We did not find an increased APO risk in AGA FGD newborns , except for cesarean delivery for non-reassuring fetal status (NRFS) with a decrease in percentile cutoff greater than 40  and 50 . Conclusions: Newborns with the highest probability of APOs are SGA non-FGDs. AGA FGD newborns do not have a higher incidence of APOs than AGA non-FGDs, although with falls in percentile cutoff over 40, they have an increased risk of cesarean section due to NRFS. Further studies are warranted to detect these newborns who would benefit from close surveillance in late gestation and at delivery.Fetal growth restriction has been associated with an increased risk of adverse perinatal outcomes (APOs). We determined the importance of fetal growth detention (FGD) in late gestation for the occurrence of APOs in small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) newborns. For this purpose, we analyzed a retrospective cohort study of 1067 singleton pregnancies. The newborns with higher APOs were SGA non-FGD and SGA FGD in 40.9% and 31.5% of cases, respectively, and we found an association between SGA non-FGD and any APO (OR 2.61; 95% CI: 1.35–4.99;  Identifying newborns who have experienced intrauterine growth restriction is one of the greatest challenges in modern perinatology. The term fetal growth restriction (FGR) is used to define those newborns who have not reached their optimal intrauterine growth potential, and FGR can occur from the early to final stages of pregnancy ,2,3 due The term small for gestational age (SGA) is usually used to refer to newborns whose birthweight is lower than the 10th centile ,20. AlthMoreover, it has been postulated that some newborns with a weight percentile between 10 and 90 who have not reached their growth potential are actually FGR and are at increased risk of adverse outcomes . AkolekaThus, fetal growth detention (FGD) has been considered as a reduction in EFW by 20 or more percentiles during the third trimester of pregnancy . This cuThe present study determined whether newborns appropriate for gestational age (AGA) who have suffered FGD, defined as a reduction in estimated fetal growth by a decrease of 20 or more centiles between the 35th gestational week and delivery, had similar APOs to those diagnosed with SGA.The GROWth declINing Newborns (GROWIN) study was an observational, retrospective cohort study of births assisted at the Villalba University General Hospital between January 2015 and June 2017. Follow-up of the newborns included fetal growth up to delivery and their evolution in the first two years after delivery. The study was approved by the Clinical Research Ethics Committee of Fundación Jimenez Díaz  (EO090-19_HGV) and the Central Research Commission of Primary Care Management (23/19).The inclusion criteria were as follows: (i) live singleton pregnancies controlled in our center from the first trimester of gestation, (ii) fetal ultrasound assessment at gestational age of 35 (range 34–37) weeks; and (iii) deliveries between 37 and 42 weeks of gestational age with fetuses without structural malformations, chromosomal abnormalities, or metabolic diseases. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies .The variables collected in the study were maternal age, weight, height, and body mass index (BMI) at the beginning of pregnancy and parity, pregnancy and fetal pathology, type of delivery, cause of instrumental deliveries or cesarean sections. The last menstrual period was adjusted by the first trimester ultrasound  and an uWe also collected perinatal outcomes to analyze APOs defined as the occurrence of 5 min Apgar score ≤ 7, arterial cord blood pH ≤ 7.10, instrumental or cesarean delivery for NRFS, basic and advanced neonatal resuscitation admission at birth in neonatal intensive care unit (NICU) due to asphyxia, sepsis, respiratory distress syndrome, and transient tachypnea. In addition, we collected newborn gender and somatometry at birth .We considered the following patient groups based on percentile birthweight: (i) SGA newborns, those with a birthweight below the 10th percentile in the population of reference charts for that specific gestational age, with no fetal growth detention (SGA non-FGD); (ii) SGA newborns with fetal growth detention (SGA FGD) determined by a decrease of 20 or more centiles with respect to the estimated percentile weight in the third trimester ultrasound reflecting a fall in growth trajectory; (iii) appropriate-for-gestational-age (AGA), those with a birthweight between the 10th and 90th percentile, with no fetal growth detention (AGA non-FGD); (iv) AGA newborns with fetal growth detention (AGA FGD); and (v) large-for-gestational-age (LGA), defined as a birthweight above the 90th percentile.Data were extracted, and quantitative variables were described by medians and interquartile ranges (p25th–p75th), and qualitative variables were described by frequencies and percentages. Comparisons of quantitative variables were performed using the Mann–Whitney test when comparing two groups, or the Kruskal–Wallis test when comparing three or more groups. Qualitative variables were compared using the Chi-square test or the Fisher’s exact test. The predictive ability of AGA FGD newborns to diagnose APOs was analyzed using the area under receiver operating characteristics (ROC) curve and a threshold was sought for a specificity of 90%. A sensitivity (detection rate) of 10% was established for false positive rates (FPR). The percentile threshold point corresponding to the FPR values was also calculated.p-value. The AGA non-FGD group was taken as a reference category for the odds ratio calculation.The association between the five study groups and the presence of APOs was analyzed using univariate logistic regression models. In addition, we analyzed independent association using multivariate analysis adjusted by nulliparity, maternal BMI, hypertension, and diabetes. The models were summarized by the odds ratio, its 95% confidence interval and the Moreover, we explored how a greater decrease in percentile for the AGA FGD group could increase the risk ratio of APOs. We calculated the relative risk with a confidence interval at 95% for three decreases in percentile cutoffs .The significance level was set at 0.05 for all comparisons. Statistical analyses were performed using R v. 4.0.0 programming language .A total of 1067 pregnant women of 1528 eligible women were included in the present study .p < 0.001). Differences were also found in pregnancy pathology in terms of gestational diabetes, finding more cases in the LGA group (p = 0.014). SGA non-FGD had a median percentile at third trimester ultrasound (15.5) lower than SGA FGD had (44.5). In the study group AGA FGD, newborns were smaller than AGA non-FGD, with a median birthweight of 3105 (345) g vs. 3362 (465) g (p < 0.001) and median birthweight centile of 33.8 (27.1) vs. 60.4 (37.5) (p < 0.001), respectively.The descriptive characteristics of the 1067 participants divided into the five study groups are shown in p = 0.050), instrumental (p = 0.030), cesarean deliveries for NRFS (p = 0.034), and admission at birth in NICU (p = 0.023). The newborns with higher APOs were SGA FGD (31.5%) and SGA non-FGD (40.9%).p-values to predict APOs. Evaluations in the multivariate analysis showed that SGA was the group with the highest risk for any APO, OR 1.49  for SGA FGD and OR 2.61  for SGA non-FGD, and only the result for SGA non-FGD was significant for any APO. We also found an increased risk in SGA non-FGD for instrumental delivery for NRFS  or admission at birth in NICU . SGA FGD had a higher risk of cesarean delivery for NRFS  and advanced neonatal resuscitation . LGA presented a higher risk of basic neonatal resuscitation .We also estimated how a greater decrease in the percentile cutoff could increase the APO risk ratio for the AGA FGD group. The newborns with the highest rate and risk of APOs were SGAs, and the only group that presented a significant risk corresponded to the SGA non-FGD group. We did not find an association between AGA FGD infants, determined by a decrease of 20 or more weight centiles between the third trimester ultrasound and delivery, and a higher incidence of APOs compared with AGA non-FGD newborns. However, AGA FGD newborns with decreases in percentile cutoffs of over 40 had an increased risk of cesarean section due to NRFS. Therefore, the