Aim of our study was to compare the prognostic value of the Umbilical-to-Cerebral ratio (UCR) directly to the Cerebroplacental ratio (CPR) in the prediction of poor perinatal outcomes in pregnancies complicated by Fetal Growth Restriction (FGR).A retrospective study was carried out on pregnant women with either a small-for-gestational age (SGA) fetus or that were diagnosed with FGR. Doppler measurements of the two subgroups were assessed and the correlation between CPR, UCR and relevant outcome parameters was evaluated by performing linear regression analysis, binary logistic analysis and receiver operator characteristic (ROC) curves. Outcomes of interest were mode of delivery, acidosis, preterm delivery, gestational age at birth as well as birthweight and centiles.p = 0.027; OR: 0.810, 0.369–1.781; p = 0.601). ROC curves plotted for CPR and UCR showed almost identical moderate prediction performance.Boxplots and Scatterplots illustrated the different distribution of CPR and UCR leading to deviant correlational relationships with adverse outcome parameters. In almost all parameters examined, UCR showed a higher independent association with preterm delivery , APGAR score < 7  as well as weight under 10th centile  in binary logistic regression compared to CPR which was only associated with preterm delivery  and APGAR score < 7 . When combined with different ultrasound parameters in order to differentiate between SGA and FGR during pregnancy, odds ratios for UCR were highly significant compared to odds ratios for CPR (OR: 0.065, 0.168–0.901; Since UCR is a better discriminator of Doppler values in abnormal range it presents a viable option to Doppler parameters and ratios that are used in clinical practice. UCR and CPR showed equal prognostic accuracy conserning sensitivity and specificity for adverse perinatal outcome, while adding UA PI and GA_scan increased prognostic accuracy regarding negative outcomes.The online version contains supplementary material available at 10.1007/s00404-021-06268-4. Fetal Growth Restriction (FGR) is a serious obstetric complication affecting 5–10% of pregnancies worldwide , 3. TherCurrently, there is controversy regarding the definition of FGR. This condition is most commonly defined as the fetus failing to reach its genetically predetermined growth potential..In this context, fetuses with an estimated weight below the 10th centile are referred to as “small for gestational age “(SGA). Sometimes, the terms “FGR” and “SGA” are even used synonymously. This has led to uncertainty regarding the diagnosis of FGR. In the current guideline on the diagnosis and management of FGR, the ISUOG  states that the fetal size alone is not sufficient to identify FGR, unless abdominal circumference (AC) or estimated fetal weight (EFW) is below the 3rd centile. To distinguish between SGA and FGR Doppler velocimetry of uteroplacental and fetoplacental circulations may be used .The current German guidelines define SGA and FGR as follows: SGA pregnancies show an estimated fetal weight below the 10th centile without further detectable pathologies such as abnormal Doppler of the umbilical artery or oligohydramnios. In contrast, FGR is defined as EFW below the 10th centile and/or a drop in fetal growth velocity combined with a resistance in the pulsatility index (PI) of the umbilical artery (UA) or uterine artery PI above the 95th centile and/or the presence of oligohydramnios .According to the ISUOG guidelines, two phenotypes of FGR are distinguished: by definition early onset FGR is diagnosed before 32 weeks of gestation with alterations of fetal circulation being determined by placental insufficiencies leading to high morbidity and mortality rates. In contrast, late onset FGR (> 31 + 6 weeks of gestation) is based on more unspecific placental lesions and a reduced tolerance to hypoxemia in fetuses near term, correlating with poor perinatal outcomes .In the absence of effective treatment options, the major challenges in FGR pregnancies are the assessment of intrauterine fetal risks and optimal timing of delivery. The surveillance of pregnancies affected by FGR has improved through advances in Doppler ultrasonography. Due to different underlying pathomechanisms of early- and late-onset FGR that result in specific pregnancy surveillance and management strategies, different Doppler parameters are useful in their detection and monitoring.In early-onset FGR, reduced placental perfusion is reflected by an increased UA PI, mean cerebral artery (MCA), as well as an increased ductus venosus (DV) pulsatility.Especially in cases with late-onset FGR, it has been shown that as a response to long-term hypoxia, the perfusion of the brain increases with a reduction of vascular resistance in the MCA PI, also described as the “brain-sparing effect”.Quantified as the cerebroplacental ratio (CPR), the ratio MCA PI/UA PI is said to reflect alterations in placental or fetal blood flow more sensitively than the UA PI or MCA PI alone , 8. In cTo estimate the optimal timing of delivery, it is essential to use prediction parameters with high sensitivity. However, recent literature indicates variable accuracy for predicting adverse outcomes with CPR, making its clinical utility controversial –11. LateTo the best of our knowledge, most publications report the predictive value of the CPR rather than the UCR and so far studies directly comparing the predictive potential of poor perinatal outcomes in FGR pregnancies are rare.The aim of our study was to compare UCR with CPR and other established ultrasound parameters in their prediction of negative outcomes in pregnancies complicated by FGR and SGA fetuses.In our single-center study, we retrospectively evaluated SGA and FGR pregnancies presenting for routine ultrasound examinations at the author′s department. Ultrasound examinations were carried out by specialists in prenatal diagnosis and perinatal care. The study was designed according to the Declaration of Helsinki and was approved by our Institutional Review Board.Gestational age (GA) was calculated using the crown-rump length during the first trimester of pregnancy. SGA and FGR were defined as described in the current German guideline on Fetal Growth Restriction . DopplerData acquisition was carried out between 2005 and 2019. Only singleton SGA and FGR pregnancies between 24 and 40 weeks of gestation with complete follow-up were included in this study. Exclusion criteria were maternal age below 18 years, major fetal malformation or aneuploidy, as well as fetal infection. If more than one Doppler measurement was recorded, the one closest to delivery was chosen to maximize prognostic accuracy.Images were acquired using an iU22 and EPIQ7  and Toshiba Aplio ultrasound systems . Doppler measurements, fetal estimated weight as well as data on pregnancy outcome were obtained from our hospital data base .Relevant outcome parameters were mode of delivery, umbilical cord pH, APGAR score at five minutes, GA at birth (GA_birth), birth weight and birth weight centiles. Adverse outcome was defined as umbilical cord pH < 7.21, 5-min APGAR score < 7, premature birth < 37th week, extremely premature birth < 30th week, obstetric intervention (operative delivery or cesarean section [CS]) or low (< 10th centile) or very low birth weight (< 3rd centile).Before running tests that assume a normal distribution of the data, we ran log transformations to reduce skewness. The Kolmogorov–Smirnov and Shapiro–Wilk test were used to assess the distribution of the data, boxplots and histograms were used to visualize the distributions of CPR and UCR. Binary logistic regression analysis and multivariate logistic regression analysis were performed to assess the association between UCR and CPR and the different outcome parameters birth weight, GA, umbilical cord pH, GA_birth, mode of delivery, birth weight centiles, and APGAR score as well as determining FGR or SGA. Multiple ultrasound parameters were combined to detect predictive markers with a maximized sensitivity. Scatterplots, boxplots and histograms were generated to graphically visualize and compare the different test models of CPR and UCR.Receiver operating characteristics (ROC) curves were generated to determine the area under the curve (AUC) to evaluate the diagnostic ability of the ratios as prognostic markers. Youden’s score was used to detect optimal sensitivity and specificity.