Pervasive exposure to per-and polyfluoroalkyl substances (PFASs) shows associations with adverse pregnancy outcomes. The aim of the present study was to examine the determinants of different serum PFAS concentrations in late pregnancy and their relationship with birth outcomes in southern Malawi. The sample included 605 pregnant women with a mean age of 24.8 years and their offspring from three districts in the southern region of Malawi. Six PFAS were measured in serum from third-trimester women. The serum PFAS concentrations were assessed with head circumference, birth length, birth weight, gestational age and ponderal index. Participants living in urban areas had significantly higher serum levels of PFOA, PFNA and SumPFOS, while SumPFHxS concentrations were higher in women from rural settings. High PFOA, PFNA and SumPFHxS concentrations were generally inversely associated with head circumference. Birth length was negatively associated with PFOA and PFNA while SumPFHxS was negatively associated with birth weight. SumPFOS was inversely associated with gestational age. Urban area of residence was the strongest predictor for high PFAS concentrations in the maternal serum and was generally associated with adverse birth outcomes. The results highlight the need to investigate SumPFHxS further as it follows a pattern that is different to similar compounds and cohorts.  Per-and polyfluoroalkyl substances (PFASs) are highly fluorinated aliphatic substances that consist of carbon (C) chains of different length with a perfluoroalkyl moiety CnF2n+1-) [- [1]. ThGlobally, there are growing concerns about the links between exposure to PFAS compounds and adverse health effects . A wide A number of studies have suggested an association between higher concentrations of some PFAS and low birth weight ,17,18,19This is a cross-sectional study of delivering women giving birth and their offspring. The study was conducted in the southern region of Malawi, in antenatal clinics/wards and labor wards of three government health facilities. The health facilities that were randomly selected for the study include Ndirande Health Centre, Chiradzulu District Hospital (CDH) and Thyolo District Hospital (TDH). Ndirande Health Centre is located in Blantyre, which is the commercial city of Malawi, while Chiradzulu and Thyolo district hospitals are located in Thyolo and Chiradzulu districts, respectively. All study sites are located in the southern region of Malawi. Ndirande Health Centre is situated in an urban setting while the other district hospitals represent the rural setting. Study participants were recruited between August 2020 and July 2021 using data collection tools that were pretested in a pilot survey conducted soon before the main survey. Personal characteristics, socioeconomic status, lifestyle, infant information and environmental characteristics were collected through a questionnaire administered by a trained research nurse. A total of 605 women and neonate pairs were recruited into the study. However, 40 were excluded from the serum PFAS analysis due to a lack of biological samples, yielding a final study population of 565. ® (REF # 367614). The red-top vacutainer containing the whole blood was then left to stand at room temperature for about 60 min for complete clot formation before centrifugation at ≤1200× g (3276 rotations per minute) for 10 min at room temperature (18–25 °C). After centrifugation, the serum was transferred to two glass tubes with green lids  using a disposable glass pipette. Transfer of serum to the green-lid tubes was performed with caution to avoid pipetting the red cells along with the serum. All collected biological samples were stored in a freezer at a temperature between −35 °C and −20 °C before being shipped to University Hospital of North Norway (UNN), Department of Laboratory Medicine, for analysis.Blood samples were collected from the mothers at an optimal time before delivery (36 ± 12 h prior to delivery). Methods for collection and transportation of whole blood and serum samples were adapted from CTQ Laboratory guidelines, Quebec, Canada . In brie4OAc in MilliQ-water and 2 mM NH4OAc in methanol as mobile phase. Quantification was conducted by applying the Masslynx and Targetlynx software  and achieved by the internal standard method with isotope-labelled PFASs. Method quantification level (MQL) was defined as ten times a signal-to-noise ratio or three times the limit of detection (LOD). LODs (minimum limit of detection) were set as concentrations calculated by the Targetlynx software for each individual sample (LODi) and each individual analyte with a signal-to-noise ratio of 3 divided by the related sample amount. Where blank contamination was detected (background contribution during sample preparation), a blank subtraction was performed batch wise by calculating an average of the blanks added to three times their standard deviation. An eight-point calibration curve with concentrations ranging from 0.01 pg/µL to 10 pg/µL was applied for quantification. Sample preparation, instrumental analysis, quantification and quality controls have been described in detail elsewhere . BrieflyAccuracy and precision of the method was described in detail in the associated method article . For qua3). Ponderal index was calculated using the following formula: ponderal index = weight(kg)/height3 (m3).Birth outcome variables measured in this study were gestational age (weeks), birth weight (kilograms), birth length (cm), head circumference (cm) and ponderal index (kg/mp < 0.05 (two-tailed) was set for all analyses. Statistical analyses were carried out using the Stata for Mac . A total of 24 compounds were analyzed, but most of the compounds were under the limit of detection. However, 6 out of the 24 PFASs analyzed compounds—namely PFOA, PFNA, PFDA, PFUDA, SumPFHxS and SumPFOS—had detection limits of over 60% and hence were used for the statistical analysis. Data were given as arithmetic means, standard deviation (SD), median, and minimum and maximum or proportion (%) for describing sociodemographic characteristics of the study population. A significance level of PFAS concentrations were log-transformed before assessing linear associations due to non-normal distribution of the concentrations among participants.The study was carried out following ethical rules and guidelines. Ethical clearance was obtained from the College of Medicine Research and Ethics Committee (COMREC)- Malawi (P.11/18/2546) and REK-Norway (#355656 2020). Permission to conduct the study at the selected sites was sought from Blantyre , Chiradzulu (for CDH) and Thyolo (for TDH) district health offices. Participation in the study was voluntary, based on signed written consent from the mother. Confidentiality was maintained by assigning pseudo-anonymized identification numbers to all study participants. The sampling of blood and extraction of information did not interfere with the health service delivery process and took place either before or after delivery, depending on the individual circumstances of each study participant.The selected maternal sociodemographic characteristics of the n = 605 individuals are presented in Participants ages ranged from 16 to 45 years, with a mean (SD) age of 24.8 (6.2) years. Out of the 605 participants recruited, 308 pregnant women were recruited from urban  and 297 from rural  settings. In this regard, mean age of the pregnant women recruited from the urban setting was almost 2 years older than those from rural areas, with a mean of 25.6 (SD = 6.7) and 23.9 (SD = 5.7) years of age, respectively. Similarly, the mean age of spouses from the urban setting was 30.7 (SD = 6.4) versus 28.1 (SD = 7.8) for rural. The data showed a significant difference in gravidity, parity and educational levels between the two groups. In this regard, nulliparity was significantly high in rural areas. Para 1 and multiparty were statistically high in urban areas as compared to rural.Over half (69.7%) of the women from the rural areas either did not attend any formal school or were educated up to primary level only as compared to only 38.6% from the urban area. Furthermore, a vast proportion (61.4%) of those recruited from the urban area attained education up to secondary or tertiary level, while only 30.3% from the rural area attained such levels. A high percentage of women (96.8%) residing in the urban areas used tap water as their source of drinking water in comparison to only 8.1% from the rural locations. Shallow wells and boreholes were the most common  sources of drinking water for the rural study participants. A total of 572 neonates were recruited in this study. Out of this, 296 were boys (51.8%). The mean birth weight, length and head circumference were 3.09 kg, 45.28 cm and 33.15 cm, respectively, in the overall sample. Detailed information about neonates according to area of residence  is also outlined in Six out of the twenty-four PFASs analyzed compounds—PFOA, PFNA, PFDA, PFUDA, SumPFHxS and SumPFOS—had detection limits of over 60% and hence were used for the statistical analyses. Multiple linear regression analysis of maternal sociodemographic/lifestyle characteristics versus the concentrations of different PFASs provided a relatively comprehensive description of the main maternal risk factors related to serum PFAS levels .p = 0.003), PFUDA  and SumPFOS  serum concentrations. Conversely, high concentrations of SumPFHxS were associated with living in rural areas . However, there was no statistically significant inverse association between serum PFNA and PFDA concentrations and area of residence.Adjusted for maternal age, parity, maternal educational level, area of residence  and source of drinking water, living in the rural setting was associated with decreased maternal PFOA . Similarly, a negative association was also observed between In_PFOA and birth length . Conversely, a positive association was observed between In_PFOA