risk of APO increases if the birthweight percentile is less than 10, but there is less evidence of APO risk related to the percentile fall between ultrasound at 35 weeks and delivery.Our results regarding SGA newborns and other APOs, such as respiratory distress syndrome, arterial cord blood pH < 7.10, admission at birth, and prolonged stay in NICU were similar to those previously reported ,35,36,37When SGA is suspected by ultrasound, these fetuses are closely monitored antenatally. By contrast, if AGA fetuses are suspected, there is not such a close follow-up. It has been suggested that newborns with an intrauterine restriction who do not reach their full genetic growth potential, in spite of a normal birthweight, are at higher risk of APOs than SGA ,39. We dPrenatally undetected FGR is the most important risk factor for stillbirth. It increases the risk up to 8-fold and goes undiagnosed in most pregnancies, so preventive strategies should focus on improving its prenatal detection . Fetal gFetal growth velocity is defined as the rate of fetal growth over a given time interval and is usually represented as a deviation from growth velocity charts (changes in centiles or Z-score with advancing gestation), which is significant to determine fetal growth ,42.In terms of fetal growth velocity and individual biometric measurements, there is an initial peak growth of BPD, HC, FL, and AC at 13, 14, 15, and 16 weeks, respectively, and BPD, HC, and AC have a second acceleration at 19 to 22, 19 to 21 and 27 to 31 weeks, respectively . In geneAccording to the Delphi consensus , a fall Although the cutoff point of 50 centiles is random, it shows the importance of growth velocity deceleration as a significant contributor to present APOs in SGA ,44 and AMacDonald et al.  concludeChatzakis et al.  found thPacora et al.  found thHowever, Bligh et al. , in a coHence, clinical efforts should focus on the diagnosis and prediction of SGAs, especially those with the highest number of APOs, such as the SGA non-FGD group, the group of greatest interest, in order to proceed according to established protocols . The besThus, in a specific group of pregnant women, it could be recommendable to repeat ultrasound prior to delivery. Furthermore, although they are a smaller group, identifying AGA newborns with an intrauterine growth restriction is important to be able to monitor them more closely in the third trimester. It is, therefore, important to continue to search for new methods of this monitoring, which would probably entail a combination of maternal, obstetric, and fetal factors.Our research has several strengths as it includes a large sample size. We also defined the study groups following the longitudinal growth, not by cross-sectionally measuring the fetal biometry. We investigated the percentile decrease in both AGA and SGA newborns separately, on the basis of birth weight, so we do not have the bias of a percentile drop in newborns who are already SGAs and therefore have an increased risk of APOs based only on their percentile at birth.Regarding limitations, this was a retrospective study, and when calculating EFW weight by ultrasound, an error of the technique can be assumed . HoweverNewborns with the highest probability of APOs are SGAs. Of these, the only group that presents a significant risk are the SGA non-FGD newborns, which are therefore the most important group to detect antenatally. AGA FGD newborns do not have a higher incidence of APOs than AGA non-FGDs, although with decreases in percentile cutoffs of more than 40 points, they have an increased risk of cesarean section due to NRFS. Further research is required to determine whether this group would benefit from closer surveillance during late pregnancy and birth.


Objective: This study was designed to summarize the clinical characteristics, diagnosis and treatment of pharyngeal bronchogenic cysts in children to help in making the correct diagnosis and developing an appropriate treatment plan.Methods: The clinical data of 13 children with bronchogenic cysts in the pharynx, who were treated in otolaryngology head and neck surgery department between September 2013 and July 2019, were analyzed retrospectively. The clinical characteristics were evaluated, and the related factors for diagnosis and treatment were analyzed. Clinical characteristics and imaging features of three cases whose lesions located in the nasopharyngeal, oropharynx, and laryngopharyngeal were demonstrated.Results: All 13 children were male, the youngest being 4 days old, the oldest 6 years and 6 months, and the median age being 1 year and 4 months. Eight patients were diagnosed during a physical examination, and five patients visited the doctor with different degrees of upper airway obstruction. The mass was located in the nasopharynx in one patient, in the oropharynx in eight patients, and in the laryngopharynx in the other four patients. Computed tomography (CT) scanning, which is helpful for a topical diagnosis, showed a dense homogeneous mass. Electronic nasopharyngoscopy showed cystic masses of different sizes in the pharynx. All the children underwent cyst resection under general anesthesia, and the postoperative pathology result was a bronchogenic cyst. One child was lost to follow-up, but the remaining 12 children were followed up for between 6 months and 6 years, during which no recurrence of a cyst was found.Conclusion: Bronchogenic cysts are a rare cyst of the head and neck, and the most common site of the cyst is the oropharynx. The impact on airway obstruction depends on the location and size of the cyst. CT scanning is of great significance for diagnosis. Surgical treatment should be carried out as soon as possible after diagnosis, as surgery is the most effective way to treat bronchogenic cysts. Follow-ups should be carried out regularly to prevent cyst recurrence. Bronchogenic cysts are a rare congenital disease resulting from the abnormal development of primitive foregut, and they occur in one or more tissues of the respiratory system. Although the pathogenesis is unknown, the hypothesis of embryo abscission and translocation proposed by Govaerts et al. is generally accepted . It suggThe clinical data of 13 children with a bronchogenic cyst in the pharynx, who were treated in the Department of Otorhinolaryngology Head and Neck Surgery at Henan Children's Hospital, between September 2013 and July 2019, were analyzed retrospectively. The postoperative pathology result for all the patients was a bronchogenic cyst. All the children were male, the youngest being 4 days old, and the oldest 6 years and 6 months, and the median age was 1 year and 4 months.The lesions can be divided, according to their location, into nasopharynx bronchogenic cysts, oropharynx bronchogenic cysts, and laryngopharynx bronchogenic cysts. Obstruction of the upper airway to varying degrees manifests as nasal obstruction, snoring, respiratory distress, and dyspnea. On enhanced computed tomography (CT), a typical bronchogenic cyst manifests as a single-chambered, different-sized, round or quasi-round cyst. If secondary infection, bleeding and rupture occur, it may cause the compression of surrounding tissues. Cystic masses of different sizes with clear boundaries can also be seen in the pharynx with the use of electronic rhinolaryngoscopy.Before the operations in this study, the location of the bronchogenic cyst was determined based on imaging and electronic nasopharyngoscope. All 13 children underwent a plasma-assisted operation under general anesthesia. Eight of them, who had oropharyngeal cysts, underwent partial resection of the mass, one patient with a nasopharynx (eustachian tube circular pillow) cyst underwent endoscopic partial resection of the cyst via the oral approach, and the remaining four patients, with laryngopharyngeal  cysts, underwent endoscopic-assisted partial resection of the cyst. All the children underwent surgical removal of the part of the cyst that protruded into the pharyngeal cavity , that is to say, a partial resection.The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University. Since the participants were under the age of 16, written informed consent was obtained from their parents.All 13 children were male. The primary site of the mass was in the nasopharynx (eustachian cushion) in one child, in the oropharynx in eight children , and in the laryngopharynx in four children . The postoperative pathology result of all the children was a bronchogenic cyst see .Eight patients were diagnosed during a physical examination, while five patients visited the doctor with varying degrees of upper airway obstruction and then underwent electronic nasopharyngoscopy, CT, and Magnetic Resonance Imaging (MRI). Among these children, one child had dyspnea shortly after birth and was treated with mechanical ventilation through endotracheal intubation. When the symptom was alleviated, the ventilator was removed. When dyspnea occurred again, a laryngopharyngeal mass was found during the second intubation. Three children visited the doctor with progressive dyspnea and snoring, and masses were found at the root of the tongue and epiglottis valley. One child snored at night with buccal respiration; examination showed that there was a cystic mass in the eustachian cushion of the nasopharynx.For all the patients, the part of the mass protruding into the cavity of the pharynx was surgically resected . One child  was lost to follow-up after the operation, but the remaining 12 children were followed up for between 6 months and 6 years. No recurrence of the cyst was found, there was no snoring or dyspnea, and normal growth and development were observed in all 12 cases during the follow-up period.The child was a boy aged 6 years and 6 months. He was admitted to hospital due to snoring at night with buccal respiration for 15 days. A physical examination revealed that there was a 1.0 × 1.0 cm mass, protruding from the midline to the left in the right posterior palatopharyngeal arch. The surface of the mass was smooth and soft, and there was no tenderness; no fistula or mass was found in the neck. Electronic nasopharyngoscopy showed that there was a cystic mass of ~2 × 2.5 × 1.0 cm with a smooth surface in the left eustachian cushion, which passed though the posterior margin of the soft palate to protrude into the oropharynx and midline . PharynxThe child was a 4-day-old boy. The child was admitted to hospital due to dyspnea and underwent mechanical ventilation for 4 days. A laryngeal mass had been found 1 day before admission, and the child had been found to have shortness of breath and dyspnea shortly after birth. The respiratory tract was cleaned, and he inhaled pure oxygen through a mask in the local neonatal department. The dyspnea did not improve, and a chest X-ray showed atelectasis on the left side. The child underwent endotracheal intubation and mechanical ventilation and was then transferred to the superior local hospital, where he underwent symptomatic treatment that included ventilator-assisted ventilation, water fasting, anti-infection, and fluid supplement. On the 3rd day, dyspnea occurred again after ventilator withdrawal, and a laryngopharyngeal mass was found during the second intubation, which is when the patient was transferred immediately to our hospital. Electronic nasopharyngoscopy showed that there were new grayish-white cystic masses in the right epiglottis and in some aryepiglottic folds. They were ~1.0 × 1.2 cm in size, their surface was smooth, and they concealed the glottis . CT examThe child was a boy aged 2 years and 2 months. The child was admitted to hospital due to the discovery of a new eustachian object 2 months earlier. Close examination showed a new grayish-white object with a smooth surface, which was the size of a broad bean, located at the posterior left tonsil. Electronic nasopharyngoscopy revealed a cystic mass with a smooth surface and a size of ~1.2 × 1.3 cm in the lateral wall of the posterior pharynx of the left palatopharyngeal arch . CT examBronchogenic cysts are caused by the migration and development of epithelial cells separated from the tracheobronchial tree during embryonic development. They can be classified into one of three types according to the location of the lesion: intrapulmonary, mediastinal, and ectopic. The disease can occur in all ages, and while the pulmonary type and mediastinal type are common, the ectopic type is rare. Nevertheless, in the present study, all 13 children had ectopic bronchogenic cysts, which can occur in the neck, subcutaneous space, pericardium, retroperitoneal space, intraspinal cavity, and elsewhere –10. CuypA bronchogenic cyst of the pharynx is a congenital disease, of which the clinical manifestations are varied and atypical. The disease is usually asymptomatic in clinical practice, and most occurrences are found during a physical examination. The severity of the symptoms varies according to the location, size, and complications of the cyst. There are a few reports of cases of abscess, severe ecphysesis, or respiratory distress , 20, whiImaging examinations, such as CTs and MRIs, play an important role in the diagnosis and treatment of bronchogenic cysts. They can be used to determine the site of the disease, scope of the disease, and presence of invasion into the surrounding structures to provide a basis for the formulation of an operation plan –23. HowePathological examination is the gold standard for diagnosis of bronchogenic cysts, and three pathological criteria must be met: first, the cyst must have an overlying smooth muscle layer; second, it must contain epithelium derived from the foregut; and lastly, it must be attached to part of the foregut tissue. Pathological examination reveals that bronchogenic cysts occur in one or more tissues of the respiratory system, including the ciliated columnar epithelium, smooth muscle, cartilage, and fibrous connective tissue , 25, 26.Bronchogenic cysts are rare, and the misdiagnosis rate is high. The differential diagnosis subjects include intraoral thyroglossal cysts, branchial cleft cysts, dermoid cysts and epidermoid cysts, lymphangiomas, hemangiomas, teratomas, and cystic neuromas; in other words, bronchogenic cyst diagnosis involves the exclusion of many other cystic pharyngeal masses. Preoperative imaging examinations and, if necessary, enhanced CT or MRI can be used to initially determine the nature of the cyst and to understand the relationship between the cyst and the relevant surrounding tissues in order to determine the appropriate surgical method. The final diagnosis, however, requires a pathological diagnosis. , 12, 13.The treatment of patients with a bronchogenic cyst depends on their clinical symptoms. Unless the risk of surgery is so high that it is unacceptable, regardless of how old the patient is, the symptomatic cyst should be removed. As a result of hemorrhage, infection in the cyst or cyst enlargement compressing adjacent organs, patients with a bronchogenic cyst will have corresponding clinical symptoms, and a malignant transformation may occur. Therefore, it is suggested that the bronchogenic cyst should be resected in the early stage to relieve the clinical symptoms and prevent complications –29. The Our study indirectly supports the hypothesis of embryo exfoliation and translocation, in which it is proposed that in the process of embryo development, during embryo abscission and migration, the embryo is planted on the surface of the original pharynx when passing through the original pharynx cavity, forming a superficial bronchogenic cyst in the pharynx.The disease has a good prognosis and a low recurrence rate . After tPatients with no clinical symptoms of pharyngeal bronchogenic cyst should not be treated, but patients with clinical symptoms and no obvious contraindications to surgery should be treated as soon as possible.A bronchogenic cyst is a rare cyst of the head and neck, and the most common site of the cyst is the oropharynx. The impact on airway obstruction depends on the location and size of the cyst. CT scanning is of great significance for diagnosis. Surgical treatment should be carried out as soon as possible after diagnosis, as surgery is the most effective way to treat a bronchogenic cyst, and follow-ups should be carried out regularly to prevent cyst recurrence.The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.YX and DS: conception and design of the research. XN and JZ: critical revision of the manuscript for intellectual content. XN: writing of the manuscript. SW: obtaining financing. LJ: statistical analysis and acquisition of data. DS: analysis and interpretation of the data. 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.