® Statistics version 27  was used and results with p < 0.05 were considered statistically significant.As required, data are presented as absolute numbers with median, first and third quartile or as relative frequencies. SPSS161 pregnancies affected by FGR and 172 SGA pregnancies were included in our study. Of all eligible cases, 4 cases of stillbirth, 2 neonatal deaths and 6 terminations of pregnancy were excluded, leaving 333 patients for final analysis.Maternal sociodemographic and obstetric characteristics as well as intrapartum outcomes are presented in Table p < 0.001). Maternal age did not noticeably differ between groups. In the FGR cohort, the prevalence of maternal diabetes was higher , while no differences were noted in regard to hypertensive disorders or smoking .The median gestational age at time of ultrasound scan (GA_scan) differed between groups, with the FGR group showing an earlier GA_scan than the SGA group , the incidence of premature birth was over three times as high as in the SGA group .Median GA at delivery was noticeably smaller in the FGR cohort  which is coherent with the lower median GA at delivery in the FGR group. There were equal cases with birth weight below the 10th centile  and more cases with birth weight centiles below 3  centile in this group compared to the SGA cohort, although statistical significance was not reached.Median birth weight in FGR pregnancies was lower  and fewer spontaneous vaginal deliveries in the FGR group than in the SGA group .There was a noticeably higher incidence of CS  which can be traced back to FGR being defined by abnormal Doppler parameters. Neither ratio showed a normal distribution within either group according to the Kolmogorov–Smirnov and Shapiro–Wilk-tests. When comparing the distributions of CPR and UCR, CPR tended towards a more symmetric distribution : UCR shows a more distinctive discrimination of abnormal values (> 1) with outliers becoming more apparent.p = 0.001; OR: 2.908, 1.468–5.761; p = 0.001), APGAR score < 7  and birth weight under the 10th centile  in pregnancies with FGR. CPR only showed an association with preterm delivery below 37 and 30 weeks  and APGAR score below 7 . In almost all parameters examined, UCR presented lower p values than CPR.In binary logistic regression analysis Table , UCR shop = 0.027; OR: 0.810, 0.369–1.781; p = 0.601) as can be seen in Table Similar results were found when combining UCR or CPR with multiple ultrasound parameters in order to differentiate between SGA and FGR during pregnancy: odds ratios for UCR were highly significant compared to the odds ratios for CPR , < 30 weeks  and for an APGAR score below 7 . Neonatal acidosis performed poorest with an AUC of 0.461. Moderate results were found for the prediction of birth weight below the 10th and 3rd centile, CS and instrumental delivery. Different cut-off values for CPR and UCR are shown in Table Using different outcome parameters ROC plotted for CPR and UCR showed almost identical moderate prediction performance regarding p < 0.001).When combining different ultrasound parameters in forward stepwise regression analysis for the prediction of adverse outcome parameters Table  a combinp values for most tests performed. When graphically visualizing both ratios, the presentation of UCR confirmed its ability to better model an association with high-risk pregnancies.The results of our study demonstrated that while UCR and CPR reach similar prognostic accuracy concerning overall outcome, using UCR as a model shows better correlations with negative outcome parameters. In our analysis, UCR showed a higher association with outcome parameters as well as more noticeable In recent years, focus in prenatal diagnostic was set on establishing CPR as standard prediction marker for assessing adverse perinatal outcome to determine optimal timing of birth, while little attention was given to the prognostic relevance of UCR.Our main test results for the predictive accuracy of CPR were consistent with the values previously published: CPR was associated with adverse pregnancy outcomes including preterm delivery and APGAR score below 7 , 16, 17,This is in accordance with a recent study that analyzed whether establishing UCR instead of CPR adds any benefit to the prediction of adverse outcomes in singleton pregnancies. While similar AUC values were generated, the study of Leavitt et al. was limited to the direct comparison between logistic regression analysis and ROC curve results without including any additional Doppler parameters or the effects of the varying distribution of the models CPR and UCR .The different performances of CPR and UCR were previously described by a secondary analysis of the TRUFFLE study  for the Possible explanations for the differences in the results of statistical tests can be found in the different distribution of the ratios leading to converse behavior in abnormal range: while the values of the CPR are compressed trending towards zero, the UCR strives towards an asymptote leading towards infinity. Consistent with our own findings, it becomes evident that with increased alteration of fetal Doppler indices the effect on the UCR grows exponentially, allowing it to distinguish the collective with a negative outcome (SI 1). Abnormal outliers become more apparent and differentiate the extent of abnormality more clearly. This may also have an impact on the different correlational relationships of UCR and CPR with numeric variables as illustrated in the scatterplots in Fig. This ultimately raises the question whether the resulting statistical discrepancy can be traced back to this simple mathematical relation of inversing the ratios of ACM PI and UA PI. It is necessary to reflect whether the noted statistical differences may result from wrong application or interpretation of statistical models: inversing the ratio leads to a change in the distribution, as can be seen in Fig. In accordance with a previous study that deals with a low-risk collective, we believe neither ratio to be adequate as sole screening marker, but that CPR and UCR only gain clinical relevance when combined with other parameters under specific conditions indicating a high-risk collective such as FGR—where minimization of very poor outcomes without significantly increasing the rate of cesarean sections and admissions to NICU should be the primary objective. It is important to consider these limitations when implementing CPR and UCR into clinical practice .Our research showed good results when PI UA and GA_scan are combined for the prediction of adverse neonatal outcomes. We therefore propose establishing these two parameters as essential standard prediction markers for pregnancies at risk and to add other parameters such as UCR or CPR for further diagnosis.One major limitation of previous studies is the inconsistent or even synonymous use of SGA and FGR, impeding direct comparison of results , 23–25. To assess the predictive value of CPR regarding fetal outcome, Gramellini et al., among other researchers, used different categorical cut-off values ranging from < 1.0 to < 1.1 , 19, 26 To the best of our knowledge, there are longitudinal reference ranges  as well Customized centiles with ethnicity- and gender-specific norms for assessing perinatal risk are a promising approach to improving the detection of FGR and SGA—further research with our data is conceivable .Study limitations lie within the nature of the retrospective design. In retrospect, inter- and intra-researcher variability is unknown and reliability of correct and systematic measurements cannot be confirmed. During the study period, two different data bases were used to collect the data. Merging the two sets of data may have provoked systematic or technical biases which we were unaware of as well as incomplete or missing maternal data. Possible residual confounders by unmeasured factors may remain. Another potential limitation is the rather long time interval between ultrasound and delivery that might cause a loss of predictive validity.One major strength of our study was the high number of cases that we identified using strict inclusion criteria. Unlike most other studies we used SGA fetuses instead of normal pregnancies as control collective. This allowed us to distinguish more precisely between growth-restricted pregnancies at risk of decompensation and pregnancies where no intervention is indicated.Another advantage is the uniform high data quality, because all ultrasound examinations were performed by qualified investigators with adequate experience and high-end equipment.At present, no other effective intervention for FGR pregnancies has been approved aside from delivery. Previously, a low CPR was used as a marker for alterations in cerebral or placental blood vessels to predict poor perinatal outcome in particular for late onset FGR. In our study, UCR showed a similar prognostic accuracy to CPR, but a closer correlation to adverse outcome parameters.Adding UA PI and GA_scan to logistic regression analysis increased the prognostic accuracy regarding negative outcomes. These findings indicate that the UCR should be prospectively examined as a prognostic tool, while keeping the statistical characteristics and challenges of reversing the ratio in mind.Our study emphasizes the need for standardization of medical terms such as FGR and SGA to develop generally valid management protocols for FGR pregnancies.Supplementary SI 1 Boxplots of CPR and UCR (SGA vs. FGR) to visualize discrimination in abnormal range: UCR shows a more distinctive discrimination of abnormal values (> 0.93) with outliers becoming more apparent. Values below 1.08 were considered abnormal for CPR. (DOCX 24 KB)Below is the link to the electronic supplementary material.