and ponderal index . No associations were observed between In_PFOA and birth weight or gestational age in both models.Multiple linear regression analysis of birth outcomes and maternal serum PFAS concentrations shows the possible associations between different maternal serum PFAS concentrations and birth weight, head circumference, birth length, gestational age and ponderal index. These results were examined by multiple regression analysis while adjusting for maternal age, area of residence , maternal educational level, parity and source of drinking water . A statip = 0.001). Similarly, negative associations were also observed between In_PFNA and birth length  and gestational age . However, there was no statistically significant association between In_PFNA and birth weight and ponderal index. Furthermore, a statistically significant negative association was observed between natural log of maternal serum SumPFHxS (In_SumPFHxS) concentrations and birth weight . Similarly, an inverse statistically significant association was observed between In_SumPFHxS and ponderal index .There was a statistically significant negative relationship between natural log-transformed maternal serum PFNA concentrations (In_PFNA) and head circumference . An inverse association was also observed between In_SumPFOS and gestational age . Conversely, statistically significant positive associations were observed between In_PFOA and ponderal index . A similar trend was also detected between In_SumPFHxS and head circumference .Another statistically significant negative association was observed between the natural log of SumPFOS (In_SumPFOS) serum concentrations and birth weight  were mostly inversely associated with some, but not all, birth outcomes. There were very few notable positive associations between PFASs and birth outcomes as follows: SumPFHxS with head circumference (cm) and PFOA with ponderal index.Maternal serum PFOA, PFDA and PFUDA concentrations observed in this study were lower compared to other studies from Sweden, Norway, Canada, Spain, Russia, Uzbekistan and Denmark ,29,30,31The median for maternal SumPFOS concentrations observed in the present study 0.533 ng/mL) was slightly lower that the levels observed in Ushuaia and Salta  regions in Argentina  ng/mL wa. The undArea of residence was one of the main determinants for the blood serum PFAS concentrations, with higher blood serum PFOA and PFNA concentrations detected in those living in urban areas than those living in rural areas. This difference could be explained by differences in socioeconomic conditions and lifestyles, including dietary habits. PFASs are used in many industrial and consumer applications such as textile impregnation, paper production, fire-fighting foam, lubricants production and electroplating . These cDrinking water is known to be one of the main sources of PFASs exposure for humans ,35,36,37p > 0.05). These results are consistent with the Brazilian Ribeirão Preto (BRISA) study and a systematic review that included results from nine different studies that found no significant association between PFOA and birth weight [p = 0.009). Similarly, the meta-analysis of 23 papers conducted by Yang et al. [p < 0.001). However, the results showed a statistically significant inverse association between maternal serum PFOA concentrations and head circumference. Furthermore, there was also an inverse association between PFOA concentrations and length at birth. Various research studies have shown that both PFOA and PFOS can cross the placental barrier ,42,43,44h weight ,46. In cg et al.  also fouIncreased maternal serum PFNA concentrations in the present study were statistically associated with low birth weight. This finding was similar to the study conducted in Spain by Manzano-Salgado et al. . HoweverMaternal serum SumPFHxS concentrations showed a statistically significant association with low level of education. This association may be reflective of behavior and lifestyle factors associated with socioeconomic status. Unexpectedly, a statistically significant positive association was observed between maternal SumPFHxS concentrations and head circumference. This is in contrast to a study by Xiao et al.  that obsOur study has several important strengths. To our knowledge, this is the first study assessing PFAS concentrations in delivering women from Malawi. In this regard, our study provides highly valuable benchmark information on PFAS exposure status of delivering women from Malawi. Furthermore, our study contributes to a body of knowledge on the rather underrepresented research area on PFAS from the African continent. Different socioeconomic status and lifestyle sites were included in the present study, hence providing a representative sample for all settings. Furthermore, we measured a panel of 24 PFASs, including PFDA, PFNA and PFHxS, which have not been as extensively studied as PFOA and PFOS. We also acknowledge several limitations of our study. The number of patients assessed for eligibility matched the sample size calculation. However, some participants refused to have their blood sample collected, which reduced the total number of data analyzed in the final data set. However, we assumed that this would not have a significant effect on the power of the current study.The present study explores and presents PFAS concentrations among delivering women in Malawi. Area of residence was the predictor for high concentrations of PFASs detected in serum of women from urban settings. Maternal serum PFAS concentrations were associated with some but not all birth outcomes. PFAS concentrations assessed in the present study, except SumPFHxS, are lower as compared to other parts of the world. Follow-up studies are needed to evaluate the association between the source of drinking water and maternal serum PFAS concentrations. There is a need to conduct further investigations on PFHxS as it follows a totally different pattern compared to similar compounds and many other cohorts.


Effective intraoperative image navigation techniques are necessary in modern neurosurgery. In the last decade, intraoperative ultrasonography (iUS), a relatively inexpensive procedure, has gained widespread acceptance.To document and describe the neurosurgery cases, in which iUS has been employed as the primary navigational tool. This includes a discussion of the advantages that iUS may possess relative to other forms of neuronavigation.The application of iUS as an intraoperative navigation tool during neurosurgery holds great potential as it has been shown, relative to other neuronavigation techniques, to be quick, repeatable, and able to provide real-time results. The ideal intraoperative navigational modality for neurosurgeons is the one that is accurate, user-friendly, and most of all cost-efficient –4. Over https://docs.google.com/forms/d/e/1FAIpQLSfqHcExcft3FwcTKiKb2A0b5i828UhnoXe1smoXPDIdH6_g/viewform?usp=sf_link ] iUS neuro-navigation. We applied a Linear-type and convex transducer  and conversely hyperechoic in tissues with high enchogenicity, such as in gliomas, calcifications, meningiomas, and vascular anatomical structures, such as the choroid plexus . ImagingThere are 41 neurosurgeons, 33 males, and eight females, from 15 countries, 12 of whom were from low-and-middle-income countries (LMIC), while three were from middle-income (MIC) and high-income countries (HIC). Regarding years of experience, 73.8% had, at most, 5 years of working experience as neurosurgeons, being relatively junior residents, while 26.2% had at least 6 years of working experience, being individuals at the registrar to consultant professor level.All the surgeries were performed by Professor Albert Sufianov at the Federal Center of Neurosurgery, Tyumen, Russia, with the assistance of the same surgical team. Intraoperative ultrasonography was performed after the craniotomy, both before and after opening the dura mater.Low-grade subcortical gliomas can be difficult to locate after the dura mater has been opened. However, as shown in One of the key challenges during the surgical treatment of high-grade gliomas is the achievement of the optimum balance between maximizing the resection of the lesion and minimizing the effect on healthy tissue . It is in this regard that iUS demonstrates one of its key strengths in being able to provide real-time information on the lesion's location and boundaries. On iUS, they demonstrate varying levels of echoicity and are normally heterogenic. Despite being able to detect deep HGGs, intraoperative evaluation of the extent of resection of deep high-grade gliomas may be challenging when in B-mode iUS. This is because both malignant tumor tissue and peritumoral edema are hyperechoic . This poIn The iUS can be used to visualize a range of vascular abnormalities, including arteriovenous malformations (AVM). We illustrate our experience in a case of a 17-year-old female who presented with seizures and worsening headaches. Preliminary CT and MRI were suggestive of a 4-cm left occipital AVM (Spetzer Martin Grade 3). The iUS's Doppler mode allows for the precise imaging of arterial feeders and venous drainage. This mode is extremely valuable in AVM surgery because it depicts vascular flow in real-time. Locating the main arteries and veins of a tumor, as well as the patency of the venous sinuses and proof of the tumor's vascularity, aids in safe removal .The iUS is fairly useful for determining the level and localizing the lesion during spine surgery. We have had remarkable success using iUS for both extramedullary and intramedullary lesions, such as neurofibromas, ependymomas, and astrocytomas, in both extramedullary and intramedullary settings. The iUS can be used to safely aid and remove tumor successfully through the surgery, without disturbing the flow of surgery. The iUS made it easier to confirm tumor location and extension, plan myelotomy, and estimate the extent of the lesion .One