Maternal gestational weight gain (GWG) influences not only on pregnancy outcome but also impacts on mothers’ and children's long-term health. However, there is no consensus on recommendations of optimal GWG in Asians or the Chinese population.We performed a secondary analysis of the birth outcome of Chinese women who had joined the “Hyperglycemia and Adverse Pregnancy Outcome” study in Hong Kong and their children's cardiometabolic risk at 7-year of age. Optimal ranges of GWG were derived from models based on the probabilities of small for gestational age and large for gestational age (model 1), lean and fat infants (model 2) and the integration of model 1 and 2 (model 3), and were compared with that recommended by the Institute of Medicine (IOM) on children's cardiometabolic risk.GWG range derived from model 2 is associated with 8 cardiometabolic risk factors, while that from models 1 and 3 are associated with 1 and 7 of them respectively. Mothers whose GWG lie within the recommended range increases from 40.8% according to the IOM recommendation to 50.2% according to that derived from model 2.Optimal GWG derived from model 2  appeared to be associated with the lowest cardiometabolic risk in the offspring.General Research Fund of the Research Grants Council of the Hong Kong SAR, China . Evidence before this study•Optimal gestational weight gain (GWG) is an important factor to the pregnancy outcome and the long-term health of the offspring.•Most of the previous studies evaluate the risk of small for gestational age (SGA) and large for gestational age (LGA) to determine the optimal GWG.•The most used reference was that recommended by the Institute of Medicine (IOM) but was predominantly for the Caucasian population.•There is a paucity of literature in the optimal GWG for Asian or Chinese population.Added value of this study•Compared with optimal GWG based on the infants’ SGA and LGA, optimal maternal GWG derived from infants’ adiposity appears most discriminative with the association of children's future cardiometabolic risk.•Infants’ fat mass and fat-free mass both increase at different rates with their own birth weight and with maternal GWG related to the mothers’ pre-pregnancy BMI, so that the percentage of body fat increases with both infants’ birth weight and maternal GWG.•More women would fall into optimal GWG based on model derived from infants’ adiposity (50.2%) than that based on the IOM recommendation (40.8%).•Optimal GWG ranges for multiparity appeared to be lower than those for the nulliparity as well as for the whole population.Implications of all the available evidence•Our study provides a reference on the methodology for future study to determine optimal GWG in the Chinese or Asian population.•Neonatal body fat percentage can now be reliably estimated from routine anthropometric measurements at birth so it is feasible to include adiposity as an outcome index to determine optimal GWG.•The optimal GWG may differ between primigravida and multiparity so future studies on should consider parity as a factor of GWG.Alt-text: Unlabelled box1Maternal gestational weight gain (GWG) influences pregnancy outcomes, as well as mother's and offspring's long-term health. Excessive GWG increases the mother's risk of caesarean delivery, gestational hypertension and gestational diabetes mellitus (GDM), and the baby's risk of being large for gestational age (LGA) and macrosomia. Excessive GWG also increases the risk of postpartum weight retention and type 2 DM. [3]Whilst there are still controversies about the practice of routine weighing in pregnancy and the reference on optimal GWG, the recommendations from the Institute of Medicine (IOM) last revised in 2009 is the most commonly used reference for the Caucasian population. However, the IOM guidelines are based on data from USA-dwelling, Caucasian and Black women that may not be generalizable to women from Asia. In fact, studies from the Asian continent suggested that Chinese and Japanese mothers should have GWG less than that proposed by the IOM. ,5 ComparMost of the previous studies derived optimal GWG based on infants’ birth weight that result in the lowest rates of SGA and LGA at delivery. However, other than the birth weight, GWG also impacts on offspring's body fat composition, ,11 adipo22.1This is a secondary analysis of data obtained from the mother-child dyads who participated in the original “Hyperglycemia and Adverse Pregnancy Outcome (HAPO)” study in 2000-2006, and from those who also participated the follow-up study during 2009-2013 in Hong Kong. In the original HAPO study, 1667 pregnant women with a singleton pregnancy underwent a 75 g oral glucose tolerance test (OGTT) at 24–32 weeks’ gestation at the Hong Kong study centre. All the participants and clinicians were blinded from the OGTT result, but mothers whose glucose levels at the OGTT or the random glucose levels at late gestation exceeded the pre-determined safety range were treated accordingly and were excluded from further study. Pre-pregnant weight was obtained by participant’ recall at the first antenatal visit and at recruitment of the original HAPO study. Maternal height was measured at the first antenatal visit. Maternal weight just before delivery was measured in the antenatal ward upon admission in early labour. The gestational weight gain was obtained from the data set of the HAPO study and verified from the electronic data captured into the hospital computerised system.2), normal weight (BMI 18.5 – 23.9 kg/m2), overweight (BMI 24.0 – 27.9 kg/m2), and obese (BMI≥28 kg/m2).We adopted the BMI categorization endorsed by the National Health and Family Planning Commission of China for Chinese population. 17 For these analyses, the average of the two measurements was used unless a third measurement was taken. Birth weight was obtained without diaper using a calibrated electronic scale. Flank skinfold thickness was measured with calipers  on the neonate's left side, just above the iliac crest on a diagonal fold on the mid-axillary line.Neonatal measurements were obtained in a standardized method by trained research staff within 72 hours of delivery as previously described in the original HAPO study. th percentile and above the 90th percentile of the standard growth curve respectively. Infant's body fat mass was estimated with the equation: 0.39055 (birth weight) + 0.0453 (flank skinfold) - 0.03237 (length) + 0.54657 as previously used in the HAPO study. LBW and macrosomia were defined when the infant's birth weight was below 2500 g and above 4000g, respectively. In the present study, SGA and LGA were defined with reference to the data obtained from a territory-wide study conducted between 1998 and 2001 in Hong Kong that included ten-thousand Chinese infants to establish gestational age-specific birth weights for boys and girls. O study. ,19 Fat-f2.2glu) at OGTT during pregnancy]. The optimal GWG in each subgroup was derived based on three models: model 1 by birth weight (targeted to the lowest sum of probabilities of SGA and LGA); model 2 by neonatal adiposity (targeted to the lowest sum of probabilities of fat and lean infants); and model 3 by integrating models 1 & 2 . Equations to calculate the individual probability (equation 1 and 2) and sum of probabilities (equation 3 to 5) were described in the supplementary note 1. The lower and upper bounds of the optimal GWGs were the points at which 1% increase in the sum of probabilities from its lowest value were observed Categorical variables were compared by using Chi-Square test or Fisher's exact test. Normally distributed continuous variables were expressed as mean ± SD and compared using one-way ANOVA. Non-normally distributed continuous variables were expressed as median (IQR) and compared by using Kruskal-Wallis tests. Post-hoc pairwise comparison was performed when the null hypothesis was rejected. Binary regression models, both “logit” and “complementary log-log” links, were used to assess the associations between the odds of SGA, LGA, fat and lean at birth with maternal GWG among mothers who were underweight, normal weight and overweight; there were too few obese mothers (n=33) for the statistical analysis. The link with a lower Akaike information criterion (AIC) value was regarded as a better model, and was used for the development of the reference ranges for optimal GWG. Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained after adjusting for maternal age, parity, gestational hypertension/preeclampsia, smoking status in pregnancy and maternal glycaemic status in pregnancy , glucose and insulin levels  and compared them with the GWG recommended by the IOM using the analyses we described previously elsewhere. www.r-project.org/. P values < 0.05 were used to indicate significance for two-tailed statistical test results.Statistical analyses were performed using SPSS version 25  and R (version 4.0.3) downloadable at 2.3The HAPO study was funded by the National Institute of Child Health and Human Development (grant no. R01-HD34242) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant no. R01-HD34243). The HAPO follow-up study at the Hong Kong Centre was supported by the funding from the General Research Fund of the Research Grants Council of the Hong Kong SAR, China . The funding source had no role in the study design, secondary data analysis, data interpretation or manuscript writing.3With reference to the IOM recommendation, 630 mothers (42.1%) had GWG which exceeded recommendations, whilst 261 (17.4%) had GWG below the recommendations. Meanwhile, we also observed a slightly greater proportion of infants being classified as SGA than being classified as lean , but a lower rate of infants classified as LGA than being fat  in the entire cohort. The frequency distributions of maternal weight gain of the four subgroups are shown in Supplementary figure 3. Among the underweight mothers, 50.0% had GWG fell within, while 23.5% were below and 26.5 % exceeded the IOM recommendation. Majority of the overweight (63.0%) and obese (76.9%) mothers had GWG exceeding the IOM recommendation; nearly half (44 %) of normal weight mothers also exceeded the IOM recommendation in the weight gain.Infants’ fat mass and fat-free mass were positively associated with maternal GWG and their own birth weights in a slight curvilinear manner , thus the infants’ percentage of body fat increased with maternal GWG and their own birth weights. For each kg increase in maternal GWG, the percentage of body fat  increased by 0.30% , 0.15%  and 0.15%  in underweight, normal weight and overweight mothers, respectively. The rate of increase in body fat percentage per kg increase maternal weight gain was 2-fold in children born to underweight mothers compared with those born to normal weight and overweight mothers. On the other hand, for each 100-gram increase in the infants’ birth weight, the rate of increase in body fat percentage  were similar in all three subgroups: i.e. 0.70% , 0.66%  and 0.75%  in underweight, normal weight and overweight mothers, respectively.Maternal GWG significantly altered the odds of neonates being SGA, LGA, lean and fat at birth in women who were underweight and normal weight after adjustment for various confounders. However, maternal GWG was only found to alter the odds of neonates born LGA and fat after similar adjustment in overweight mothers. The difference of AIC values between logit link and complementary log-log link were all less than 1 (supplementary table 1). These associations obtained by using logit link were also demonstrated in The sum of probabilities (95% CI) of SGA and LGA , of lean and fat  and of SGA, LGA, lean and fat  by logit link were shown in In contrast, the adjusted ORs (95% CI) of nulliparity associated with SGA, LGA, lean and fat in the overall cohort were 1.4 (0.94-2.1), 0.45 (0.28-0.71), 1.8 (1.2-2.9) and 0.46 (0.31-0.68), respectively. Optimal GWG ranges for the multiparous women appeared to be lower than that for the nulliparous (supplementary table 3), as well as that for all pregnant women regardless of parity (supplementary table 2).The maternal and neonatal adverse outcomes of mothers who gained weight within the optimal GWG in models 1 to 3 were compared with each other as well as with that recommended by the IOM were shown in Model 1 was found to be only associated with children's BMI, whereas the other two models and that from IOM were associated with children's adiposity traits, blood pressure, beta-cell function and insulin sensitivity to different degree when the mothers gained weight exceeding the optimal ranges and the respective recommendation. Compared to model 3, children whose mother has GWG exceeding reference range derived from model 2 were associated with more insulin indices .4The main objective of our study is to explore the association between maternal GWG in pregnancy with adverse pregnancy outcomes and to determine the appropriate weight gain reference, which would result in optimal infant body size and fat mass, along with other optimal pregnancy outcomes. From the three models that are based on the infants’ birth weight, their adiposity or the combined model using both birth weight and adiposity together, models based on adiposity appears most discriminative. The model is better at predicting the children's future cardiometabolic risk, predominantly their adiposity measures, blood pressure, insulin resistance and pancreatic beta cell secretory function.Contrary to the widely accepted IOM recommendation for the Caucasian population, there has never been a similar universally agreed recommendation for the Asian population. All the recommendations were mostly based on the infants’ rates of SGA and LGA, and other adverse pregnancy outcomes such as preterm delivery, caesarean section, GDM and preeclampsia, but seldom touched on other neonatal complications, nor the children's long-term health. Taking into consideration several recent studies showing the influence of GWG on the children's birth weight and their cardiometabolic health, we also included the children's cardiometabolic traits in the exploration of optimal weight gain in pregnancy. ,12,21The main disadvantage of modelling GWG reference ranges solely based on SGA and LGA, which are derived from infant's birth weight alone, is the inability to differentiate between the infants’ fat mass, i.e. their adiposity, from their fat-free mass. In our study, we observed a higher rate of infants being classified as lean rather than SGA, but a lower rate of infants classified as fat than being LGA. As neonatal adiposity could be reliably estimated from routine anthropometric measurements at birth, it is now feasible and more practical to include adiposity into the outcome in future studies which aim to establish the optimal GWG. [22]in utero environment contributed mainly to the infant's fat mass, whereas lean body mass or fat-free mass was the genetic component of foetal growth. Sparks proposed that the The median GWG in all four BMI subgroups of our cohort were comparable with that reported in two other Chinese populations from urban Shanghai and Changsha. ,26 Howev2, could be 0.5-1.5kg greater than that currently recommended by the IOM. For normal weight and overweight, the upper reference levels are similar to that of IOM. Compared to the IOM recommendation, the reference range for GWG determined from neonatal adiposity in the present study provides a wider interval, hence re-classifying 10% of the mothers initially outside the recommended reference based on the IOM, into within recommended GWG according to the proposed reference. It has been reported earlier that in a multi-ethnic population, overweight and obese women gaining less than 5 kg in pregnancy will have higher risk of SGA, decreased neonatal fat mass, lean mass and head circumference. Similar to that suggested from a Dutch study, Additionally, parity was found to be associated with the risks of infants born LGA, lean or fat. Optimal GWG ranges for multiparous women appeared to be lower than for the whole population. The present recommendations, including that from the IOM, had not considered the impact of parity separately. Further study with a larger population size are required to develop separate recommendations for nulliparous and multiparous women.2 for any subgroup analysis. Mothers recruited into the original HAPO study were healthy without previous history of hyperglycaemia and relatively young. Therefore, the cohort may not be entirely representative of the general obstetric population, which would involve a broader range of BMI, as well as including mothers with medical conditions. Moreover, there is no good standard reference on the estimation of neonatal fat mass. Nonetheless, the computation of fat mass from the skinfold thickness had been used for several times in the previous publications with the other HAPO study papers. [The present study was however limited by the small sample size, and inadequate number of obese mothers with pre-pregnancy BMI > 28 kg/m papers. ,17 Simil5The present study highlighted the methodology to assess an optimal GWG in Chinese women during pregnancy and compared that with the recommendation from IOM. The standard birth weight varies among different ethnic groups so as the definition of SGA and LGA. The baby's fat mass and fat-free mass increase at a slightly different rate with baby's own birth weight and mother's GWG. We could demonstrate in the present study the optimal GWG derived is associated with lower rate of lean and fat babies in underweight, normal weight and overweight Chinese mothers.6This study was conceptualized and designed by Dr Wing Hung Tam. Dr Claudia H.T. Tam contributed to the study design, methodology and advised on the statistical analysis. Dr Yuanying He performed all the data analysis and wrote the manuscript. Dr Wing Hung Tam and Dr Ronald C.W. Ma were responsible for obtaining funding, and acquired all the data from the HAPO follow-up study with Ms Lai Yuk Yuen. Dr Patrick M. Catalano contributed to the study design and advised on the data analysis. All authors contributed to the critical review of the manuscript.7All the authors declared no conflict of interest.