We aimed to determine the prevalence and factors associated with preterm delivery at Kabutare hospital, Rwanda.a cross-sectional study was conducted between August and September 2020. Mothers were interviewed using a standard pretested semi-structured questionnaire and additional data were extracted from medical records of obstetric files. Gestational age was assessed using the Ballard score. Adjusted Odds Ratios and their 95% confidence intervals were calculated for multivariable logistic regression analysis to take care of all potential confounders.Conclusion: preterm delivery was high in Huye district. Thus, we recommend ANC sessions to emphasize on maternal nutritional education which is of good quality and quantity, discourage maternal alcohol consumption as well as passive smoking.the prevalence of preterm birth was 17.5% (95% CI: 12.9% - 22.9%). The independent factors associated with preterm birth after considering multiple logistic regression were husband being a smoker (adjusted Odds Ratio (aOR) = 5.9; 95% CI; 1.9-18; p= 0.002), antenatal care (ANC) attendance ≤ 3 visits  and low mother's Mid Upper Arm Circumference (MUAC) < 23cm .  Preterm birth is the onset of delivery before 37 weeks of gestation, or lesser than 259 days from the last menstrual cycle . It is oIn Rwanda, 43,000 babies were born too soon each year and 2,070 children under five die due to direct preterm complications ,9. Thus,Study design and setting: this was a facility based cross-sectional study done among preterm babies delivered at Kabutare hospital, Huye district, Rwanda. Study variables included maternal socio-demographic characteristics, pregnancy lifestyle factors by preterm birth, antenatal and obstetric factors associated with preterm birth. Kabutare hospital is a district hospital which receives many high-risk pregnancies referred from 12 health centers of which some are preterm babies. It has a busier maternity department and registers about 300 births every month. It equally has a busy neonatal unit that provides specialized neonatal care (SNC) services. The hospital SNC is comprised of medical staffs: paediatricians (2), medical officers (2) and 12 nurses (12). Kabutare district hospital is located in Huye district, southern province of Rwanda, at 126 km from the capital Kigali. Huye district has a population of 328,605 inhabitants covering an area of 581.5 km2. Its density population is 510.3 inhabitants per km2.Study population: the study population comprised of postnatal women who delivered preterm babies between August and September 2020. The sample size was determined using single population proportion formula by considering confidence level (95%), margin of error = 0.04 and proportion of preterm rate in Rwanda being 10% [eing 10% . By addiInclusion/exclusion criteria: consenting postnatal women aged between 18 and 49 years who had delivered a singleton preterm baby within the study period were included. On the other hand, non-consenting postnatal women, mentally unstable, those who had memory loss or those who were sick thus unable to participate were excluded from the study.Study variables: the dependent variable was spontaneous preterm birth. The independent variables were as follows: (i) maternal socio-demographic characteristics ; (ii) maternal pregnancy lifestyle factors  antenatal care (ANC)-related factors  and obstetric-related factors .Operational definitions: preterm birth was the commencement of labor with an intact or pre-labor rapture of the membrane and birth before 37 weeks of gestational age. The inter-delivery was defined as the number of months since the previous birth. It was considered as either being short or optimal if the birth interval was ≤ 24 months or ≥ 25 months, respectively.Study procedure: we conducted a systematic sampling which enabled us recruit all mothers who had delivered within 24 hours at Kabutare hospital from August to September 2020. Informed consent was obtained from the mothers whose babies had been admitted to the newborn care unit (NBU). A semi-structured pre-test questionnaire was administered to the mothers while additional data were obtained from the mothers' and babies' obstetric and neonatal records for those admitted as required, respectively. Data were collected from medical records by two trained research assistants who were supervised by the principal investigator. For every case, information was collected regarding socio-demographic characteristics, medical history, antenatal care attendance (ANC), medical conditions diagnosed before or during current pregnancy and details of lifestyle and anthropometric measurements and maternal and perinatal outcome including complications. Maternal nutritional status was assessed by measuring the left mid-upper arm circumference (MUAC) using non-stretchable MUAC tapes used for screening pregnant mothers. A low MUAC was defined as a measurement of less than 23 cm. While, gestational age was calculated using last menstrual period and confirmed within 24 hours of birth by clinical assessment using the Ballard Score.Ethical considerations: ethical approval was obtained from Mount Kenya University Kigali, Rwanda The School of Postgraduate studies, Mount Kenya University, Kigali first approved the research proposal and ethical clearance was obtained from the Institutional Research and Ethics committee of Mount Kenya University (N°: MKU04/DVCARA/2019-2020/077). After obtaining ethical approval, permission was obtained from the director general of Kabutare district hospital for authorization to proceed with the data collection. The participants were told about the study objectives and that their participation was voluntary and they could withdraw at any time, without giving any reason. Written informed consent was obtained for participation in the study. No inducements or rewards were given to participants to join the study. Confidentiality was maintained at all times. Data collected as part of the study were not linked to individual or personal identifiers and was reported in accordance with the STROBE guidelines.Data analysis: data were entered into Microsoft Access database, cleaned and uploaded into a password protected android tablet. The outcome variables were dichotomized and coded as 0 and 1, representing those that did not have a preterm birth and those that had a preterm birth, respectively. Data were analyzed using Stata version 17 Univariate analysis was done to include frequencies and proportions that was displayed in form of tables and figures. Bivariate analysis using Chi-square test was conducted to identify the association between the independent and dependent variables. Adjusted Odds Ratios, and their 95% confidence intervals were deliberated for multivariable logistic regression analysis to take care of all potential confounders. The goodness of fit was assessed using Hosmer-Lemeshow test with Chi-square value 1.74 and p-value of 0.884 which indicated that the fitted model was adequate.Socio-demographic characteristics: of all 240 women who were interviewed, mean age was 29 years. Maternal socio-demographic characteristics are shown in Prevalence of preterm birth: out of 240 women who delivered in Kabutare hospital, 42 babies were born as preterm giving prevalence of 17.5% (95% CI: 12.9% - 22.9%).Pregnancy lifestyle factors: compared to women who delivered at term, women who delivered preterm when pregnant lived lifestyles associated with cigarette smoking, drinking alcohol and passive smoking  = 5.9; 95% CI; 1.9-18; p= 0.002), ANC attendance ≤ 3 visits  and mother's MUAC < 23cm  (p=0.004) .Our results add importantly to the literature about the prevalence of preterm birth from remote hospital setting . Our finThe preterm rate for this study almost doubled the WHO estimates of 9.5% for sub-Saharan Africa  as well Our findings revealed that mothers who attended less than 4 times of WHO recommended ANC visits had 4-fold higher probability to deliver a preterm baby. This agrees with a meta-analysis and systematic review . In addiPaternal smoking was independently associated with preterm births where neonates whose fathers were smoking were six times more likely to have prematurity. It is evidenced that a lot of chemicals including nicotine can be passed to the fetus through passive smoking to pregnant women  thus, adOur findings revealed that a low maternal MUAC was six times more associated with preterm birth. This was in agreement with authors from Ethiopia  and BangMaternal smoking and liquor drinking during pregnancy were significantly connected with premature birth during bivariate analysis but was insignificant after multivariable analysis. However, there is evidence that smoking during pregnancy may pass nicotine to the fetus through placental barriers and it is 15% more concentration present in placenta than maternal blood. The risk of premature delivery is high amid those mothers that are active smokers during pregnancy . HoweverThe strength of this study is that mothers who had live births were shortly interviewed after birth and babies their assessed for gestational age, minimizing recall bias. Moreover, some women may recall or provide information about preterm birth selectively, depending on their experience during birth or pregnancy outcome. In terms of limitations, the nature of study design being cross-sectional may not show the cause-effect relationship. We used last menstrual period to determine preterm birth with and clinical assessment of gestation using the Ballard score might lead to over/under estimate of the burden. Use of secondary data for some variables is another limitation of our study. There is need for a cohort study to further investigate the effect of paternal smoking on preterm birth.The prevalence of preterm birth at Kabutare district hospital was 17.5%. Husband being smoker, ANC attendance ≤ 3 times and low mother's MUAC < 23cm were notably associated with preterm delivery. We recommend that ANC sessions to re-emphasize on maternal nutritional education/counseling which is of good quality and quantity, discourage maternal alcohol consumption as well as passive smoking. Policymakers should extend screening and nutritional programs of pregnant mothers within antenatal care package.Globally, the leading cause of neonatal mortality in preterm birth which may hinder the achievement of sustainable development goals 3.2 target;In Rwanda, 43,000 babies are born too soon each year; out of that, 2,070 die due to direct preterm complications which explains why there was a slight decline in neonatal mortality rate from 20 to 19 per 1,000 livebirth in 2015 and 2020, respectively;It is well known that the degree of prematurity inversely relates to the likelihood of increased mortality and morbidity.One out of five babies were born as preterm in a rural Rwandan district hospital;Having a husband who smokes cigarettes, attendance of less than three antenatal care visits and maternal undernutrition were notably associated with preterm delivery;To reduce this burden of prematurity, antenatal care providers should re-emphasize on the importance of pregnant women nutritional screening and education/counselling which is of good quality and quantity, discourage maternal alcohol consumption as well as passive smoking.