of the most common causes of drug intractable epilepsy is focal cortical dysplasia (FCD). In epilepsy surgery, considering that normal and dysplastic brain tissues are often indistinguishable, we have utilized iUS to localize epileptogenic lesions and, thereby, improve surgical outcomes. Cortical characteristics demonstrated perfect concordance between iUS  and MRI T2-weighted/FLAIR images , especially in Focal cortical type II. The lesion margins on IUS pictures are even clearer than on MRI images. As a result, we believe that iUS is a valuable tool for epilepsy surgery .As a neuro-navigation modality, iUS navigation in neurosurgery requires a review in terms of utility and user-friendliness, assisting resection extent, and financial burden in terms of purchasing it in neurosurgical centers. The survey conducted suggested there appears to be widespread global availability and familiarity with iUS. Additionally, the general opinion appears to be that the application of iUS during neurosurgery provides relatively quick and accurate information on lesion location and boundaries without negatively affecting intraoperative workflow. The investigators have observed that the introduction of high-resolution iUS during neurosurgery at the study site has provided a relatively convenient and user-friendly modality for intraoperative identification, localization, and characterization of neurosurgical lesions.Relative to other modes of intraoperative neuronavigation such as MRI and CT-scan, some of the key features and potential advantages of iUS that the investigators have noted include:Provision of real-time information on lesion location and extent even in the face of “brain shift”; This maximizes lesion resection while minimizing the negative effects on surrounding healthy tissue.Significant reduction in surgical time. A time duration evaluation use of intraoperative MRI was evaluated in a study conducted by Sacino et al. Their study observed that they had an operative time range of 1.5–3 h of additional surgery as a result of the technicalities of performing iMRI. The preparation and transportation of the patient to the MRI cabinet, conducting the MRI, and returning to the operation room were major factors that contributed to additional operative time. Additionally, when back in the theater, re-sterilization, and re-gowning of the patient, nurses, and surgeon compounded into the time factor . This waCost-effectiveness about acquisition, running, and maintenance of iUS apparatus – It is important to appreciate that the prohibitively high costs associated with CT- and MRI-based neuronavigation techniques limit their availability and use in LMICs .Non-invasive nature and associated safety for both patient and neurosurgeon.Intraoperative repeatability.Unfortunately, as is the case with any technique applied in many fields, iUS has some disadvantages, key of which is the steep learning curve. However, the investigators are of the opinion that the rate at which different surgeons will acquire the skill to effectively employ iUS is largely a function of their years of surgical experience , 9.The application of iUS in neurosurgical practice will continue to evolve in the face of improvements in surgical techniques, as well as new and improved technologies.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.KS, RS, II, and AS: conceptualization. KS, LB, and LM: data curation. KS, AS, and RS: formal analysis. KS: investigation and project administration. RS and LB: resources. LB, RS, II, and LM: software. LB and LM: supervision. KS, RS, and II: validation. KS and RS: roles/writing—original draft and writing—review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Os odontoideum is a rare abnormality of the upper cervical spine, and os odontoideum associated with a retro-odontoid cyst has been described as a marker of local instability.This paper reports a case of a 52-year-old female patient who was diagnosed with os odontoideum associated with a retro-odontoid cyst. The patient underwent posterior C1–C3 fixation without surgical removal of the cyst. Magnetic resonance imaging (MRI) two days later revealed that the retro-odontoid cyst was still present and that there were no significant changes to it when compared with the preoperative MRI.Retro-odontoid cysts associated with unstable os odontoideum can lead to symptomatic spinal cord compression. Posterior C1–C3 fixation can restore atlantoaxial stability by allowing the gradual resorption of the cyst and ensuring spinal cord decompression. Fixation can also avoid the surgical risk associated with a high-riding vertebral artery. Os odontoideum is a rare malformation of the upper cervical spine, and its combination with a retro-odontoid cyst has been described as a marker of local instability. Different terms are associated with retro-odontoid structures involving spinal cord compression, including mass, cyst, pseudotumor, granuloma, and pannus. It is also thought that the atlantoaxial instability related to os odontoideum may prompt the appearance of a retro-odontoid cyst. The nonspecific symptomatic indications of the two together are erratic and vary from cervical pain to neurological disorders , 2.This paper reports a case of os odontoideum associated with a retro-odontoid cyst that was treated with posterior C1–C3 fixation without surgical removal of the cyst. Using magnetic resonance imaging (MRI) that was performed immediately and three months after the fixation operation, it was found, for the first time, that the retro-odontoid cyst did not disappear immediately but was gradually resorbed.A 52-year-old female patient had displayed numbness (paresthesia) and weakness in her limbs for 3 months. No hemodynamic or respiratory complications were observed during her initial care, and a neurological examination indicated a AIS was D  , and a cTo evaluate the existence of any recent neurological disorders, a cervical MRI was performed, which led to the discovery of a retro-odontoid cyst with T2 hyperintensity and T1 hypointensity. The cyst was exerting pressure on the spinal cord, and the intramedullary T2 hyperintensity signified a spinal cord disorder . Figure It was decided to perform a C1–C3 fixation , and, twOs odontoideum was first described by Giacomini in 1886. This abnormality is an anatomical variation of the C2 odontoid process and defined as a small bone of varying size with a smooth margin of the surrounding cortex, separated from the axis.The etiology of os odontoideum remains controversial but is focused on congenital and acquired causes. With respect to the former, the disorder is often associated with congenital malformations such as Klippel–Feil syndrome, trisomy 21 syndrome, Morquio syndrome, or neurofibromatosis. In terms of the latter, an insufficient arterial blood supply and unrecognized or repeated minor trauma, resulting in transverse ligament contracture, have been found to result in secondary odontoid base contraction , 7.A synovial cyst is a cystic mass lined with pseudo-lamellar columnar cells and containing clear or yellow fluid. Although synovial cysts often occur in the lumbar spine, they rarely occur in the inferior cervical axis and rarely involve the odontoid process. The cause of posterior odontoid cysts is unknown, but previous studies have suggested that these cysts are associated with growth of synovial rests, pluripotent stromal cell proliferation, atlantoaxial instability, and trauma . The assComputed tomography and MRI are of great significance in the diagnosis of this type of cyst, which produces a low T1 signal and a high T2 signal. Cysts may also appear black on T2-weighted MRI, possibly due to bleeding and blood products. Peripheral angiographic enhancement is also common, which may be linked to the adjacent epidural plexus. However, cervical synovial cysts cannot be accurately distinguished from other lesions by MRI features, and in many cases, accurate diagnosis can only be made after surgery –32.Hypoplasia of the odontoid associated with an independent oval ossicle, with smooth margins widely separated from the C2 vertebra and well above the superior facets of the axis, is termed os odontoideum. It is a rare condition with a controversial pathogenesis and poorly understood natural history. The neurological manifestations of os odontoideum arise from bulbospinal compression both at rest and during motion due to craniovertebral junction (CVJ) instability. Consequently, the surgical management of os odontoideum should aim at achieving both neural decompression and stabilization of the CVJ .With regard to anterior decompressive procedures, in particular, it has been widely reported that alternative transoral decompressive strategies have been improved with the introduction of endoscopy, neuronavigation, exoscopy, and intraoperative neuroradiological assessment such as the O-arm CT scan. All these approaches contribute to reducing the invasiveness of decompressive procedures and increasing their effectiveness –37. In aIn 2021, Goel  searchedIn the case reported here, the immediate postoperative MRI showed that the retro-odontoid cyst was still present and had not changed significantly from that of the preoperative MRI findings. However, at the 3-month postoperative follow-up, the MRI confirmed the complete disappearance of the retro-odontoid cyst and the decompression of the spinal cord. This demonstrated, for the first time, that the retro-odontoid cyst did not disappear immediately after surgery but was gradually resorbed.Retro-odontoid cysts associated with unstable os odontoideum can lead to symptomatic spinal cord compression, but posterior C1–C3 fixation can restore atlantoaxial stability. This approach will allow for the gradual resorption of the cyst postoperatively and ensure spinal cord decompression, and it can also avoid the inherent risks of an operation to remove a cyst when the vertebral artery is high-riding.


