorders. White matter (WM) abnormalities are commonly reported in psychiatric disorders. Whether peripartum insufficiencies in brain oxygenation, known as birth asphyxia, are associated with WM of patients with severe mental disorders is unclear.To examine the association between birth asphyxia and WM in adult patients with schizophrenia and bipolar disorders (BDs) compared with healthy adults.In this case-control study, all individuals participating in the ongoing Thematically Organized Psychosis project were linked to the Medical Birth Registry of Norway (MBRN), where a subset of 271 patients (case group) and 529 healthy individuals (control group) had undergone diffusion-weighted imaging (DWI). Statistical analyses were performed from June 16, 2020, to March 9, 2021.Birth asphyxia was defined based on measures from standardized reporting at birth in the MBRN.Associations between birth asphyxia and WM regions of interest diffusion metrics, ie, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), were compared between groups using analysis of covariance, adjusted for age, age squared, and sex.F = 11.46; P = .001), reflecting a stronger association between birth asphyxia and FA in the case group than the control group. RD, but not AD, also displayed a significant diagnostic group × birth asphyxia interaction  = 9.28; P = .002) in the PLIC, with higher values in patients with birth asphyxia and similar effect sizes as observed for FA.Of the 850 adults included in the study, 271 were in the case group  and 579 were in the control group . Birth asphyxia measures were identified in 15% to 16% of participants, independent of group. The posterior limb of the internal capsule (PLIC) showed a significant diagnostic group × birth asphyxia interaction (In this case-control study, abnormalities in the PLIC of adult patients with birth asphyxia may suggest a greater susceptibility to hypoxia in patients with severe mental illness, which could lead to myelin damage or impeded brain development. Echoing recent early-stage schizophrenia studies, abnormalities of the PLIC are relevant to psychiatric disorders, as the PLIC contains important WM brain pathways associated with language, cognitive function, and sensory function, which are impaired in schizophrenia and BDs. This can cause hypoxic injury and, in severe cases, lead to permanent brain damage or death in offspring. Common causes of birth asphyxia are mechanically obstructed labor (shoulder dystocia), abnormal fetal positioning, and placental abruption as well as dysfunction or maternal hypotension.16 suggesting that a genetic liability for schizophrenia predisposes the developing fetus and newborn to these complications. However, severe OCs are defined by a broad range of perinatal complications . In our clinical cohort studies,17 we found significantly more cases of several severe OCs co-occurring in the presence of birth asphyxia (>50%) than when birth asphyxia was not present (<3%), confirming that birth asphyxia is more frequent in complicated pregnancies.The genetic risk of developing schizophrenia is multiplied by a factor of 5 in the context of severe OCs,18 so milder insults may cause injury or alterations in those with a genetic liability for schizophrenia development.16 Birth asphyxia had a prevalence of 14% in our previous studies, without case-control differences,20 suggesting that the birth asphyxia variable from the MBRN contains a wide range of birth asphyxia exposure.The Medical Birth Registry of Norway (MBRN) offers unique insight into the occurrence of birth asphyxia in the peripartum period, but it does not specify its severity , its treatment, or information from neonatal magnetic resonance imaging (MRI) examinations. Also, inflammatory presentation increases vulnerability,6 FA reflects the degree of diffusion directionality, and higher FA has often been interpreted as indicating better integrity.21 While FA is sensitive to structural alterations, the biological specificity is relatively low and cannot distinguish between different pathophysiological processes, such as dysmyelination or demyelination, inflammation, and axonal injury. Combining FA with axial diffusivity (AD) and radial diffusivity (RD), which reflect the diffusion along and perpendicular to the primary axis of the diffusion tensor, respectively, may allow for higher neurobiological specificity. For instance, decreased AD has been linked to axonal damage, while increased RD has been linked to either dysmyelination or demyelination.24Diffusion tensor imaging (DTI) is a method for indirectly characterizing WM microstructure and gross architecture. In DTI studies of individuals with schizophrenia and BD, WM abnormalities are commonly reported, with significantly lower fractional anisotropy (FA) in patients compared with healthy control participants.Using prospective birth registry and DTI data, the aims of this study were to (1) examine the prevalence of birth asphyxia measures in patients and healthy control participants; (2) test whether the association of a history of birth asphyxia with DTI metrics differed between patients and healthy control participants; (3) determine whether birth asphyxia–associated WM differences in patients are also associated with age of disease onset, disease severity, medication use, and symptoms.25 and received approval from the Regional Committee for Medical Research Ethics–South East Norway. The Norwegian Data Inspectorate also approved the study. Patient and healthy control participant inclusion and exclusion criteria for the TOP study and sample information are described in the