Downstream statistical analyses aimed to quantify changes in Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD), by employing whole-brain, tract-based spatial statistics (TBSS). ECT increased FA in the right splenium of the corpus callosum and the left cortico-spinal tract. AD in the left superior longitudinal fasciculus and the right inferior fronto-occipital fasciculus was raised. Increases in MD and RD could be observed in overlapping white matter structures of both hemispheres. At baseline, responders showed significantly smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus compared with non-responders. By harmonizing multicenter data, we demonstrate that ECT modulates altered WM microstructure in important brain circuits that are implicated in the pathophysiology of depression. Furthermore, responders appear to present a more decreased WM integrity at baseline which could point toward a specific subtype of patients, characterized by a more altered neuroplasticity, who are especially sensitive to the potent neuroplastic effects of ECT.ECT is proposed to exert a therapeutic effect on WM microstructure, but the limited power of previous studies made it difficult to highlight consistent patterns of change in diffusion metrics. We initiated a multicenter analysis and sought to address whether changes in WM microstructure occur following ECT. Diffusion tensor imaging (DTI) data ( Neuroimontal WM . In a susciculus . This inwith ECT . Finallywith ECT  (n = 13)observed . The incobserved . In our n = 3)), ECT treatment in accordance with the Dutch Guidelines on Electroconvulsive Therapy [For this multicenter study, 4 different cohorts were combined. Sample I consisted of 17 patients recruited at the University Psychiatric Center (UPC) in Duffel, Belgium. Sample II consisted of 13 patients recruited at the GGZ in Geest, Amsterdam, the Netherlands. Sample III and IV were both recruited at the department of Psychiatry of the Radboud University Medical Centre, Nijmegen, the Netherlands, and consisted of 17 and 11 patients respectively. For all samples, patients needed to fulfil the following inclusion criteria: a diagnosis of unipolar depression as defined by the DSM-IV-TR criteria  using aAll clinical assessments were conducted within 1 week before(T0) the start of the first ECT session and within 1 week after (T1) the last ECT session.Depressive symptoms were assessed using the Hamilton Rating Scale for Depression–17 items (HDRS-17) . TreatmeFor this multicenter DTI study, DTI scans were collected at three different sites employing four different scanners constituting as such 4 different samples: (I) the UPC Duffel sample (II), the Amsterdam UMC sample, (III) the Radboud UMC-1 sample, (IV) the Radboud UMC-2 sample. For each sample, a single-shot, diffusion-weighted, echo planar imaging sequence was consistently obtained within the week before a participant’s first ECT session (T0) and within 1 week (T1) after completion of the acute course. Scanners and Acquisition parameters for each site were as followed: (I) A 3 T Siemens Magnetom Prisma MRI scanner : TE, 71 milliseconds; TR, 8500 milliseconds; image resolution: 2.0 mm isotropic; b value, 1000 s/mm2; 30 directions; 75 axial slices. (II) A General Electrics Sigma HDxt 3 T scanner ; TE, 76 milliseconds; TR, 7150 milliseconds; image resolution: 2.4 mm isotropic; b value, 1000 s/mm2; 30 directions; 60 axial slices. (III) A 1.5 T Siemens Avanto system : TE, 85 milliseconds; TR, 7400 milliseconds; image resolution: 1.6 mm isotropic; b value, 1000 s/mm2; 34 directions; 75 axial slices. (IV) A 3 T Siemens Magnetom Prisma MRI scanner : TE, 76 milliseconds; TR, 7200 milliseconds; image resolution: 2.0 mm isotropic; b value, 1000 s/mm2; 75 axial slices; 30 directions.Preprocessing and statistical analyses were performed on all pre- and post-ECT DTI scans collected using FSL 6.0.3 . For each subject, diffusion-weighted images were corrected for motion and eddy-current distortions using the eddy commando with the b0 image as reference for alignment . After ehttps://github.com/Jfortin1/ComBatHarmonization) is an empirical Bayesian method for data harmonization that was originally designed for genomics [The ComBat harmonization method, as implemented in MATLAB was used after imaging processing and before downstream statistical analyses (TBSS) to remove inter-site scanner-related technical variability while preserving inter-site biological variability and maximize statistical power . To notegenomics . ComBat genomics , 25, 26.genomics . As a magenomics . For thihttp://www.fmrib.ox.ac.uk/fsl/randomise/index.html), which combines the general linear model with permutation testing, was then used for voxel-based analysis of each diffusion metric. The anatomical locations of clusters showing significant effects were identified using the Johns Hopkins University DTI-based WM atlas [t-tests established longitudinal WM changes in FA, MD, RD and AD before (T0) vs after (T1) ECT. To assess the possible influence of ECT laterality and number of ECT sessions on those WM changes reaching statistical criterion following ECT, we carried out an analysis of covariance (ANCOVA), with change as the dependent variable and number of ECT sessions and electrode position as independent variables. Second, we investigated whether the observed changes could be linked to changes in depressive symptoms as a result of ECT. To do this difference scores (T0–T1) were computed for the HDRS-17 scores and a paired t-test was carried out. Exploratory Pearson correlations between the significant changes (T0–T1) in diffusion metrics and changes in HDRS-17 scores (T0–T1) were then performed. To assess the possible associations between change in diffusion metrics and changes in HDRS scores at a whole brain level, we also performed a GLM with the change in HDRS scores as regressor. Bonferroni correction was employed for the correlational analysis with a p value fixed at 0.004 ). To assess on a whole brain-level the relationship between clinical response and changes in DTI metrics we performed a cross-sectional comparison in WM change between responders and non-responders. Further, a cross-sectional analysis in WM properties between responders and non-responders at baseline (T0) was carried out.Voxel-wise statistical analysis of the harmonized diffusion data  was carried out using TBSS . The response rate to ECT was 62.3%. Responders and non-responders did not differ on baseline demographic variables.Fifty-eight DTI datasets were obtained  both before and after ECT. Demographics, clinical characteristics, and ECT treatment information are presented in Table p = 0.0169) was observed between the number of ECT sessions and an increase of MD in the left cortico-spinal tract, this interaction failed however to remain significant after Bonferroni correction.After FDR correction, only increases in diffusion metrics remained significant. After ECT, a significant increase of FA was observed in the right splenium of the corpus callosum and the left cortico-spinal tract. Furthermore, patients showed significant increases in AD in the left superior longitudinal fasciculus and in the right inferior fronto-occipital fasciculus. Increases in MD and RD could be observed in overlapping WM structures of both hemispheres. MD did increase in the left superior longitudinal fasciculus, the left cortico-spinal tract and the left inferior fronto-occipital fasciculus. RD did increase in the right anterior thalamic radiation, the left inferior longitudinal fasciculus and the right inferior fronto-occipital fasciculus. Finally, the right forceps minor showed both an increase in MD and RD . Specifically, responders showed significantly smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus compared with non-responders. No differences between groups were observed for the RD and MD metrics , which was removed before analysis. Further, at the whole brain level no significant associations were found between changes in diffusion metrics and changes in HDRS scores.Employing a harmonization approach we are the first to observe an increase in FA in the splenium following ECT. This brain region is the most posterior part of the corpus callosum, composed of reciprocal fibers from the temporal association and parietal association, connecting regions of the parietal and occipital lobes through the forceps major , 32.Reductions of FA are consistently reported in the corpus callosum of patients with depression , 33–36 aOur post-ECT analyses revealed an increase of AD in the left superior longitudinal fasciculus and the right inferior fronto-occipital fasciculus. Altered integrity of these WM tracts has been frequently observed in depressed patients and is suggested to underpin fronto–subcortical dysconnectivity –36. SomeWe observed an increase of MD, encompassing the left superior longitudinal fasciculus, the left cortico-spinal tract, the left inferior fronto-occipital fasciculus and the right forceps minor. These findings are in line with both Repple et al. (2019) and Gryzelewski et al. (2020) but in contrast to the study of Lyden et al. , who obsIt is thought that during the transient increase of permeability of the blood-brain barrier certain neuroactive reactants such as the brain-derived neurotrophic factor (BDNF), an important neuroplastic agent, may get released from the circulation to the brain, promoting neuroplastic mechanisms , 53. ThiSimilar to findings of Gryzelewski et al. (2020), we observed an increase of RD in the right anterior thalamic radiation, the left inferior longitudinal fasciculus, the right inferior fronto-occipital fasciculus, and the right forceps minor . On the The identification of neuroimaging biomarkers of treatment response holds promise toward personalizing ECT and improving treatment outcomes. To our best knowledge, we are the first to demonstrate smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus in responders compared to non-responders. Whereas the forceps major emerges from the splenium to connects regions of the parietal and occipital lobes , 32, theThe relationship between baseline neuroplasticity and treatment outcome following ECT has been sparsely investigated, but Neyazi et al.,  found prBeyond its longitudinal design, the main strength of our study resides in its harmonization approach, in which the imaging data are combined before performing statistical inferences, increasing the statistical power compared to meta-analyses. In addition, by pooling imaging data across sites our study enriched the clinical picture of the sample by increasing the variability in symptom profiles and demographic variables . MoreoveFurther, the ComBat method assumes the site effect parameters to follow a particular parametric prior distribution, which might not generalize to all scenarios or measures, and it is not yet clear how non-linearities in the signal due to site effects propagate through the preprocessing techniques, as well as model fitting procedures . It shouThe lack of a control dataset to confirm our findings should be mentioned. As a matter of fact, the specificity of these ECT related effects should be scrutinized by comparing them with a sample of depressed patients put on other forms of treatment. Further, differences in WM changes following ECT between treatment resistant and other forms of depression should also be addressed, as form specific alterations of structural brain characteristics have been suggested by previous research . FinallyIn summary, ours is the first multicenter analysis to investigate changes in diffusion metrics following ECT. Our data demonstrate that ECT normalizes altered WM microstructure in important brain circuits that are implicated in the pathophysiology of depression. Importantly, our findings parallel functional neuroimaging findings that ECT could enhance top-down cognitive control over emotional states to regulate mood. Furthermore, initial evidence indicates that ECT responders present a more altered WM integrity at baseline, indicating as such a subgroup of depressed patients, especially sensitive to ECT.