Data consisted of 10,423 VLBW infants from the Korean Neonatal Network database during January 2013–December 2017. Five adverse birth outcomes were considered as the dependent variables, i.e., gestational age less than 28 weeks, gestational age less than 26 weeks, birth weight less than 1000 g, birth weight less than 750 g and small-for-gestational age. Thirty-three predictors were included and the artificial neural network, the decision tree, the logistic regression, the Naïve Bayes, the random forest and the support vector machine were used for predicting the dependent variables. Among the six prediction models, the random forest had the best performance . According to the random forest variable importance, major predictors of adverse birth outcomes were maternal age (0.2131), birth-month (0.0767), PM10 month (0.0656), sex (0.0428), number of fetuses (0.0424), primipara (0.0395), maternal education (0.0352), pregnancy-induced hypertension (0.0347), chorioamnionitis (0.0336) and antenatal steroid (0.0318). In conclusion, adverse birth outcomes had strong associations with PM10 month as well as maternal and fetal factors.This study aimed to analyze major predictors of adverse birth outcomes in very low birth weight (VLBW) infants including particulate matter concentration (PM The burden of preterm birth including its mortality and morbidity seems to be increasing in most countries3. Neonatal intensive care has advanced over the last few decades but extremely preterm  or extremely low birth weight  infants have been subjected to death, neonatal complications or long-term neurodevelopmental impairment6, which presents a great challenge for the health care system as well7. Small for gestational age (SGA) is another significant contributor for the global burden of preterm birth9 and it is very important to identify the risk factors of these adverse birth outcomes above.Preterm birth brings a significant disease burden for infants and children in the world. On a yearly basis, fifteen million newborns are preterm on the globe and this is a major cause of one million deaths among those aged 0–4 years in the world11. This is particularly notable in a country such as Korea, where air pollution including particulate matter (PM) has registered rapid growth over the past few decades along with rapid industrialization and urbanization. Especially, maternal exposure to PM is reported to be a major cause of adverse health outcomes. Maternal exposure to PM2.5  or PM10  is found to have positive relationships with preterm birth17 and low birth weight20. However, little literature is available on associations between maternal exposure to PM and more adverse birth outcomes such as EP, ELBW or SGA. Furthermore, no endeavor has been made regarding the utilization of machine learning for the prediction of adverse birth outcomes among very low birth weight  infants. In this context, this study employed machine learning and a national prospective cohort registry database to examine main predictors of adverse birth outcomes in VLBW infants including PM10 as a marker of air pollution.On the other hand, air pollution has become an important health issue in the world, increasing global mortality and morbidity. In 2016, ambient air pollution resulted in 4.2 million premature deaths worldwideGA < 28, GA < 26, BW < 1000, BW < 750 and SGA, respectively. Indeed, the mean and standard deviation of maternal age were 31 and 4.28, respectively. Monthly PM10 (micrograms per cube meter) were 52 (January), 49 (February), 60 (March), 57 (April), 60 (May), 43 (June), 35 (July), 34 (August), 34 (September), 38 (October), 47 (November) and 48 (December). Yearly PM10 (micrograms per cube meter), temperature average (degree Celsius), temperature min (degree Celsius) and temperature max (degree Celsius) in 2013, 2014, 2015, 2016 and 2017 were: 48, 46, 48, 48 and 47 for yearly PM10; 12.85, 14.10, 13.85, 14.80 and 14.60 for yearly temperature average; 7.35, 8.55, 8.50, 10.05 and 9.30 for yearly temperature min; and 19.05, 20.50, 20.05, 20.45 and 20.65 for yearly temperature max. The results of univariate analysis were presented in Table P values were smaller than 0.10 for the following variables: birth-month with GA < 28, GA < 26, BW < 750 and SGA; sex  with GA < 28, GA < 26, BW < 1000 and BW < 750 (positive relationship); number of fetuses with GA < 28, GA < 26, BW < 1000 and BW < 750 (negative relationship); maternal age with SGA (positive relationship); and PM10 month with BW < 1000 and BW < 750 (positive relationship).Descriptive statistics are shown for participants’ adverse birth outcomes and their predictors in Table 10 excluded) and 0.72 (PM10 included), were higher than its logistic-regression counterparts, 0.69 (PM10 excluded) and 0.68 (PM10 included). Based on random forest variable importance in Table 10 excluded), main predictors of adverse birth outcomes were maternal age (0.2276), birth-year (0.1216), birth-month (0.1165), sex (0.0415), number of fetuses (0.0404), primipara (0.0373), maternal education (0.0361), pregnancy-induced hypertension (0.0325), chorioamnionitis (0.0319) and antenatal steroid (0.0307). Likewise, according to random forest variable importance in Table 10 included), major predictors of adverse birth outcomes were maternal age (0.2131), birth-month (0.0767), PM10 month (0.0656), sex (0.0428), number of fetuses (0.0424), primipara (0.0395), maternal education (0.0352), pregnancy-induced hypertension (0.0347), chorioamnionitis (0.0336) and antenatal steroid (0.0318)  ranked 4th and 5th in BW < 1000 and BW < 750, respectively; pregnancy-induced hypertension (8th on average) ranked 4th in SGA; and chorioamnionitis (9th on average) ranked 4th in GA < 28. Also, it needs to be noted that maternal education ranked within the top 10 across board.The performance of the random forest was the best among the six models in this study Table . Its arenth 0.116, sex  database in VLBW infants. Among the six prediction models for adverse birth outcomes, the random forest had the best performance . According to the random forest variable importance, major predictors of adverse birth outcomes were maternal age, birth-month, PM10 had affect to EP, ELBW and SGA. Environmental changes according to the month such as air pollution, ambient temperature, the synthesis of vitamin D from sunlight could affect the adverse birth outcomes. Recently, existing literature reports the positive association of adverse birth outcomes with maternal exposure to PM during specific trimester or entire pregnancy22. A meta-analysis study reported that PM10 was found to increase extremely preterm birth21, and in particular, the incidence of preterm birth increased in Asia with high concentration of air pollution22. Unlike previous studies, this study found that high air pollution exposure in the birth month, rather than specific trimester or entire pregnancy period, was strongly associated with adverse birth outcomes. This result was consistent with some previous studies that maternal exposure to PM during the birth month was a major risk factor for adverse birth outcomes24. A time-series study conducted by Liu et al. showed that short term exposure to air pollution one week before childbirth increased preterm birth23. In addition, Trasande et al.'s air pollution research model showed that PM2.5 concentration in the birth month was associated with low birth weight and VLBW24. A possible pathway between maternal exposure to PM and adverse birth outcome would be oxidative stress, placental dysfunction, endothelial dysfunction and abnormal fetal growth26. But more examination is to be done on this issue.In this study, birth month and PM27, which suggests the following mechanism: In the presence of a male fetus the trophoblast causes a more pro-inflammatory environment, and the maturation of the fetal hypothalamic–pituitary–adrenal axis and the expression of placental genes follow sex-dependent patterns.Sex  was the fourth most important predictor for adverse birth outcomes in VLBW infants in this study. This result is consistent with a recent review28. One way to explain this discrepancy is that more active prenatal screening and monitoring were done in the case of multiple fetuses in this study: Pregnancy with multiple fetuses often involves in vitro fertilization, which can associate with high socioeconomic status and active prenatal care29.The number of fetuses was found to have a negative association with adverse birth outcomes in VLBW infants in this study. This finding does not agree with a recent review, which reports that the number of fetuses is a strong risk factor for adverse birth outcomeMaternal age was the first most important predictor for adverse birth outcomes in VLBW infants but the result of univariate analysis was significant only for SGA in this study. The participants of this study were limited to VLBW infants and more investigation based on broader participants is to be done for more conclusive result.SGA; and chorioamnionitis (ninth on average) ranked fourth in GA < 28. Chorioamnionitis is considered to be a major predictor of preterm birth31. It is expected to encourage pro-inflammatory cytokines, uterine contraction and preterm labor; or it is supposed to promote matrix metalloproteinase activation, fetal membrane degradation and preterm birth32. Also, early