eMethods in the STROBE) reporting guideline for case-control studies.This study is part of the Thematically Organized Psychosis (TOP) study, which is the main study protocol at the Norwegian Center for Mental Disorders Research . All participants gave written informed consent, and the study was conducted in accordance with the Declaration of Helsinki26 Clinical features of severe birth asphyxia include neonatal encephalopathy , an Apgar score of 5 or less at 10 minutes after birth, continued need for resuscitation, fetal acidosis, and others.27 While some information is not available in the MBRN , birth asphyxia together with respiratory complications in affected newborns could indicate conditions contributing to insufficiencies in the supply of oxygen reaching the brain. Birth asphyxia was defined as having had a complication coded KP15 (threatening intrauterine asphyxia), AS54 , AS61 (asphyxia), 7762 (respiratory distress), 7763 (primary apnea), 7765 (atelectasis pulmonary), 7767 , 7768 (cyanosis attack), or 7769 (other hypoxic conditions/asphyxia) in the MBRN.Birth data were collected from the MBRN.28 FA, AD, and RD maps were processed using tract-based spatial statistics,29 part of the FSL software.30 We extracted FA, AD, and RD from 34 lateral regions of interest (ROIs) representing both projection and association fibers and 5 ROIs from commissural fibers based on the intersection between the WM skeleton and relevant ROIs in probabilistic Johns Hopkins University WM atlases.32We obtained diffusion-weighted imaging (DWI) from two 3T MRI scanners  , 2 bilateral ROIs , 5 commissural ROIs, and average skeleton FA, AD, or RD resulted in a total of 25 ROIs, representing all major WM fasciculi,35 medication use and psychotic symptoms .36 Age of disease onset was assessed retrospectively and defined as the year of the first occurrence of psychotic symptoms  for patients with psychotic disorders and the year of first occurrence of a major mood episode  for patients with BDs. Current medication use was assessed by clinical interviews and/or medical record review.From the structured clinical interview, information was obtained about the age of disease onset, disease severity ,2 tests for categorical variables. Post hoc, pairwise group comparisons were performed if there were significant main effect sizes of group. Statistical analyses were performed using SPSS version 27 (IBM Corp).Within and between-group comparisons were performed with 1-way analysis of variance for continuous variables and Pearson χ38 For our primary FA analysis of whether the associations of birth asphyxia differed between individuals in the case and control groups, results of interaction tests were declared significant if they survived correction for multiple comparisons, with a Bonferroni correction threshold of 0.05 / 25, or P = .002. Effect sizes were reported as Cohen d values38 for birth asphyxia–positive/birth asphyxia–negative differences within groups.We assessed the 25 WM FA ROIs using a full factorial 2 × 2 analysis of covariance with birth asphyxia (birth asphyxia positive or negative) and group (case or control) included as between-group factors, covarying for age, age squared, and sex. Age squared was added to model the association of age more accurately, given that both linear and nonlinear age effects have been reported for FA.38 sensitivity analyses were performed within both case and control groups separately to assess whether differences in birth asphyxia were still present.For significant FA regions from the main analysis, follow-up analyses were performed to examine associations in diagnostic subgroups, RD, and AD. Because we were interested in neural abnormalities associated with birth asphyxia and their further association with clinical outcomes, follow-up analyses were performed to explore whether variation in FA and its interactions with group and birth asphyxia were associated with age of disease onset, chlorpromazine equivalence scores, PANSS scores, or GAF scores in separate multivariable linear regression models. These analyses are described in detail in the eMethods in the Of the 850 adults included in the study, 271 were in the case group  and 579 were in the control group . In the case group, 111 (41%) had BD, and 160 (59%) had schizophrenia. Clinical and demographic data are presented in P = .04).16 There were no significant sex differences in those who experienced birth asphyxia in the BD and schizophrenia groups.Birth asphyxia was identified in 93 of 579 participants in the control group (16%), 17 of 111 in the BD group (15%), and 26 of 160 in the schizophrenia group (16%), and this prevalence did not significantly differ between groups . Of thosComparing the schizophrenia group with the control group, there were significantly more cases of preterm birth (11 [7%] vs 13 [2%]), low Apgar scores (21 [13%] vs 30 [5%]), breech deliveries (13 [8%] vs 21 [4%]), and emergency cesarean deliveries (9 [6%] vs 14 [2%]). Additionally, we found significantly more severe OCs co-occurred in the presence of birth asphyxia , than when birth asphyxia was not present (82 of 486 control group participants [17%]), across groups .F = 11.46; P = .001), which survived correction for multiple comparisons. The significant interaction revealed lower mean (SD) FA in patients with birth asphyxia (0.68 [0.02]) compared with patients without birth asphyxia (0.69 [0.02]), which was not found in the control group   = 5.66; P = .004) revealed the lowest mean (SD) FA in patients with birth asphyxia and schizophrenia  followed by those with birth asphyxia and BD , with