Infants were classified by gestational age (GA) and SGA status. The vaccinations included: hexavalent (HEXA), measles-mumps-rubella, varicella, pneumococcal conjugate (PCV), and meningococcal C conjugate. Time-to-event (Kaplan–Meier) analyses were conducted to evaluate the timing of vaccination according to GA; logistic models were performed to evaluate the associations between GA and SGA with vaccination timeliness. Time-to-event analyses show that the rate of delayed vaccine receipt increased with decreasing GA for all the vaccinations, with a less marked gradient in later vaccine doses. Compared to full-term infants, very preterm infants significantly showed an increased odds ratio (OR) for delayed vaccination in all the vaccinations, while moderate/late preterm infants only showed an increased OR for HEXA-1, HEXA-3, PCV-1, and PCV-3. SGA infants had a significantly higher risk of delayed vaccination only for HEXA-1 and PCV-1 compared to non-SGA infants. In conclusion, vaccinations among preterm and SGA infants showed considerable delay. Tailored public health programs to improve vaccination timeliness are required in these high-risk groups.Preterm and small-for-gestational-age (SGA) infants are more susceptible to vaccine-preventable diseases. To evaluate routine vaccination timeliness in these high-risk groups, a full birth cohort of infants ( Timely immunization is essential to protect infants from vaccine-preventable diseases; a delayed immunization leads to an increased period of susceptibility and thus to an increased infection risk. Preterm infants (PTI) are more susceptible to infections compared to those born full term due to immunological immaturity and the decreased transfer of maternal antibodies, which are mainly transferred during the last trimester of pregnancy ,2. ThereSeveral studies have shown that routine immunization schemes based on chronological age are both safe and effective in developing protective immune responses in preterm and low-birth-weight infants ,8,9. To Despite these recommendations, a delayed onset of immunizations and under-vaccination were observed in PTI, low-birth-weight (birthweight less than 2500 g) and small-for-gestational-age (SGA) infants ,22,23,24Although the rate of preterm births is increasing in most Western countries , there aIn Italy, routine immunizations are carried out through a network of public vaccination clinics, and childhood vaccinations recommended in the Italian national Immunization program are actively offered and guaranteed free of charge for all children ; as for The aim of this study was to evaluate—in a full birth cohort of infants born in 2017 and 2018 in the Tuscany region, Italy—the timeliness of the routine immunization schedule in different categories of preterm infants and SGA infants compared to infants born at term and of adequate weight for GA. Furthermore, a secondary aim of the study was to explore factors associated with delayed vaccinations.The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Tuscany region  (protocol code 183/2020 and 5 August 2020).This is a retrospective cohort study conducted on the administrative data of the Public Health Care System (TPHCS) of the Tuscany region. Tuscany is a region with a population of more than 3.7 million residents located in central Italy. The TPHCS provides universal health coverage for all Tuscany residents, and routine immunizations are offered free of charge to all infants according to the Italian routine vaccination schedule.All infants born in Tuscany from 1 January 2017 to 31 December 2018 who were registered in the Tuscany region birth registry were included in the study. The data of infants on vaccination and residence were linked from the Tuscany region vaccination registry and from the Tuscany region population registry using an anonymous unique identifier. Infants were followed up until 24 months of age. Infants with a missing/erroneous unique identifier, those with missing data for GA, and those who died or changed region of residence during the follow-up period were excluded. Furthermore, for each one of the vaccines considered, infants who resulted in being completely unvaccinated at the end of the follow-up were excluded because the study aimed to evaluate determinants of timeliness of vaccinations and not those associated with no vaccination . There wHEXA vaccine: first dose (between 61st and 90th day) and third dose (between 306th and 395th day); MMR vaccine (included MMR or MMRV vaccination): first dose (between 396th and 455th day);Var vaccine (included Var or MPRV vaccination): first dose (between 396th and 455th day);PCV vaccine: first dose (between 61st and 90th day) and third dose (between 396th and 455th day);MenC vaccine: first dose (between 366th and 455th day).The primary outcome was the timeliness of vaccination. The following vaccines were considered: HEXA, MMRV, MMR, V, PCV, and MenC. For each vaccine, the timing of the doses foreseen by the regional routine vaccination schedule were considered . In partFor each participant, the timing of each vaccination was calculated based on chronological age, without correction for GA. Doses administered a day after the recommended period were considered as delayed. Furthermore, vaccination delay was further characterized considering the following categories: minimal delay (delayed less than one month), moderate delay (delayed 1–3 months), severe delay (delayed 3–6 months), and extreme delay (delayed 6 months or more).Furthermore, the timeliness of the first vaccinations and of vaccine doses to be administered by the 15th month of life was also studied. Administration a day after the 90th day of at least one between HEXA-1 and PCV-1 vaccines was defined as delayed vaccination at first vaccination; similarly, administration a day after the 455th day of at least one among HEXA-3, MMR, V, PCV-3, and MenC vaccines was considered delayed vaccination at the 15th month of life. Maternal data and the data of infants were retrieved from the Tuscany region birth registry. For each infant the following covariates were considered: date of birth; sex; GA at birth; SGA status ; multiple births; sibling birth order ; conception by assisted reproductive technologies (ART); urbanization level of residence ; and birth hospital level of newborn care . SGA status was calculated according to the Italian reference charts  . FurtherAs far as the maternal data are concerned, the following variables were considered: age at delivery ; nationality ; education level ; and employment status .Categorical variables were presented as percentages, while continuous variables were described as median and interquartile range (IQR). In the descriptive analysis, infants were stratified based on GA at birth into four groups: very preterm infants (VPTI: GA < 32 weeks), moderate and late preterm infants (MLPTI: GA between 32 and 36 weeks), full-term infants (FTI: GA ≥ 37 weeks).For each one of the considered vaccine doses, a time-to-event analysis using the Kaplan–Meier method was calculated to evaluate the timing of vaccination according to GA; log-rank test was performed to compare the survival curves of the different GA groups .A multivariate logistic regression analysis was performed to evaluate the associations between GA and SGA status with vaccination timeliness. Multivariate logistic regression models were fitted for each one of the considered vaccine doses. In the models, the GA variable was categorized into three groups ; the SGA status variable was categorized into two groups . All the models included the following independent variables: sex, multiple birth, sibling birth order, conception by ART, urbanization level of residence, birth hospital level of newborn care, maternal age at delivery, nationality, maternal education level, and maternal employment status.In order to evaluate determinants of delayed vaccination, two distinct logistic regression models were performed considering the outcomes of timeliness of the first vaccinations and of vaccine doses to be administered by the 15th month of life. The following independent variables were considered: GA, SGA, sex, multiple birth, sibling birth order, conception by ART, urbanization level of residence, birth hospital level of newborn care, maternal age at delivery, nationality, maternal education level, and maternal employment status.Data analysis was performed using Stata 15 SE .A total of 52,164 infants were born in Tuscany from 1 January 2017 to 31 December 2018. From these, 11,112 (21.3%) infants were excluded from the study: 591 (1.1%) infants had a missing or erroneous unique identifier, 8793 (16.8%) infants died or did not reside in the Tuscany region during the follow-up period, and 1270 (2.4%) infants resulted in being completely unvaccinated at the end of the follow-up. A total of 41,502 (79.6%) infants were included in the study. In the studied population, 20,204 infants were females, representing around the 49% of the sample see . A totalData on age at vaccination and timeliness of vaccination by GA and SGA status are reported in The distribution of vaccination timing for GA and vaccine doses is reported in p < 0.001). Infants born before 28 weeks and those born between 28 and 32 weeks of gestation showed the highest rate of delayed vaccine receipt in all the vaccine doses. The differences across GA groups in vaccination onset were less marked in later vaccine doses .In p = 0.07) for first vaccinations. Maternal employment status and age at delivery were not significantly associated with delayed vaccination in both models. A number of other factors did not act consistently between the two models. In particular, infants born in second level hospitals and infants living