onset preeclampsia is reported to cause abnormal placentation and spiral artery remodeling, which in turn lead to restriction on blood flow to uterine arteries and abnormal fetal growth35.Some predictors were outside the top 5 on average but within the top 5 in certain adverse birth outcomes in this study: pregnancy-induced hypertension (eighth on average) ranked fourth in 36.Firstly, this study did not analyze possible mediating effects among predictors. Secondly, this study adopted the binary categories of adverse birth outcomes , which can be extended to multiple categories with more clinical insights. Thirdly, it was beyond the scope of this study to investigate a variety of mechanisms between PM and adverse birth outcomes. Little effort has been made and more examination is needed in this direction. Fourthly, synthesizing different modes of machine learning methods for different types of adverse birth outcome data would break new ground on this topic. Fifthly, this study did not consider indoor enviromental factors, which were reported as major predictors of adverse birth outcomes along with PM10 month on adverse birth outcomes in VLBW infants using machine learning. Adverse birth outcomes such as EP, ELBW or SGA have strong associations with PM10 month as well as maternal and fetal predictors among the VLBW infants. For the prevention of adverse effects on birth outcomes, clinical and/or policy measures are needed regarding these predictors.The current study is the first to evaluate the predictors including PM37.Data consisted of 10,423 VLBW infants from the Korean Neonatal Network (KNN) database during January 2013-December 2017. The KNN started on April 2013 as a national prospective cohort registry of VLBW infants admitted or transferred to neonatal intensive care units across South Korea . It collects the perinatal and neonatal data of VLBW infants based on a standardized operating procedureGA < 28), GA less than 26 weeks (GA < 26), birth weight less than 1000 g (BW < 1000), BW less than 750 g (BW < 750) and SGA. Thirty-three predictors were included: sex—male , birth-year , birth-month , birth-season-spring , birth-season-summer , birth-season-autumn , birth-season-winter , number of fetuses , in vitro fertilization , gestational diabetes mellitus , overt diabetes mellitus , pregnancy-induced hypertension , chronic hypertension , chorioamnionitis , prelabor rupture of membranes , prelabor rupture of membranes > 18 h , antenatal steroid , cesarean section , oligohydramnios , polyhydramnios , maternal age (years), primipara , maternal education , maternal citizenship , paternal education , paternal citizenship , unmarried , congenital infection , PM10 year (PM10 for each year), PM10 month (PM10 for each birth-month), temperature average (for each year), temperature min (for each year) and temperature max (for each year). PM10 and temperature data came from the Korea Meteorological Administration . The definition of each variable is given in Text Five adverse birth outcomes were considered as binary dependent variables , i.e., gestational age less than 28 weeks , an outcome of the test (branch) and a value of the dependent variable . A naïve Bayesian classifier performs classification on the basis of Bayes’ theorem. Here, the theorem states that the probability of the dependent variable given certain values of independent variables can be calculated based on the probabilities of the independent variables given a certain value of the dependent variable. A random forest is a collection of many decision trees, which make majority votes on the dependent variable (“bootstrap aggregation”). Let us take a random forest with 1000 decision trees as an example. Let us assume that original data includes 10,000 participants. Then, the training and test of this random forest takes two steps. Firstly, new data with 10,000 participants is created based on random sampling with replacement, and a decision tree is created based on this new data. Here, some participants in the original data would be excluded from the new data and these leftovers are called out-of-bag data. This process is repeated 1000 times, i.e., 1000 new data are created, 1000 decision trees are created and 1000 out-of-bag data are created. Secondly, the 1000 decision trees make predictions on the dependent variable of every participant in the out-of-bag data, their majority vote is taken as their final prediction on this participant, and the out-of-bag error is calculated as the proportion of wrong votes on all participants in the out-of-bag data39.The artificial neural network, the decision tree, the logistic regression, the Naïve Bayes, the random forest and the support vector machine were used for predicting preterm birth39. Data on 10,423 observations with full information were divided into training and validation sets with a 70:30 ratio (7296 vs. 3127). Accuracy, a ratio of correct predictions among 3127 observations, was employed as a standard for validating the models. Random forest variable importance, the contribution of a certain variable for the performance (GINI) of the random forest, was used for examining major predictors of adverse birth outcomes in VLBW infants including PM10. The random split and analysis were repeated 50 times then its average was taken for external validation45. R-Studio 1.3.959  was employed for the analysis during August 1, 2021–September 30, 2021.A support vector machine estimates a group of “support vectors”, that is, a line or space called “hyperplane”. The hyperplane separates data with the greatest gap between various sub-groups. An artificial neural network consists of “neurons”, information units combined through weights. In general, the artificial neural network includes one input layer, one, two or three intermediate layers and one output layer. Neurons in a previous layer link with “weights” in the next layer . This “feedforward” operation begins from the input layer, runs through intermediate layers and ends in the output layer. Then, this process is followed by learning: These weights are updated according to their contributions for a gap between the actual and predicted final outputs. This “backpropagation” operation begins from the output layer, runs through intermediate layers and ends in the input layer. The two processes are repeated until the performance measure reaches a certain limitThe KNN registry was approved by the institutional review board (IRB) at each participating hospital . Informed consent was obtained from the parent(s) of each infant registered in the KNN. All methods were carried out in accordance with the IRB-approved protocol and in compliance with relevant guidelines and regulations.The names of the institutional review board of the KNN participating hospitals were as follows: The institutional review board of Gachon University Gil Medical Center, The Catholic University of Korea Bucheon ST. Mary’s Hospital, The Catholic University of Korea Seoul ST. Mary’s Hospital, The Catholic University of Korea ST. Vincent’s Hospital, The Catholic University of Korea Yeouido ST. Mary’s Hospital, The Catholic University of Korea Uijeongbu ST. Mary’s Hospital, Gangnam Severance Hospital, Kyung Hee University Hospital at Gangdong, GangNeung Asan Hospital, Kangbuk Samsung Hospital, Kangwon National University Hospital, Konkuk University Medical Center, Konyang University Hospital, Kyungpook National University Hospital, Gyeongsang National University Hospital, Kyung Hee University Medical center, Keimyung University Dongsan Medical Center, Korea University Guro Hospital, Korea University Ansan Hospital, Korea University Anam Hospital, Kosin University Gospel Hospital, National Health Insurance Service Iilsan Hospital, Daegu Catholic University Medical Center, Dongguk University Ilsan Hospital, Dong-A University Hospital, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Pusan National University Hospital, Busan ST. Mary’s Hospital, Seoul National University Bundang Hospital, Samsung Medical Center, Samsung Changwon Medical Center, Seoul National University Hospital, Asan Medical Center, Sungae Hospital, Severance Hospital, Soonchunhyang University Hospital Bucheon, Soonchunhyang University Hospital Seoul, Soonchunhyang University Hospital Cheonan, Ajou University Hospital, Pusan National University Children’s Hospital, Yeungnam University Hospital, Ulsan University Hospital, Wonkwang University School of Medicine & Hospital, Wonju Severance Christian Hospital, Eulji University Hospital, Eulji General Hospital, Ewha Womans University Medical.Center, Inje University Busan Paik Hospital, Inje University Sanggye Paik Hospital, Inje University Ilsan Paik Hospital, Inje University Haeundae Paik Hospital, Inha University Hospital, Chonnam National University Hospital, Chonbuk National University Hospital, Cheil General Hospital & Women’s Healthcare Center, Jeju National University Hospital, Chosun University Hospital, Chung-Ang University Hospital, CHA Gangnam Medical Center, CHA University, CHA Bundang Medical Center, CHA University, Chungnam National University Hospital, Chungbuk National University, Kyungpook National University Chilgok Hospital, Kangnam Sacred Heart Hospital, Kangdong Sacred Heart Hospital, Hanyang University Guri Hospital, and Hanyang University Medical Center.Supplementary Information.