similar effect sizes in both groups. In the control group, higher mean (SD) FA was shown in the group with birth asphyxia   . This pa = 0.24) .F = 9.28, P = .002) but not for AD  = 2.49, P = .12) and showed higher mean (SD) values in patients with birth asphyxia (0.37 [0.05]) compared with those without (0.36 [0.02]), which was not found in the control group . Additional follow-up analyses are reported in eAppendix 1, eFigure 5, and eFigure 6 in the In follow-up analyses of the PLIC, a significant interaction between birth asphyxia and diagnostic group was observed for RD , a biophysical characterization of WM microstructure, was only detected in the PLIC, and increases in whole brain ODI were associated with poorer responses to treatment.48 Even though differences within the PLIC were not evident in large meta-analysis data sets,6 it could be that delayed maturation of corticospinal tract, differences in disease stages, or differences in medication use could explain these discrepancies.Interestingly, the PLIC was one of the few WM regions where no FA abnormalities were detected in adult patients with schizophrenia and BD in 2 large meta-analyses conducted by the ENIGMA SZ51 which may not be fully captured in large data sets of chronic adult patients and healthy control participants. Considering the interacting environment of pregnancy and birth, the interplay between birth asphyxia and diagnosis may explain more of the variability in PLIC, which is not revealed with simple main effects. Given that birth asphyxia was equally occurring in all groups, our findings support the idea that having a history of birth asphyxia is an interactive, rather than a directly causal, risk factor in the development of a psychiatric disorder.Genetic and environmental factors are thought to disrupt normal development from early in life, resulting in cumulative molecular and histogenic responses,52 Higher RD values were significantly associated with the PLIC of patients with birth asphyxia, which gives an indication that the low FA values could be driven by abnormalities in myelin. Myelination of axons progresses from the brainstem and deep brain structures prior to birth to peripheral brain regions mainly during the first year after birth but also throughout life.55 Myelination of deep brain structures, like the ventro-lateral nuclei and sub-thalamic nucleus, begins first at 29 weeks’ gestational age and then in the PLIC at 39 to 40 weeks.56Severe hypoxia-ischemia in preterm or term infants tends to affect brain regions in the border zones between the end fields of major cerebral arteries  and in areas that are actively myelinating .57 Because gestational age was similar between groups (39-40 weeks), it could be that PLIC abnormalities in patients with birth asphyxia may be associated with genetics or other mechanisms underlying both myelination and an intolerance to hypoxia, which was not found in the individuals in the control group. The functional hypoxia-inducible lipid droplet-associated (HILPDA) protein is a novel regulator of intracellular lipid and energy metabolism expressed under hypoxia.58 HILPDA expression, attenuated in schizophrenia,59 might represent a protective factor that explains the higher FA in the PLIC of individuals in the control group with birth asphyxia.Myelination of the PLIC is considered an important landmark for evaluating neonatal brain development.60 and the prevalence reported here is nearly 100 times more. We found an equal prevalence of birth asphyxia among the groups, which is unexpected if genetic risk of schizophrenia predisposes patients to early insults around birth. Since obvious organic pathology and/or brain lesions in their MR images and neurological disorders precluded recruitment, it could be that the birth asphyxia measure and design of the TOP study do not fully capture the severe end of the hypoxic spectrum, which results in a series of functional deficits later in life. Even so, the birth asphyxia measures from the MBRN are likely associated with a range of hypoxia and asphyxia exposures, which were less tolerated because of genetic susceptibilities already present in newborns who later developed a psychiatric disorder.This study has limitations, including the wide definition and lack of details in the measures of birth asphyxia from the MBRN. The wide definition might account for the high prevalence (>15%) of birth asphyxia, as birth asphyxia resulting in hypoxic-ischemic encephalopathy only occurs in 1.8 per 1000 live births,61 which have been reported in patients with shizophrenia62 and BD.63 Future studies including myelin-sensitive MRI sequences, such as multishell diffusion MRI metrics,51 may allow for stronger biological interpretations.We studied adults, whereas examining myelination trajectories in newborns and during early development would be of interest for future studies. Another limitation is the use of WM DTI metrics, which lack biological specificity. DTI metrics can be affected by various neurobiological processes, such as neuroinflammation, edema, and WM fiber crossing,This study reported DTI abnormalities in the PLIC of patients with birth asphyxia that were not detected in the control group, potentially indicating early myelin damage or impeded brain development caused by an intolerance to birth asphyxia. Abnormalities of in the PLIC might be especially relevant to patients because the PLIC contains important WM brain pathways associated with language, cognitive functions, and sensory functions, which are impaired in schizophrenia and BD. Results should be replicated in independent samples.