in rural areas showed a significantly increased risk of delayed first vaccinations. Maternal foreign nationality was significantly associated with a lower risk of delayed vaccination only for vaccinations to be administered by the 15th month of age. A lower maternal education level was significantly associated with a decreased risk of vaccination delay for first vaccinations, while it was associated with an increased risk of delay for vaccinations to be administered by the 15th month of age.The results of the multivariate logistic regression models evaluating the determinants of delayed vaccination for the first vaccinations and for vaccine doses to be administered by 15th month of life are reported in The present study assessed the timeliness of immunization in an area-based, full birth cohort of the Tuscany region, Italy with the aim of comparing immunization timeliness between PTI and FTI as well as between infants born SGA and those who were not SGA. In total, around 70% of MLPTI and 40% of VPTI received their first immunizations on time compared to more than 77% of FTI. We showed that PTI were at higher risk of delayed vaccination compared to FTI in all the routine vaccinations considered; in particular, this increased risk of delayed vaccination was present in all prematurity classes, with VPTI presenting the highest risk of delay. Furthermore, the entity of the increased risk of delayed vaccination in PTI was higher in vaccine doses administered early in life, such as HEXA and PCV first doses, compared to later vaccine doses such as HEXA and PCV third doses, and MMR, Var, and MenC. As far as SGA status is concerned, we found that these infants had a significantly increased risk of delayed vaccination for the first doses of HEXA and PCV compared to infants who were not SGA; contrary to what we observed in PTI, such increased risk for SGA was not present in all the later vaccine doses considered. Multivariate regression analyses show that multiple births negatively influenced the timeliness of the first immunizations and of those to be administered by the 15th month, while infants who were first born/only child and those conceived by ART showed a timelier administration of these vaccines. To the best of our knowledge, this is the first study assessing the timeliness of routine immunizations in a full birth cohort in Italy. Many years ago, a study was conducted in an Italian cohort composed of only very preterm infants; furthermore, in this study, the vaccination timeliness was evaluated in absolute terms, and no comparisons with FTI or with other preterm categories were made to evaluate the delay in relation to other reference groups . Despite international guidelines and recommendations indicating that PTI should be vaccinated following the same schedule used for FTI ,11,12, aIndependently from gestational age at birth, infants who were born SGA were at a higher risk of delayed vaccination only for the doses of first vaccines—i.e., HEXA-1 and PCV-1. The role of SGA in influencing the timeliness of immunization is scarcely investigated in the literature. Similar to our findings, Woesteberg et al.  reportedFirst-born infants and infants conceived by ART experienced a timelier vaccination both at the first vaccine doses and for vaccine doses foreseen in later ages. These findings are probably related to the fact that—in both cases—there may be increased attention from parents with regards to all the aspects related to the health of their child, including vaccinations. On the other hand, multiple birth infants showed a higher risk of delayed vaccination, irrespective of their gestational age, and this may be explained by the higher organizational difficulties in attending vaccination appointments experienced by parents of multiple birth infants. Maternal sociodemographic variables examined in our study did not show a clear influence on the timeliness of vaccination. While maternal age and employment status were not associated with the timeliness of immunization, maternal education level and nationality were associated with the timeliness of immunization for vaccines doses to be administered in later ages. In particular, a higher education level and a foreign nationality were associated with a timelier vaccination. As for the maternal education level, a higher level of vaccine literacy and better opportunities for obtaining information probably explain the finding. As for the role of nationality, it is possible to speculate that foreigners may tend to rely more on official information provided by the primary care and preventive care services, while Italians may tend to have multiple sources of information, ultimately resulting in increased risk of exposure to misinformation about vaccine safety and benefits, especially for vaccines that are more strongly linked to false claims such as the MMR vaccine . The present study has several strengths. In addition to being carried out on a very large cohort of infants, the study involved an area-based, full birth cohort, thus providing an accurate picture of the timeliness of vaccination in the Tuscany region, Italy and minimizing potential selection bias. The selection of a full birth cohort has also allowed natural comparison groups—i.e., FTI and infants who were not born SGA—to evaluate the vaccination timeliness in preterm and SGA infants not only in absolute terms but also in relative terms. Furthermore, the study is based on data registered in the birth and vaccination regional registries; these data are directly and punctually collected by obstetrics, nurses, and doctors who provided birth care (within 10 days after birth) or administered the vaccines, respectively. These data collection procedures minimize the risk of misclassifications and recall bias. Lastly, this is one of the first studies that evaluated vaccination timeliness in SGA and non-SGA infants.The study also has some limitations. Firstly, a proportion of infants registered in the birth registry were not linked with the vaccination registry and thus were excluded from the study. This was due to multiple causes: infant death after birth, infants who moved to another region during the follow-up period, and inherent technical problems in record linkage. However, this exclusion is probably not related to the characteristics of infants and vaccination timeliness and likely biased results towards the null. Indeed, the characteristics of the population studied and reported in This large area-based, full birth cohort study shows that preterm infants—including MLPTI—had a significant delay in first immunizations compared to FTI. Although to a lesser degree, the timeliness gap between FTI and PTI persisted in later vaccine doses within the series and in vaccine doses that have to be administered at older ages. The findings of the study highlight an increased risk of vaccine-preventable infections in a population group that is already exposed to a greater vulnerability to infections. Several parental and provider factors may explain vaccination delay in PTI, including vaccine safety and efficacy beliefs, perceptions of medical vulnerability, knowledge and understanding of vaccine recommendations, as well as vaccine communication between doctors and families. Further research is needed to better identify specific reasons behind vaccination delay in PTI. Timeliness of immunization in PTI remains a public health priority and strategies that integrate multiple interventions, such as training of health professionals, tailored parental information and education programs, and improved accessibility to immunization services are needed.


Hypospadias is one of the most common male congenital malformations worldwide. It is characterised by the abnormal positioning of the opening of urethra, and may lead to problems with urination and sexual function. Various factors were suggested to contribute to hypospadias pathogen. This study aimed to evaluate the relationship between perinatal factors and neonatal hypospadias based on a large sample of male newborns.N = 97) and without any birth defects  who were born in January 2015 to December 2019 were enrolled in this study. A statistical analysis of perinatal factors, such as maternal age, primiparity, multiple births, hypertensive disorders of pregnancy (HDP), diabetes mellitus (DM), placenta previa, thyroid diseases, hepatitis B, obesity, meconium-stained amniotic fluid, gestational age, low birth weight (LBW), small for gestational age (SGA) and in vitro fertilization (IVF) was used to assess the risk factors for hypospadias.This retrospective case–control study was conducted at the International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine. Male infants with hypospadias (P <  0.01), multiple births  and hyperthyroidism , which suggested these factors were significant independent risk factors for hypospadias.The overall incidence of hypospadias in male infants was 0.23% . The univariate analysis of potential risk factors for hypospadias showed that HDP, primiparity, multiple births, hyperthyroidism, preterm delivery, LBW and SGA had a statistical association with hypospadias. After adjusting for potential confounders in a multivariate regression analysis, the odds ratios (OR) and 95% confidence intervals (CI) were calculated for the following risk factors for hypospadias: HDP (OR: 3.965, 95% CI: 2.473–6.359, Perinatal factors, such as HDP, multiple births and hyperthyroidism may be associated with hypospadias in male infants. Hypospadias is one of the most common male congenital malformations worldwide. It is defined by an abnormal urethral opening, and it is characterised by an abortive development of the urethral spongiosum and ventral prepuce; it may be