Nutritional care during the neonatal period is a cornerstone towards achieving optimal care. However, very limited data is available on optimizing parenteral and enteral nutrition that directly affects infant survival among Ethiopian neonates. Therefore, the objective of this study is to identify determinants of time to full enteral feeding achievement among low-birth-weight neonates admitted to neonatal intensive care units of public hospitals in Hawassa city.A facility-based retrospective cohort study was conducted in Adare general hospital and Hawassa University’s comprehensive specialized hospital from August 2018 to 2019. Charts of infants with a birth weight of 1000-2000g (n = 273) neonates who were admitted to the neonatal intensive care unit (ICU) were reviewed. The sample size for each hospital was allocated proportionally and subjects were selected by using a simple random sampling technique. Data were entered using Epi. data version 3.1, and analysis was performed using SPSS version 20. Kaplan-Meier estimator and a Cox proportional hazard model were used.The mean (SD) age when an enteral feed (trophic feeding) was first commenced was 2.13(1.373) days. The median time to achieve full enteral feeding was 8 days with IQR (7–10 days). Gestational age reduces the time to full enteral feeding by 18.8% for each additional week of gestation . The time to achieve full enteral feeding was shorter by 70.4% among neonates who were small for gestational age, as compared with that appropriate for gestational age .According to this study, the time that the neonate takes to achieve full enteral feeding was relatively short. Gestational age and weight for gestational were the determinants for time to full enteral feeding achievement. Further research needs to be conducted to explore further, in addition to current findings. During the neonatal period, nutritional care is a cornerstone towards providing optimal care to reduce the risk of short-and long-term adverse outcomes , 2. Low Nutritional care provided to LBW neonates, especially infants with a birth weight of 1000-2000g, is largely either parenteral or enteral nutrition or a combination of both . In mostStudies carried out in developed countries show that low birth weight-related morbidity and mortality can be substantially reduced by optimizing parenteral and enteral infant nutrition , 6, 11. Early introduction of enteral nutrition and rapid achievement to full enteral feeding is the ultimate goal for all low-birth-weight neonates in the nutritional care of preterm infants, as it reduces the need for central venous access and thus the risk of infection, and thereby reduces the length of hospital stay , 13. HowThe study was conducted in public hospitals in Hawassa city administration, Sidama Ethiopia. Hawassa is the administrative center of SNNPR and Sidama regional state. It is located 275 kilometers south of Addis Ababa. There are 3 public hospitals, 4 non-governmental hospitals, 11 Governmental and 1 non-governmental health center, and 7 diagnostic laboratories in the city. Hawassa university’s comprehensive specialized hospital and Adare general hospital were the two public hospitals that provided the service during the period. The Hawassa University’s comprehensive specialized hospital has a catchment population of 12 million people and it serves about 43,384 patients per year. The Pediatrics department of the hospital has a well-organized neonatal intensive care unit, including personnel and equipment. It provides continuous life support and comprehensive care for extremely high-risk newborn infants and those with complex and critical illnesses. Adare general hospital is not a teaching hospital but provides both preventive and curative services for more than 1,368,341 people. The neonatal ICU is one of the units in the hospital, which gives services under the pediatrics department. The hospital NICU gives all the services, including those with high-risk neonates, except those who need other specialties.A facility-based retrospective cohort study design was employed from November 2019 to December 2019.All infants with a birth weight of 1000-2000g who were admitted to the neonatal ICU of public hospitals in Hawassa city, Sidama region, Ethiopia.All randomly selected infants with birth weight 1000–2000 who were admitted to the neonatal ICU of public hospitals during the study period in Hawassa city, Sidama region, Ethiopia.All LBW newborns between 1000 and 2000 grams who were admitted to NICU within 24 hours of delivery in the selected public hospitalsAll infants with a birth weight of 1000-2000g who were admitted to NICU between August 2018 and 2019Had major congenital malformationsNever received enteral feeding because of their clinical conditions Died before initiation of enteral feedsRecords with missing or wrong data on all the predictors273.The sample size was calculated by using G* power and the following assumption were made while calculating the sample size. The degree of precision or margin of error chosen to be 0.05 with the reliability coefficient of 1.96 certainties (Z = 1.96), 80% power of the study, and 0.2 minimum effect size were taken. Then the final sample size was calculated to be Fig 1”.Public hospitals that are found in Hawassa city administration, Adare general hospital, and Hawassa university comprehensive specialized hospital (HUCSH) were included in the study because of the service they had in NICU during the specified period. Study inclusion criteria were used to select the study subject from the admission registration book of the two hospitals. Records from August 2018 to August 2019 were reviewed. The sample size was proportionally allocated for the two hospitals depending on the caseload assessed from the registration book for the year before this study. Simple random sampling was employed to draw the final sample size from the two hospitals as it permits a high degree of accuracy due to the limited area of operations of the neonatal ICU “Lost to follow-up: subjects drop out of a study for a reason unrelated to the study, such as infants moving or referred from the NICU, leaving against medical advice, and disappearing without leaving an address during the survival periodIncomplete card: when a variable could not be registered or missed on neonatal ICU feeding chart, internal referral paper, and infant medical cardSurvival time: Time in day that subjects (infants) spent since the start of trophic until full enteral feeding achievedCensored: Where subjects died after enteral feeding started, lost to follow-up (drop out), and failed to achieve full enteral feeding before 14 days of follow-upEvent (Failure): The time when infants with a birth weight of 1000-2000g neonates reached full enteral feedingA retrospective cohort enrollment was completed for infants who were admitted to NICU. The study follow-up period was 14 days. This time is considered the average time when low birth-weight infants started to regain their birth weight, and it is also considered the time when early full enteral feeding should be achieved .The data was collected using a checklist that was developed in English. Subjects were screened from the registration book by using a medical record number. Four NICU nurses who had a BSc degree in nursing and trained in NICU nurse’s training extracted data using the checklist; two medical doctors who have been working in NICU supervised the data collection.Data collectors were trained for one day about the whole course of data extraction, including familiarizing them with the tool, proper data handling, and organizing collected data. A pre-test was done on 10% of the study sample size in Yirgalem hospital neonatal ICU, which is closer but outside the proposed study area. The pre-test was used to test the clarity and understandability of the checklist.The variables and their definitions used for this study are listed below:Early-onset neonatal sepsis: Early-onset infections are acquired before or during delivery from birth to 7 days usually less than 72 hrs and diagnosed with Complete Blood Count with differential. Concern for sepsis if total WBC is abnormal  and differential with granulocytes >70%.Antenatal steroid: Antenatal corticosteroids (at least 24–48 hrs. before delivery) given to pregnant women < 34 weeks of gestational period. A complete course of antenatal steroids is diagnosed if a full dose (4 doses of dexamethasone 6mg and 2 doses of betamethasone 12mg) is taken and if a single dose of these drugs is missed, this refers to incomplete.Gestational age: was estimated by using the last normal menstrual period (LNMP) if the mother can recall her last cycle. If not, an ultrasound supported by Ballard scores is used to assess the physical and neuromuscular maturity of the newborn shortly after birth. This helps to make consistent decisions on gestational age.th percentile, appropriate for gestational age (AGA) those who are between the 10th and 90th percentile and large for gestational age (LGA) those greater than 90th percentile.Weight for gestational age (WFGA): was determined based on the International Newborn Size Standard charts and categorized the newborns as small for gestational age (SGA) whose weight for gestational age less than the 10Maintenance fluid: Immediately after birth, following admission, intravenous fluid (80–100 ml/kg/day) composed of 10% dextrose and water started as parenteral nutrition. This has to be advanced by 20 ml/kg/day for the next consecutive days depending on the hydration status of the infant. After the second day of life, other electrolytes like sodium chloride are considered in addition to glucose.Enteral nutrition: After 24–48 hours of postnatal age, enteral feeding started bilaterally with intravenous fluid as trophic. A small amount of expressed human breast milk or formula milk- 10-20ml/kg/day with a frequency of 3 to 4 times a day is introduced to stimulate and enhance gut function. Daily evaluation of feeding status done by a senior physician every morning and decision made on the way feeding progresses (progressive feeding). This includes escalating the feed by 10–20 ml/kg/day for the date, holding the feed, or keeping it at nothing per os (NPO). As the level of tolerance of the gut increases the need for intravenous fluid becomes less