Background: The full breastfeeding may lead to insufficient milk intake of newborns and increase the rate of body weight loss (BWL). Severe BWL was generally believed as a cause of significant hyperbilirubinemia in newborn babies. The study aimed to investigate the effect if early supplemental feeding in newborns with birth weight loss at the first 3 days after birth could decrease the rate of hyperbilirubinemia 72 h of birth.Methods: A total of 395 neonates with gestational age >37 weeks and birth body weight >2500g were prospectively collected between 2016 and 2018. We analyzed 280 neonates with BWL rate reaching the predictive value  for subsequent hyperbilirubinemia after 72 hours after birth. The enrolled cases were divided into four subgroups as interventional consecutive milk supplement for 0, 1, 2, and 3 days after birth for further analysisResults: For newborns with BWL reaching the predictive value on the first day after birth, the serum bilirubin levels were lower in the experimental group than those in the non-involved control group (p < 0.05). For newborns with three consecutive days of interventional milk supplementation, the serum bilirubin levels at the 72 h after birth showed the lowest levels compared with the other sub-groups with two consecutive days and one consecutive day of interventional milk supplementation (p < 0.05). Moreover, there was a significantly decreasing trend in the consecutive days of interventional milk supplementation (p < 0.05).Conclusion: Newborns with BWL over 4.5% on the first day after birth receiving early intervention milk supplementation could significantly reduce serum bilirubin levels at the72 h after birth. The more days of consecutive milk supplementation after birth may lead to the lower the 72 h serum bilirubin levels. It is recommended to early and consecutive milk supplementation after birth to be an effective way in reducing serum bilirubin levels. The Baby-Friendly Hospital Initiative (BFHI) is a global effort to promote breastfeeding launched in 1991 and was first supported in Taiwan in 2000. Hospitals across Taiwan urge exclusive breastfeeding to become maternal- and child-friendly hospitals and continue to promote the BFHI standards. However, new mothers may lack breastfeeding skills to increase milk volume, which often leads to clinically insufficient milk intake in newborns. This can result in weight loss and increased hospitalization rates due to hyperbilirubinemia  was also observed due to weight loss and improper breastfeeding  rate to predict persistent hyperbilirubinemia in clinical practice. Moreover, research indicating the need for formula supplementation to prevent severe hyperbilirubinemia remains equivocal. Use of supplemental formula in newborns has been suggested at >7% BWL after 3 days of birth –14, wherThis prospective interventional study occurred between 2016 and 2018. Neonates born after at least 37 gestational weeks with a birth body weight (BW) >2,500 g were identified at a medical hospital. Of the 395 identified neonates, 115 were excluded from the study, leaving 280 enrolled for analysis. The exclusion criteria were early onset hyperbilirubinemia (within 48 h), pathological neonatal jaundice , birth injury, prenatal asphyxia, major organ anomalies, cephalohematoma, maternal or infant exposure to unapproved drugs, maternal gestational diabetes, and infants exclusively fed formula. The study was approved by the Institutional Review Board of Taipei Tzu Chi Hospital (registration number: 04-X34-088 and the date of registration as 08/06/2016). All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from a legal guardian for study participation.The 280 eligible neonates were identified as falling into 4 subgroups based on breastfeeding status :n = 164)Group I (control group): Formula supplementation for 0 days (n = 18)Group II: Formula supplementation for 1 consecutive day (n = 32)Group III: Formula supplementation for 2 consecutive days (n = 66)Group IV: Formula supplementation for 3 consecutive days , BW 48 h after birth (second day), BW 72 h after birth (third day), delivery methods , feeding method (exclusive breastfeeding or breastfeeding combined with formula), BWL rate during the 3 days after birth, daily number of urinations, the daily weight change obtained from the neonatal inpatient record, and bilirubin levels at 72 h after birth. Serum microbilirubin was routinely checked in infants by heel stick for blood sampling using direct spectrophotometric methods at 3 and 7 days after birth. Bilirubin levels were measured using an APEL Model: BR-501 bilirubin meter. Neonates were weighed daily for at least 3, and up to 5, days after birth. Measurements were compared with the first day to identify rates of dehydration and BWL. Gestational age was not analyzed because most infants were born at 39–40 gestational weeks.All statistical analyses were performed using Kruskal–Wallis tests, Jonckheere–Terpstra tests, and multiple linear regression analysis. Bilirubin values were compared across subgroups. Correlations between BWL rate within 72 h and the total bilirubin level 72 h after birth were analyzed. Correlations between the TSB level and related clinical parameters were also analyzed. Multiple linear regression was used to analyze hematocrit levels across the neonates based on days of interventional formula supplementation. The results are reported as percentages and mean ± standard deviation. The differences between groups are presented as 95% confidence intervals. Probability levels of <0.05 were considered significant. Statistical analyses were performed using SPSS software .p < 0.001). There was a decreasing trend in percentage of BWL for day 2 and day 3. The percentage of BWL percentage decreased as the days of consecutive supplemental formula increased (p < 0.05)  . There wComparison of supplemental formula vs. no intervention based on percentage of BWL at different timepoints are shown in p < 0.05). Thus, the occurrence of hyperbilirubinemia may be effectively reduced in 72 h.The multiple linear regression results for the effect of none, one, 2, or 3 consecutive days of supplemental formula on day 3 serum bilirubin levels are shown in Reported incidences of hyperbilirubinemia have increased following implementation of the BFHI program to promote breastfeeding. In Taiwan, incidences of hyperbilirubinemia at one northern Medical Center grew from 10.88 to 23.77% during a study conducted in the year 2000 . Early iAccording to the current findings, when BWL rate was >4.5% at 24 h, >7.5% at 48 h, and >8% at 72 h, supplemental formula may be indicated to reduce neonatal hyperbilirubinemia 3 days after birth. The results of the multiple linear regression analysis also showed that 3 consecutive days of supplemental formula significantly reduced day 3 serum bilirubin levels. This may indicate that early and continuous supplemental formula better prevents hyperbilirubinemia. However, 2 consecutive days of supplemental formula did not significantly reduce day 3 bilirubin levels. These differences may be due to the timing of supplemental formula intervention within the experimental groups. If a neonate did not meet BWL criteria until later in the study, such as showing >8% BWL at 72 h, then supplemental formula was only indicated the third day. Serum bilirubin levels were tested on the third day. Thus, supplemental formula given outside of the first 24 h after birth may not be early enough to significantly affect bilirubin levels.Most medical institutions follow the Academy of Breastfeeding Medicine protocol, which indicates that breast milk should only be supplemented when newborn percentage of BWL is >10% . TherefoThus, it is essential to take other factors into account to