accompanied by penile chordee, and an absence of the urethra, which may lead to problems with urination and sexual function . The prePrevious research has shown that both genetic and environmental factors contribute to the pathogenesis of hypospadias. The intent of this study was to evaluate the relationship between perinatal factors and neonatal hypospadias based on a large sample of male newborns, and to provide a perspective for the clinical prevention of hypospadias.A retrospective case–control study was conducted on the data of pregnant women and their offspring from January 2015 to December 2019 at the International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine. A total of 84,095 infants were delivered over 5 years: 42,832 were male. Birth defects occurred in 685 males; 588 infants who had non–hypospadias malformations were excluded from the study. Thus, 97 infants with hypospadias formed the hypospadias case group and 42,147 male infants with no birth defects formed the control group , newborn birth weight (BW), birth weight for GA, the use of in vitro fertilization (IVF) and diagnosis of hypertensive disorder of pregnancy (HDP), diabetes mellitus (DM), placenta previa, hyperthyroidism, hypothyroidism, hepatitis B, obesity.2) was ≥30.0 kg/m2 at their first prenatal examination. There were four degrees of amniotic fluid based on appearance: clear or normal amniotic fluid; I degree ; II degree ; and III degree . GA was calculated from the date of the last menstrual period and confirmed by early ultrasound. A preterm delivery was a birth that took place before 37 weeks . The infants’ BW were measured after umbilical cord clamping; a low birth weight (LBW) was defined as < 2500 g. Additionally, infants were classified according to their BW for GA: small for GA ; appropriate for GA ; and large for GA . Information about IVF techniques was collected from the clinical history of the mothers.The clinical information, which was completed by obstetricians and neonatologists during the prenatal examination and upon admission into the hospital, was collected from the hospital database. Diagnostic descriptions were confirmed by clinical and laboratory findings, and imaging and pathological examinations during pregnancy and after delivery according to clinical protocols and guidelines. The maternal age and primiparity were stated by the patient and confirmed by clinical records. Multiple births were diagnosed using an ultrasound scan. HDP included the following: chronic hypertension, which was diagnosed by blood pressure ≥ 140/90 mmHg before 20 weeks of gestation; gestational hypertension, which appeared after 20 weeks of gestation without proteinuria or other findings; preeclampsia, which involved gestational hypertension accompanied by proteinuria, maternal end–organ dysfunction, and/or placental dysfunction; and superimposed preeclampsia on chronic hypertension in which the pregnant women developed proteinuria or other organ dysfunction . To screEvery procedure was carried out in accordance with the relevant guidelines. Ethics approval and use of clinical data for research purposes was granted by the Ethics Committees of the International Peace Maternity and Child Health Hospital. This clinical study was registered at www.chictr.org.cn(ChiCTR2000032771).P <  0.05 was set for all the tests. IBM SPSS Statistics Version 25.0 software was used to sort and analyse the relevant data.To evaluate the effects of the perinatal factors on hypospadias, a single factor t–test and chi–square test were used for the continuous variables and categorical variables, respectively. Directed acyclic graphs (DAGs) were depicted using DAGitty v.3.0 software to determine the minimal sufficient adjustment sets as confounding factors . Nodes rFrom a total of 42,244 male infants, 97 were diagnosed with hypospadias; thus, the incidence of hypospadias was 23 per 10,000 male infants . Six infants with hypospadias had complications from other nonfatal congenital defects: three infants had congenital heart defects, specifically a ventricular septal defect (VSD); one infant had pulmonary sequestration; one had polydactylism; and one had both VSD and a cleft hand.In this study, HDP included chronic hypertension, which developed before 20 weeks gestation, and gestational hypertension, which developed after 20 weeks gestation. The collected data showed that no case of hypospadias was found in the 119 women with chronic hypertension. However, the data for women with chronic hypertension and gestational hypertension was not adequate for analysis and, thus, HDP was not separated into the different types.P <  0.01) of the following factors in the hypospadias case group than in the control group: multi births (17.5% versus 5.5%), hyperthyroidism (4.1% versus 0.6%), preterm delivery (30.9% versus 9.0%), LBW infant (34.0% versus 5.1%), and SGA infants (27.8% versus 2.0%). The effects that maternal age, primiparity, placenta previa, DM, hypothyroidism, hepatitis B, obesity, stained amniotic fluid and IVF had on hypospadias were not significant (P > 0.05).The single factor analysis showed that there was a significantly higher proportion of women with HDP in the hypospadias case group than in control group: 25.8 and 6.8% respectively Table . In the P <  0.001), multiple births  and hyperthyroidism .DAGs were depicted to determine the confounding variables for hypospadias Fig. . HDP, hyHypospadias is the most common external genital malformation in males, it mostly manifests as simultaneous defects of the urethra and corpus spongiosum , 10. MalStudies have reported that the occurrence of hypospadias is related to genetic predisposition, HDP, abnormal placental cord insertion, placental dysfunction, hepatitis B antigen carrier, exposure to various medical and chemical substances, maternal age, preterm delivery, SGA and birth length , 10–18. The result of this study showed that there was a significant increase in the incidence of hypospadias in male newborns from mothers with HDP; the incidence was 0.86%, which was about 3.7 times higher than the overall incidence of hypospadias. Moreover, after multivariate correction, the results of the analysis still showed that the risk of hypospadias caused by HDP was more than 3 times the overall incidence, which was statistically significant. HDP included chronic hypertension, gestational hypertension, preeclampsia and superimposed preeclampsia on chronic hypertension. Previous studies showed conflicting results about the relationship between different types of HDP and hypospadias , 19. TheThe key window for the development of male reproductive organs occurs from 8 to 14 weeks of gestation . One stuThere were significantly higher numbers of LBW, SGA and preterm infants in hypospadias case group than in the control group, which suggested that these factors might increase the risk of hypospadias. However, these factors are strongly associated with gestational complications that can lead to birth defects. For example, HDP and hyperthyroidism are common causes of severe crises in pregnancies and can affect the timing of an obstetrician’s decision to deliver the baby earlier. HDP and multiple births may contribute to chronic intrauterine distress, which can affect foetus growth and development. Therefore, preterm delivery and LBW infants are common in pregnancies with these gestational complications. These findings indicated that LBW, SGA and preterm infants were not independent risk factors for congenital malformations, but rather common outcomes of the other conditions. One study reported that birth length was significantly related to the occurrence of hypospadias . While tIn our study, mothers with hyperthyroidisms during pregnancy had a significant increased risk of hypospadias in their newborns. However, the relationships between hyperthyroidism and related medical treatments and birth defects are still controversial. There were increasing evidences indicated that the drugs used to treat hyperthyroidism in early pregnancies are teratogenic. Methimazole and carbimazole exposures were believed to be associated with severe birth defects and, thus, propylthiouracil was recommended for hyperthyroidism treatment in the first trimester of pregnancy , 15, 23.Previous studies have reported that multiple births are associated with an elevated risk of hypospadias; the OR ranged from 2.58 to 3.47 , 26. MulThe California Birth Defects Monitoring Program and the Emilia–Romagna Registry (IMER) Program found that the risk of hypospadias was significantly increased in the offspring of older mothers , 28. HowThe limitation of our study was that it was a retrospective research from a single center. The data were collected from the hospital information system, which was not well–designed for specific researches. Only well collected factors were considered in this study. Therefore, certain data, such as information on the severity of the hypospadias, the medication treatment given for HDP and thyroid disease, whether the mother smoked or drink alcohol and the assessments of placenta function in the early stage of pregnancies, were not available. Further researches may require more refined classifications and a more comprehensive design to provide deep insight into the complex aetiology of hypospadias and more centers are expected to join in co–operation.Our findings suggested that some perinatal factors of the mother, such as, HDP, multiple births and hyperthyroidism, were independent risk factors for hypospadias in newborns. Future well–designed researches that involves co–operation between paediatricians and urologists would be expected to reveal more details about the relationship between perinatal factors and hypospadias.