important. This results in reaching full enteral feeding, where intravenous fluid is discontinued and keep the feeding at the volume of 140–150 ml/kg/day or calories of 110–120 kcal/kg/day.Feeding intolerance (FI): is diagnosed when infants develop either one or more of the following abdominal conditions: vomiting more than 3 times in 24 hours, gastric residual more than 50% before the next feeding, altered aspiration on NGT or OGT  and abdominal distension with visible bowel .Necrotizing enterocolitis (NEC): this is considered if feeding intolerance progress in a worsened form and this may be supported by the unstable vital sign plus or minus abnormal abdominal radiography.The data was checked from the checklist for completeness and entered Epi. data version 3.1. The data was then exported to SPSS  version 20 for analysis. Data were cleaned, recorded, categorized, and sorted to facilitate the analysis. Demographic, obstetrics, and clinical characteristics of the study subjects were summarized using descriptive statistics. The Kaplan-Meier estimator was used to calculate the median time to achieve full enteral feeding. Variance inflation factor (VIF) <10 and tolerance statistics > 0.1, were used to conduct a Collinearity diagnostic test to check for the existence of multi-collinearity among the explanatory variables.A bivariate cox-proportional hazard regression model was used to analyze the association of factors with the time at which full enteral feeding was achieved. Variables that were associated with time to full enteral feeding at 0.25 significant levels in the bivariate model were included in the final multivariable model . MultivaThe ethical approval letter, with a reference number of IRB/270/12, was obtained from the Institutional Review Board (IRB) of the College of Medicine and Health Sciences, Hawassa University. The research involves minimal risk, as the review of subjects’ medical records is for limited information. Moreover, the information is not sensitive, and the data are derived from routine, clinically indicated procedures. The need for informed consent was waived or not required as we were doing a retrospective cohort study, and official permission was obtained from HUCSH and Adare general hospital ethical issue concerned bodies. Information that was collected was kept confidential through coding and omitting personal identification. The data were used for research purposes only. The study was conducted per the World Medical Association Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects.Of the 1017 medical records, (n = 5) were excluded due to major congenital malformations, (n = 192) due to records with missing data, (n = 215) due to death before initiation of enteral feeding, (n = 2) due to newborns never received enteral feeding because of surgical intervention. Among the eligible (603) medical records, 273 of them were extracted for the final analysis.Table 1”.Almost all (93.8%) of the mothers of infants were married; 39.6% of mothers were aged 21–25 years, and 49.1% were null parity. Six percent (5.5%) of the mothers did not have any ANC follow-up for the current pregnancy. More than half (55.3%) of the neonates were born by cesarean section (CS) and 19.8% of pregnancies resulted in multiple pregnancy outcomes. Among mothers of LBW infants, 50.2% of mothers had pregnancy-induced hypertension, and 26.4% of them had severe pre-eclampsia. About 40.3% of the mothers who were expecting preterm delivery received antenatal steroid prophylaxis. Among those who received antenatal steroid prophylaxis, only 23.1% of them completed the full course of the treatment. Furthermore, 12.5% of the mothers had a history of prolonged rupture of the membrane. However, only 3.2% of them developed complications and had chorioamnionitis “ out of 273 infants, 55.7% were male. The mean (SD) of gestational age (GA) and birth weight was 33.8 (1.3) weeks and 1578 (245.9) grams, respectively. Infants with a birth weight of 1000-2000g in this cohort, those whose birth weight is between 1000-1500g less likely to achieve full enteral feeding earlier than 1500-2000g with a mean value of 7.31 vs 5.72days, respectively “ Among those infants who were included in this study, 20.5% were small for their gestational age (SGA) (less than the 10th percentile). Of the neonates, 30.4% were treated for clinical sepsis . The Apgar score, determined in the 1st and 5th minutes, was low for 53.1% and 20.5% of infants, respectively. Respiratory distress syndrome was also diagnosed in more than half of low-birth-weight infants (53.2%). Of the participants, 7 (2.6%) and 9 (3.3%) were fed on formula and mixed types of milk, respectively “Table 2”.As shown in “Follow-up and full enteral feeding attainment patterns of the cohort, as shown in the figure below, from those who were in this cohort, 100(36.6%) were censored due to: death 83 (30.4%), losses to follow-up 6(2.2%), and not experiencing full enteral feeding attainment before the study end 11(4.02%). Of those who are in this cohort, 30.4% of them were dead after enteral feeding had started this is due to RDS, EONS, low Apgar score, etc. The mean (SD) of age when an enteral feed (trophic feeding) was first commenced was 2.13(1.373) days, and 63.4% of the neonates achieved full enteral feeding within 14 days., about 194 and 54 infants were likely to achieve full enteral feeding achievement on the 5th and 10th days of the follow-up, respectively.The median (IQR) time of attainment of full enteral feeding was 8 (7–10) days. The total person-time that the cohort yields in this study were 1,838 person-days (5.04 infant-years) of follow-up. The incidence rate of full enteral feeding achievement was calculated to be 9.4 per 100 person-day. As shown in “"To determine which variables, determine the full enteral feeding achievement, maternal and neonatal clinical and obstetrics characteristics were assessed for their association with full enteral feeding achievement using cox regression. Variables that passed the bivariate analysis and multi-collinearity test were included in the multivariate analysis. Variables such as sex, marital status, pregnancy-induced hypertension, multiple pregnancies, antenatal steroid prophylaxis, Apgar score (at 1st and 5th min), mode of delivery, birth weight, type of milk, and resuscitation at birth failed to pass bivariate analysis at p-value less than 0.25 Fig 4”. However, PROM, EONS, RDS, and neonatal hyperbilirubinemia were not statistically significant even if they were included in the last model “Table 4”.In the multivariate analysis, only gestational age and weight for gestational age were significantly associated with the time to full enteral feeding achievement. GA and WFGA were negatively associated with the time to full enteral feeding achievement. After adjustment for RDS, PROM, EONS and neonatal hyperbilirubinemia, GA reduces the time to full enteral feeding by 18.8%, GA ). Being small for gestational age (SGA) reduced the time to full enteral feeding achievement by 70.4% as compared to appropriate for gestational age (AGA) , p-value = <0.001). A subgroup analysis between AGA and SGA shows Test Statistics (TS) = -5.134, and p-value = <0.001 “The present study explored the time that infants with a birth weight of 1000-2000g spend in NICU to achieve full enteral feeding. This study found that more than sixty percent of infants with a birth weight of 1000-2000g achieved full enteral feeding within 14 days of the follow-up period. They demonstrate a shorter time to achieve full enteral feeding as compared to other studies.The median time to reach full enteral feeding was 8 days with IQR (7–10 days), and the mean GA was 33.8 weeks. This is much lower than that was reported from Italy but higher from India, 13 days IQR (7–24 days) with a mean GA of 29+1 week and 7 days IQR (7–9.5 days) with a mean GA of 30.8 weeks, respectively . There aAs expected, higher gestational age was a predictor for the fastest achievement of full enteral feeding. As GA increases in a week, the time to achieve full enteral feeding decreases by 18.8%. This is slightly lower than a study from Italy, which was 15.5%, even though it is difficult to compare up-front with the current study regardless of issues like patterns of low birth weight and clinical variability . There iWeight for gestational age (WFGA) was statistically significant, with full enteral feeding achievement. According to the result of this study, being small for gestational age (SGA) is protective- it reduces the time to full enteral feeding by 70.4% more than that of appropriate for gestational age (AGA). As previously mentioned, this may also be due to the gestational age difference in the category that increases gut development and maturation as gestational gets higher. Moreover, this could be due to failure in early initiation of enteral nutrition and advancement to full in infants with birth weight 1000-2000g with small GA, which is important in rapid maturation of the gastrointestinal system and lesserfeeding intolerance.There are a few similar studies that correlate being small for gestational age (SGA) with GI maturation. According to Patwardhan et al. , the timMihatsch et al. , also shAttempts should have been designed to address limited practices of parenteral and enteral nutrition in infants who are admitted to the NICU. This study finding may be used as evidence to improve enteral feeding practices that are needed to reduce the risk of short and long-term adverse outcomes for infants due to extended periods of hospital stay.Variable that has possible confounder effects were early-onset neonatal sepsis and respiratory distress syndrome this may be adjusted in a model of multivariate cox regression.The major limitation of this study is a high percentage of attrition and missing data as a result of being a retrospective study. Furthermore, the study is limited to some clinical variables which need an advanced clinical setup to find out participants’ characteristics.According to this study, the time that the neonate takes to achieve full enteral feeding was relatively short. Gestational age and weight for gestational were the determinants for time to full enteral feeding achievement. Further research needs to be conducted to explore further, in addition to current findings.