There are indications that the frequency of cyst formation is increased in mitochondrial disorders (MIDs). Cysts can be found in various organs of MID patients but tongue root cysts have not been reported as a manifestation of a MID.In a 56-year-old male with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) manifesting with recurrent stroke-like episodes, seizures, cognitive impairment, ataxia, psychiatric abnormalities, bilateral visual impairment, bilateral hypoacusis, pre-diabetes, hyperlipidemia, myopathy, and lactic acidosis, an asymptomatic, pre-epiglottic cyst with 1 cm in diameter and protein-rich content in the right tongue root was accidentally detected on ultrasound and confirmed by MRI at the age of 50 years. The patient did not complain about dysarthria or dysphagia but had a mild cerebellar speech. The cyst was confirmed on an MRI six years later, without having changed in diameter, extension, or symptomatology. Due to the atypical location, a branchiogenic cyst was excluded. In conclusion, tongue root cysts may be a manifestation of the m.3243A>G variant. There are indications that the prevalence of cyst formations is increased in patients with a mitochondrial disorder (MID) . Cysts cThe patient is a 56-year-old male diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the variant m.3243A>G in MT-TL1 at the age of 50 years. MELAS manifested phenotypically with recurrent stroke-like episodes, seizures, cognitive decline, ataxia, psychiatric abnormalities, visual impairment, hypoacusis, pre-diabetes, hyperlipidemia, myopathy, and lactic-acidosis. At the age of 56 years, he was admitted for another stroke-like episode. He presented to the emergency department with vertigo, confusion, speech disturbance, difficulties in finding words, impaired concentration, and ataxic gait. Clinical exam revealed weak head anteflexion, cerebellar speech, visual impairment with only light/dark discrimination, hypoacusis, mild ptosis bilaterally, diffuse wasting of the upper limbs, bradydiadochokinesia bilaterally, wasting of the thighs, lower limb ataxia, and reduced Achilles tendon reflexes. There was ataxic stance and gait requiring a walker. Cerebral MRI showed a typical acute, stroke-like lesion (SLL) in an occipito-temporal distribution. In addition to the SLL, cerebral MRI accidentally revealed a cyst on the right side of the tongue root. Revision of imaging studies from a previous hospitalisation revealed that the pre-epiglottic cyst with 1 cm in diameter and protein-rich content had been first detected accidentally on ultrasound and later by MRI already at the age of 50 years (Figure The patient is interesting as a tongue cyst has not been described as a manifestation of MELAS before. Anyhow, there are indications that cyst formation is generally more prevalent in patients with a MID than in the general population -4, but sThe reason for the presumably increased prevalence of cyst formations in MIDs remains elusive but it can be speculated that it is due to reduced cell adhesion, due to ectopia, or due to abnormal proliferation of cells. It can also be speculated that enhanced focal apoptosis, disturbed mitochondrial fusion/fission, or increased mitophagy was responsible for the focal tissue rarefication. From MIDs, it is well known that the prevalence of benign and malign neoplasms is increased . The reaWe present the first case of a MELAS patient with a tongue root cyst, which was suspected to be causally related to the m.3243A>G variant. Though tongue cysts have not been reported as a manifestation of the m.3243A>G variant, there are indications that MIDs carry an increased risk of developing cysts in any organ, including the tongue. Further studies are required to assess if the prevalence of cyst formations is truly increased in MIDs and if cysts of the skeletal or striated muscles also occur in other syndromic or non-syndromic MIDs.