The majority of studies are limited to adverse perinatal outcomes and poor cognitive abilities in the short term in discordant monochorionic twins.To determine whether small and large discordant dizygotic twins differ in physical growth and intelligence development and weight and height from birth up to 6 years of age were measured in 34 dizygotic twin pairs with ≥ 20% birth weight discordance. Mental developmental index (MDI) and psychomotor developmental index (PDI) were calculated at 1 year, while the Wechsler Intelligence Scale for Children-IV (WISC-IV) full-scale intelligence quotient (IQ) was assessed at the age of 6.P < 0.05), although there was disappointing catch-up growth in smaller twins. PDI but not MDI at 1 year of age was significantly different between the two groups (P < 0.05), and smaller twins experienced higher psychomotor retardation rates (P < 0.05). Also, the influence of height and weight on PDI was statistically significant (P < 0.05). No significant difference was detected in the WISC-IV full-scale IQ at the age of 6; however, the full-scale IQ may be affected by the history of suffocation and the S/D value .The difference in height and weight in each stage differed significantly from birth to 72-months-old (Intrauterine fetal growth and development lead to birth weight differences in twins and sustain an impact on the children’s physical growth in height and weight from birth to preschool age, causing psychomotor developmental differences at 1 year of age. However, the differences in psychomotor development decrease gradually by the age of 6.The online version contains supplementary material available at 10.1186/s13052-022-01354-y. Twin growth discordance is a common finding in multiple gestations. The term describes a significant weight difference between the two fetuses of a twin pregnancy. The definition of significant discordance considered at least a 20% difference in birth weight between the twins , althougTypically, the prenatal period is the duration of rapid brain development, which includes marked changes in cortical folding , myelinaAmong healthy twins, growth discordance may be due to the inability of the uterine environment to meet the demands of multiple fetuses, leading to intrauterine growth restriction (IUGR). Twin growth discordance is a complication of both monochorionic and dichorionic twin pregnancies. The etiologies for intrauterine dysplasia in dizygotic twins emerge from maternal and fetal factors, while in monozygotic twins, non-intrauterine nutrition factors, such as twin transfusion syndrome (TTTS) and selective IUGR (sIUGR), underlie poor prognosis. Chorionicity represents a putative confounder in the prevalence of neurologic morbidity among twin survivors. The current studies on postnatal physical and mental development in discordant twins have not distinguished the chorion, which could skew the results. Therefore, the present study discusses the physical growth and intelligence development of discordant dizygotic twins. Can the smaller of the discordant twins catch up with their sibling in physical and mental development after birth?The study included all neonatal discordance dizygotic twins born at The Second Affiliated Hospital of Wenzhou Medical University (WMU) from June 2012 to June 2013 and survived to discharge. Dizygotic twins whose birth weight differed by ≥ 20% were classified as discordant twins. Informed consent was obtained from the parents before enrollment in the study. The Second Affiliated Hospital of WMU Ethics Committee approved the study. The exclusion criteria were infants with major congenital malformations, such as major cardiac malformations, chromosomal anomalies, and skeletal, renal, brain, and lung malformations. According to the birth weight in each twin pair, the smaller one was categorized into Group Twin-Low birthweight (Group Twin-L), and the larger one was assigned to Group Twin-High birthweight (Group Twin-H).Information related to maternal  and neonatal (including pregnancy systolic/diastolic peak (S/D) value, birth weight, length, head circumference, gestational age, gender, malformation, Apgar score, respiratory distress, NICU entry, and feeding option) characteristics were collected from the medical files of the mothers and infants or an in‐person interview.The height and weight parameters of each child were measured by physical examinations or collected from the Wenzhou Maternal and Child Healthcare system at birth and 1-, 3-, 6-, 8-, 12-, 18-, 30-, 36-, 48-, 60-, and 72-months-old. The electronic baby scale and clinostatic body length standard bed were designed to help monitor the weight and body length (measured lying flat with a single suit) of children < 36-months-old. A uniform height and weight scale were designed to help monitor the height and weight gain (measured standing without shoes) for children aged ≥ 36 months. All measurements were performed by the same experienced physician.Bayley Scales of Infant Development (BSID), including intelligence and exercise scales, was used to test the psychomotor and mental development of 1-year-old infants. The intelligence and exercise scales were expressed by mental development index (MDI) and psychomotor development index (PDI), respectively. After the infants gained familiarity and were cooperative in a quiet environment, the evaluation process was carried out item by item to estimate the MDI and PDI. The MDI and PDI scores were defined as follows: low (< 70), critical (70–89), moderate (90–109), and high (≥ 110).Wechsler Intelligence Scale for Children-IV (WISC-IV), including verbal test and operational test, was used to assess the intelligence development of 6-year-old children. After obtaining full familiarity and cooperation from the children in a quiet environment, the evaluation process was carried out item by item to deduce the full-scale IQ, including verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), and processing speed index (PSI). According to the scores of the full-scale IQ, children were distributed into two groups: Group IQ-Normal (IQ-N) with scores ≥ 90 and Group IQ-Low (IQ-L) with scores < 90.Cognitive performance tests were carried out by expert psychologists (who had a degree of Master of Arts in Psychology) at the Institute of Cognitive Sciences of the Second Affiliated Hospital of WMU. The examiners were fully unaware of the status of the twins. The evaluation was repeated after 15 days if the children did not cooperate satisfactorily.P < 0.05 indicated a statistically significant difference. The predictive performance of dependent variables to predict the degree of IQ scores was quantified using the area under the curve (AUC) of the receiver operating characteristic (ROC) analysis. An AUC of 0.5 represents a variable with no predictive ability, and the closer the AUC to 1.0, the higher the authenticity of the variable.The smooth spline function of R 3.5.3 was used to fit the sample data with three smoothing splines. Firstly, the parameter “CV  = true” was set to select the appropriate degree of freedom for the group with a small sample size using the leave-one-out cross-validation. Then, the fitting curves of the physical indicators of each group were drawn based on this degree of freedom. The data were analyzed using SPSS 19.0 software. Paired t-test was used to compare the measured data between normal distribution datasets, expressed as mean ± standard deviation, while paired Wilcoxon rank-sum test was used to compare the non-normal data sets, expressed as . The chi-square test was used for enumeration data, expressed as a ratio or constituent ratio. In univariate analysis, the t-test was used to compare the normal distribution variables, the Mann–Whitney U test for skewed distribution variables, and Fisher’s exact test was utilized for classified variables. In multivariate analysis, the linear regression method was applied. During the study period, 58 sets of discordance dizygotic twins were born at the Second Affiliated Hospital of WMU and survived to discharge. Of these, 6 pairs were unavailable to contact, 16 did not consent, 1 pair in whom the smaller twin was confirmed to have cerebral palsy, and 1 pair in whom the smaller twin suffered congenital heart disease were excluded. Finally, we obtained a total of 34 pairs with a 58.6% inclusion rate. All children accepted chromosomal analysis and medical tests. No chromosomal abnormalities, skeletal, renal, brain, and lung malformations was found. The mean gestational age at birth was 35 ± 1.86 (30–38) weeks. The mean birth weight difference was 738 ± 285.89 g (300–1380 g), and the mean percentage difference in birth weight was 28% (20–50%).P < 0.05). The stratified analysis further demonstrated that the weight growth rate of Group Twin-L in 0–1, 3–6 months, and 24–30 months, and height growth rate in 1–3 and 8–12 months were significantly higher than those of Group Twin-H (P < 0.05).The physical development data of 34 discordant dizygotic twin pairs at birth and 1, 3-, 6-, 8-, 12-, 18-, 30-, 36-, 48-, 60-, and 72-months-old were reviewed, and the fitting curves of body weight and height were drawn, respectively ; however, no significant difference was observed in MDI at the age of 1, and all the four index scores comprised the full-scale IQ at 6 years of age between the two groups (P > 0.05) (Table P < 0.05) .The smaller twin presented low PDI scores than the larger at the age of 1 (5) Table . The psy5) Table . HoweverF = 11.40, P = 0.0012; F = 6.21, P = 0.0153), but not on MDI  in supplementary table P < 0.05), but the representativeness of individual indicators was insufficient (R2 = 0.16), as supplementary table P > 0.05).A total of 68 cases of MDI and PDI were analyzed by multiple linear regression severally. PDI and MDI were taken as dependent variables, and the main feeder’s education degree, age, feeding option, weight, height, gender, gestational age, birth weight, S/D value, asphyxia (Apgar score ≤ 7), and infection were considered independent variables. The effects of body height and weight on were statistically significant on PDI (P < 0.05). Univariate analysis , age (P = 0.071), education degree of the main feeder (P = 0.038), asphyxia (P = 0.006), and infection (P = 0.048), and a ROC curve was drawn  and IQ-L group  are described Table . We founawn Fig. . The maxSeveral studies have shown a strong association of low birth weight to adult growth and health , 12. BirLow birth weight and prenatal malnutrition are associated with neurodevelopmental disorders , 20; howvs. Twin-H 103.58 ± 11.87). Thus, we suspected that the wide PRI score difference could be attributed to the gap in PDI at the age of 1. The smaller twins accepted preschool education inevitably under pressure from parents, who wanted to narrow the gap after the BSID assessment. Some studies on the monochorionic twin cohort [The gap in intelligence development in discordant dizygotic twins at the age of 6 appears to be bridged because no significant difference was detected in VCI, PRI, WMI, PSI, and the full-scale IQ in our study. However, smaller twins had a PRI score 4 points lower than the larger twin  and IQ-L group . Supplementary Table 2. Multiple linear regression analysis at 1-year-old. The MDI and PDI were analyzed by multiple linear regression. PDI and MDI were taken as dependent variables, and the main feeder’s education degree, age, feeding option, weight, height, gender, gestational age, birth weight, S/D value, asphyxia (Apgar score ≤7), and infection were considered independent variables. Supplementary Table 3. Effect of weight on PDI by stepwise regression analysis. The stepwise regression analysis showed that the effects of weight on PDI were statistically significant (P<0.05), but the representativeness of individual indicators was insufficient (R2=0.16).