avoid possible complications. The physiological model of neonatal physiological dehydration was developed in the United States in 2014 to identify early interventional timepoints for formula supplementation to avoid severe dehydration . HoweverThere are some limitations to this prospective study. Participants were enrolled from a single medical center, leading to a small sample size that may not be widely representative. In addition, the amount of breast milk fed to the newborns in both the control and experimental groups could not be determined. Under the BFHI rules, the mother's breast milk cannot be squeezed into a bottle to feed to the infants, and therefore could not be calculated or controlled in this study.Moreover, there are also many factors determining successful initiation of breastfeeding including the previous experience of the mother, labor room practices , the motivation of mother, the maternal prenatal and postpartum sentiments , etc. Although these factors may have a large impact, they were not assessed.Newborns with BWL >4.5% 24 h after birth showed significantly reduced day 3 serum bilirubin levels when breast milk was supplemented with formula. An increased number of consecutive days with supplemental formula after birth may further lower day 3 serum bilirubin levels. Early and continuous formula supplementation is recommended as an effective way to prevent neonatal hyperbilirubinemia 72 h after birth.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The study protocol was approved by the Institution Review Board and ethics committee of Taipei Tzu Chi hospital on June 8, 2016. IRB No.: 04-X34-088 (08/06/2016).L-LZ, E-PL, and H-PW conceived and designed the study. RK, SY, and S-CH collected and analyzed the data. L-LZ performed the statistical analysis. L-LZ and E-PL drafted the manuscript. H-PW designed and oversaw the study, interpreted the data, and revised the manuscript. All authors have read and approved the final manuscript for publication.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.


Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb + strain remains poorly characterized.The E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake.We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.Our finding suggests that transmission of colibactin-positive The online version contains supplementary material available at 10.1186/s12866-021-02292-1. Escherichia coli that harbor the gene cluster clb  responsible for the biosynthesis of the genotoxin colibactin have been linked to colorectal oncogenesis [E. coli isolates from clinical samples, which led to the isolation of the high-colibactin producer E. coli-50 that will be useful in studying the properties of colibactin-positive (clb+) E. coli and colibactin [clb + E. coli and colibactin, there is still a limited understanding on the infection route of the E. coli to the affected individuals. Since identification of the routes of infection would help develop measures to mitigate or prevent the infection, we initiated a screening effort to examine the prevalence of clb + E. coli among healthy individuals by analyzing their fecal samples [clb + E. coli infections that occur among healthy individuals. Also, it is known that the newborn gut microbiota starts to form upon exposure to the vaginal and maternal skin microbiomes after birth [E. coli strains, including clb + E. coli, are transmitted from mothers to neonates, where early colonization of neonate gut with genotoxic E. coli could influence the intestinal homeostasis at adulthood in a way that may put the individual at risk of colorectal cancer and other immune-mediated diseases [clb + E. coli could be transmitted to infants from mother or closely interacting caretaking adults, and if so, what is the source and the medium through which the strain is being passed on to the infants. Here we report that the colibactin-producing E. coli can indeed be rapidly transmitted from mother to child after birth, suggesting that a respectable number of healthy individuals may become predisposed to high risk of CRC at the very early stage of life.Colorectal cancer (CRC) is the third most common form of cancer and the second most common cause of cancer mortality in the world . It is pogenesis –10. Receogenesis  that areogenesis , 13. Thelibactin . While w samples  and are er birth . A studydiseases . Therefoclb + E. coli, we surveyed 223 healthy adults from Tokyo metropolitan area in Japan for the presence of clb + E. coli in their fecal samples. We found that 60 participants (26.9 %) were positive [clb + E. coli. For the current study, we examined 51 infants . From the subjects, one set of feces was collected at birth or within two to three days after birth, and another set was collected one month after birth. The samples were examined by PCR to detect the presence of clbB, the gene for one of the PKS–NRPS hybrid megasynthetases encoded in the colibactin biosynthetic gene cluster. We found that 8 out of 51 newborns or 15.7 % of the test samples harbored clb + E. coli immediately after birth  were not affected as determined by the PCR analysis of their fecal samples . Lastly, we did not observe any difference in the clb + E. coli infection ratio between the sexes of the infants either at birth or one month after birth in this study.As to the breastfeeding-mediated transmission, we examined the correlation between the infant feeding mode and the es Table . In totaclb + E. coli immediately after birth . Fecal samples were collected at birth to two to three days after birth (at the time of discharge within a few days after birth) and one month after birth (at the time of the one-month checkup). The collected feces were immediately placed in a sealed container and stored in a − 20 °C freezer until DNA extraction was performed.The subjects were 51 healthy infants from Tokyo metropolitan area in Japan. The size of the subject pool was deemed adequate for the study based on the known frequencies of y 26.9 % ) and chiy 26.9 % , and they 26.9 % ) in JapaDNA was extracted from the frozen fecal samples with the bead beating method using a GNOME DNA Isolation Kit . DNA quality was assessed with an Agilent 4200 TapeStation (Agilent Technologies). After the final DNA precipitation step, the DNA samples were resuspended in TE buffer and stored at − 80 °C before the PCR analysis.2HPO4, 1.5 g KH2PO4 in 1 L H2O) in a sterilized bag. The mixture was incubated at 44.5 °C for 24 h. The mixture was filtered, and the filtrate was centrifugated at 10,000 g for 6 min at 4 °C. The collected precipitate was suspended in 1 mL of sterile Milli-Q water. The suspension was plated on a MacConkey agar medium and incubated at 37 °C for 16 h. The grown bacteria were cultured, and its genomic DNA was extracted by using a DNA isolation kit (QIAGEN). The isolated DNA was resuspended in TE buffer and stored at − 80 °C before the PCR analysis.Each food sample (10–50 g) obtained from grocery stores in Shizuoka, Japan, was added to 20 mL of EC medium  present in the DNA extract by amplifying the gene fragment using a primer set of clbB-F: 5’-TGTTCCGTTTTGTGTGGTTTCAGCG-3’ and clbB-R: 5’-GTGCGCTGACCATTGAAGATTTCCG-3’ as described previously [clbB gene with the subject’s birth method, diet content and sex.The extracted fecal DNA was subjected to PCR  and qualitatively analyzed for eviously . The corEach experiment was performed at least three independent times. Representation of data as dot-plots and bar-and-whisker graphs is described in figure legends. The t test for determining the statistically difference between the expected and observed frequencies was calculated using JMP (SAS Institute Inc.) and the NORM.DIST function in Microsoft Excel version 16.16.25.Additional file 1.