To investigate the postnatal growth trajectories of preterm infants and evaluate the association between extrauterine growth restriction (EUGR) at discharge and adverse physical growth outcomes at age 3–6 years.Premature infants admitted to Shanghai Children’s Medical Center within 24 h after birth from 1 January 2016 to 31 December 2018 were enrolled. Neonatal complications, nutrition support, and anthropometric data were collected and analyzed to diagnose EUGR on different definitions at discharge. The weight and the height of each subject were collected by telephone investigation from 1 September 2021 to 31 November 2021 to access the incidences of overweight/obesity, short stature, and thinness at age 3–6 years.Z-scores were –0.37 ± 0.97 SD and –0.29 ± 1.18 SD at birth, and increased to –0.03 ± 1.11 SD and 0.13 ± 1.2 SD at follow-up, respectively. The logistic regression analysis indicated longitudinal EUGR on head circumference as the risk factor of overweight or obesity, cross-sectional EUGR on height as the risk factor of short stature, and delayed EN as the risk factor of thinness.A total of 527 preterm infants were included in the final sample. The overall mean weight and height The growth trajectories of the preterm newborns tended toward the normal direction. Longitudinal EUGR on the head circumference and cross-sectional EUGR on height at discharge were associated with adverse physical growth outcomes at age 3–6 years. Extrauterine growth restriction (EUGR) refers to preterm growth failure which an anthropometric measure is below the standard based on the postmenstrual age  . As a reZ−scores>1 SD between birth and the assessment time (Z−scores in weight or length less than −2 SD at discharge) showed that at an average age of 3.9 ± 1.7 years, children with Z−scores in height, weight, and body mass index (BMI) below −2 SD still accounted for 12.6, 13.6, and 18.4% of the study population, respectively , group 2017 (n = 160), and group 2018 (n = 198) based on the birth year, with an average age of 5.35 ± 0.26 years, 4.34 ± 0.31 years, and 3.26 ± 0.28 years at follow-up, respectively. According to the growth material at follow-up, 79 children were classified as overweight/obesity, 20 as short stature, and 35 as thinness. Written informed consent was obtained from subjects’ parents. Approval from the Ethics Committee of Shanghai Children’s Medical Center was obtained. All methods were performed in accordance with the relevant guidelines and regulations.The retrospective, single-center study was conducted from 1 January 2016 to 31 December 2018 at a neonatal intensive care unit of Shanghai Children’s Medical Center affiliated to Shanghai Jiao Tong University School of Medicine. The criteria for enrollment were as follows: (i) Gestation age was less than 37 weeks, (ii) admission in 24 h after birth, and (iii) the length of the stay was more than or 7 days. The exclusion criteria were as follows: (i) Birth with major congenital anomalies, (ii) major surgery during hospitalization, (iii) death or discharge against medical advice, and (iv) incomplete medical records. The participants who were unable to contact or provide the precise information were regarded as loss to follow-up. A total of 527 subjects were included in the final sample and divided into group 2016  growth curve.Body measurements, clinical characteristics, and nutrition intakes during hospitalization were extracted from the electronic medical charts of each subject. Weight was measured without clothes daily by an electronic scale before feeding, and after changing diapers. Height and HC were measured by trained nurses weekly with non-stretch measuring tapes. Growth h charts . The cliThe nutritional schedules of all subjects were personalized by neonatologists and nutritionists depending on the physiological and pathological conditions. Enteral nutrition was initiated mostly at day 2 after birth, unless postponed or stopped by (i) digestive tract obstruction caused by congenital gastrointestinal malformation, (ii) suspected or diagnostic NEC, (iii) hemodynamic instability, and (iv) multiple organ dysfunction. Breast milk feeding was considered as the first choice for subjects and preterm formula milk was available to offset the lack or deficiency of breast milk. Inadequate EN intakes and EN calories more than or 80 cal/kg per day, respectively, were the signs of the initiation and discontinuation of PN, which was prescribed by nutritionists based on the Chinese guidelines for nutrition support in neonates from 2016 to 2017  and adjuZ−score (WAZ), height−for−age Z−score (HAZ), and HC−for−age Z−score (HCAZ) less than −1 SD at discharge, and longitudinal EUGR on weight, height, and HC are diagnosed as the decline of WAZ, HAZ, and HCAZ above 1 SD from birth to discharge, respectively (Z−score (BMIZ) below −2 SD as thinness based on the WHO growth curve , appropriate for gestational age (AGA), and large for gestational age (LGA) are defined as the birth weight less than 10th percentile, between 10th and 90th percentiles, and above 90th percentile, respectively, according to the Fenton 2013 growth chart  and compared using the Mann–Whitney U test or Kruskal−Wallis test. Comparison between the two of the three groups were performed by Bonferroni’s adjustments or Mann–Whitney U test. The contributing factors for the body-build of preterm infants at 3–6 years of age were estimated using a multivariate logistic regression (method: forward: LR). The factors with significant differences in group comparison were included as independent variables. Birth weight, longitudinal EUGR for HC, weight at discharge, changes in HCAZ during hospitalization, and changes in WAZ during follow-up were entered into the overweight/obesity model. Birth weight, SGA, cross-sectional EUGR for weight, height and HC, and changes in WAZ and HAZ during follow-up were entered into the short stature model. Days to start EN, and changes in WAZ and HAZ during follow-up were entered into the thinness model. The statistical significance was set at p < 0.05. All statistical data were analyzed using the SPSS statistical software package, version 22.0.The categorical variables were given as numbers (percentages) and compared using the Chi−squared or Fisher’s exact test. The normal distributed quantitative variables were expressed as mean ± SD and compared using the Student’s Inclusion and exclusion criteria of participants are presented in As shown in Z−scores in preterm infants are exhibited in Z−scores for weight, height, and HC from birth to discharge, and WAZ declined more sharply than HAZ and HCAZ. Both of WAZ and HAZ rebounded significantly and came close to zero at follow−up as shown in Changes in weight, height, and HC n = 169), group 2017 (n = 160), and group 2018 (n = 198) based on the admission time. Gestational age in group 2017 was significantly larger and the decrease in WAZ during hospitalization was less than other groups. In group 2018, more preterm newborns with lower birth weight and of multiple births were admitted and experienced longer hospital stays. There was no discrepancy among all groups in WAZ, HAZ, and HCAZ at birth, those at discharge, changes in WAZ and HAZ during follow-up, and the occurrence of short stature and overweight/obesity at follow-up among these groups.The general characteristics of preterm infants are presented in The characteristics of preterm infants with overweight/obesity, short stature, and thinness at age 3−6 years are presented in Finally, the results of logistic regression analysis as listed in Z−scores differed significantly among SGA, AGA, and LGA preterm infants. They all encountered obvious declines in Z−scores during hospitalization and increased in varying degrees after discharge. Small for gestational age infants had an up-cross of Z−scores while LGA infants had a down−cross of Z−scores from birth to follow−up. The gap at birth converged toward zero at age 3−6 years. Similar findings were described in a cohort study conducted by Vandana et al.  by the age of 3−6 years, which was noticed as an almost ubiquitous consequence due to their genetic potential in some former studies . Small fLarge birth weight and sustained increase in WAZ after discharge led to a high incidence (23.5%) of overweight/obesity in the LGA group. Childhood obesity, mostly due to an excessive calorie intake and a genetic susceptibility to weight gain, add to the risk of cardiometabolic diseases in adulthood such as hypertension, coronary heart disease, and diabetes , 18. TheThe advances in perinatology and neonatology have dramatically reduced mortality in preterm infants, yet increased the number of low birth weight, multiple births, and critically ill newborns in need of mechanical ventilation. However, the data did not show significant increase in the incidences of sepsis, NEC, and EUGR from 2016 to 2018. This can be attributed to the close cooperation between the nutrition support team and multidisciplinary team as well as the improvement we made in nutrition support in accordance with the newly published guidelines , includiAlthough the majority of preterm infants had returned to their normal growth paths by the age of 3−6 years, cases of overweight/obesity, short stature, and thinness cannot be ignored. The diagnosis of EUGR at an early stage may be used as detection marker for these unsatisfactory developmental results. Takayanagi et al. demonstrated that in very low birth weight infants, cross-sectional weight EUGR was associated with short stature and thinness around the age of 6 years, whereas obesity was rarely seen in this group .In contrast, the longitudinal EUGR on HC at discharge was identified as an independent risk factor for overweight/obesity in our study. The dysplasia of the nervous system can influence the formation of an unhealthy lifestyle, and thus obesity , 25. AmoWithin our expectation, cross-sectional EUGR on height at discharge was one of the major predictors for short stature at age 3−6 years. Short stature is closely associated with congenital genetic factors since half of the children with short stature was originated from SGA in our data. Matsumoto et al.  revealedZ−scores from 14−21 days to discharge to avoid the effect of physiological weight loss, and discovered that post-loss EUGR on HC was an independent risk factor for neurodevelopmental impairment. Further research should be conducted to reveal whether “post−loss” EUGR can better predict adverse physical development outcomes.The rates of EUGR on weight, both cross−sectional and longitudinal, were relatively high as a result of physiological weight loss after birth and may not reflect the real state of body growth. Maiocco et al.  proposedThere are several limitations in this study. This is a retrospective single center study with low follow-up rate. The data obtained by telephone inquiry may be insufficient of consistency and accuracy. Besides, the factors that may affect growth during childhood, such as parental information, nutrition after discharge, and diseases during follow−up, were not included.The growth trajectories of preterm newborns tended toward the normal direction. However, it is possible to observe short stature in SGA and obesity or overweight in LGA children. The longitudinal EUGR on head circumference and cross-sectional EUGR on height were associated with overweight/obesity and short stature, respectively. At the same time, the early start of EN may prevent preterm infants from thinness at age 3−6 years. The post-discharge monitoring of growth and the cultivation of a healthy lifestyle played a prominent role in the optimal physical development of preterm infants.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human subjects were approved by the Ethics Committee of Shanghai Children’s Medical Center. Written informed consent was obtained from subjects’ parents.SL and HF: methodology, formal analysis, data curation, writing the original draft, reviewing, and editing. RZ, GZ, and LP: data curation and investigation. FB: conceptualization. LH: conceptualization, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.