P < 0.001) and late pregnancy (P < 0.001) groups than in the control group. Furthermore, levels of neonatal thyroid stimulating hormone (P = 0.032) and birth weight (P = 0.043) were significantly lower than those in the control group. We also observed a significant inverse association between maternal FT4 levels in early pregnancy and neonatal birth weight (P=0.028), especially in male newborns (P=0.036). In summary, after thyroidectomy for thyroid cancer, a sufficient dose of thyroxine supplementation in early pregnancy is significantly associated with reduced birth weight and may need to be monitored.Patients are often supplemented with a sufficient dose of thyroxine after thyroidectomy for thyroid cancer. However, the influence of thyroxine supplementation on fetal growth in pregnant women after thyroidectomy for thyroid cancer remains unclear. The aim of this study was to investigate the effect of thyroxine supplementation on neonatal birth weight. This cohort study included 49,896 pregnant women . Thyroid parameters were examined in pregnant women and their newborns. The associations between maternal thyroid function and neonatal birth weight and small for gestational age were studied using regression analyses. In the levothyroxine supplementation group, free thyroxine (FT4) levels were significantly higher in both early pregnancy ( Thyroid cancer is a common endocrine malignancy in young women. The prevalence of thyroid cancer in pregnancy  was reported . Women oThyroid hormone is a well-known regulator of growth and development in the human body and plays a crucial physiological role in early placental development and intrauterine fetal growth , 4. FetaFetal thyroid hormone production starts around 14th week of pregnancy, and the fetal thyroid gland is functionally mature between the 18th and 20th weeks. Therefore, fetal thyroxine during the first half of pregnancy depends on placental transfer of maternal thyroid hormones , 8. In tin vitro fertilization (IVF) or had a twin pregnancy or had other pre-existing thyroid diseases . The study protocol was approved by the Medical Ethics Committee of the International Peace Maternity and Child Health Hospital. Written informed consent was obtained from all participants.A total of 49896 pregnant women who delivered in a large specialized hospital for women and children between January 2016 and December 2018 were included in the study. Of these, 278 patients underwent a total thyroidectomy due to papillary thyroid cancer and they required a sufficient dose of LT4 for replacement treatment or the TSH suppression (sufficient dose of LT4 in this study refers to supplementary LT4 that can suppress TSH levels near the lower limit of pregnancy-specific reference range). Data were collected from electronic medical records. Information on thyroid function parameters was available for the included pregnant women. Data were also available on potential confounders, including gestational age at birth, maternal age, parity, education level, pre-pregnancy body mass index (BMI), gestational hypertension, gestational diabetes, medical history, and fetal sex. Alcohol consumption and smoking status were not included in the analysis because their use was rare among pregnant women in our study population. Exclusion criteria for the study population mainly included women who underwent Maternal serum samples were obtained in the first trimester (11–13 weeks) and third trimester (31-33 weeks) of pregnancy. Fasting blood samples were drawn from the median cubital vein and the serum was separated by centrifugation within 6 h. The levels of TSH, FT4, total triiodothyronine (TT3), and thyroid peroxidase antibody (TPOAb) were measured using the Architect i2000 immunoassay  according to the manufacturer’s protocol. The TPOAb concentration was considered positive when levels were above 5.61 IU/mL. The reference ranges for TSH, FT4 and TT3 were defined by the 2.5th and 97.5th percentiles of the entire population of pregnant women who gave birth in our hospital between January 2016 and December 2018 after exclusion of twin pregnancies, IVF, women who had other pre-existing thyroid diseases and women with positive TPOAb. Neonatal plantar blood was collected within one week after delivery, and TSH levels were measured according to the manufacturer’s protocol.Z scores based on the gestational age-specific means and standard deviations of the corresponding measurements. An early ultrasound scan of the crown-rump length was used to correct gestational dating when the difference using the last menstrual period was equal to or greater than 7 days. The TSH indices of neonatal plantar blood were measured within one week of birth.The primary outcome was neonatal birth weight (in grams) of live born, full-term neonates . Birth weight was measured by midwives and obstetricians attending birth and was studied as a continuous variable. SGA was defined as a gestational age-adjusted birth weight below the 10th percentile in the study cohort. Large for gestational age (LGA) was defined as a gestational age-adjusted birth weight above the 90th percentile in the study cohort. To combine and compare birth weights according to gestational age, we standardized the raw birth weight using 2). Information on fertility treatment and fetal sex was obtained from midwives and obstetricians.Information on covariates was obtained from questionnaires and clinical registries during pregnancy, including gestational age at birth, maternal age, parity, educational level, pregnancy-induced hypertension, gestational diabetes mellitus, and medication use. At the first outpatient visit, maternal height and weight were measured to calculate the BMI  method. After excluding missing values, the research objects were matched between the LT4 supplementation group and the control group according to the scores of potential variables on gestational age at birth, maternal age, BMI, gestational hypertension, gestational diabetes, fetal sex, and maternal thyroid function indices.Continuous and categorical variables were expressed as mean ± standard deviation (SD) and percentages, respectively. Birth weight was adjusted for gestational age at delivery. The differences in maternal thyroid function in the first and third trimesters of pregnancy, as well as neonatal TSH of plantar blood and birth weight were compared using Student’s t-test or Mann-Whitney test. The rates of SGA and LGA were compared between the two groups using the χP < 0.05.All statistical analyses were performed using R statistical software  or IBM SPSS Statistics for Windows . Statistical significance was set at After exclusion of twin pregnancies, IVF, and other pre-existing thyroid diseases, the final study population comprised 278 pregnant women with a history of thyroidectomy for thyroid cancer and 39,363 pregnant women without thyroid surgery (All thyroidectomies were performed before pregnancy. The median time from thyroidectomy to pregnancy was 4 years (2-7 years). In this group, the dose of LT4 was determined based on the level of TSH, and the mean LT4 dose was 122.5ug per day (87.5–200ug/d). Some cases increased the dose of LT4 during pregnancy, with the increased dose ranging from 12.5ug to 50ug per day, which is about 12.5%–33.3% increase in the percentage of the initial dose. All pregnant women were administered oral LT4 throughout their pregnancies.vs. 14.24 ± 1.71, P < 0.001) and third trimesters , and the TT3 level in the LT4 supplementation group was significantly lower both in the first  and third trimesters . The mean TSH level in the LT4 supplementation group was not significantly different from the control group. The differences in the maternal thyroid function indices between the two groups are shown in When comparing the differences in the maternal thyroid function indices in the first and third trimesters of pregnancy between the two groups, the FT4 level in the LT4 supplementation group was found to be significantly higher both in the first  . After propensity score matching, there was no significant change in the directionality of the difference in birth weight . Subgroup analysis revealed a consistent difference in men before and after propensity score matching. However, there was no significant difference in the risk of SGA between the LT4 supplementation group and the control group . The results are presented in We found a difference in the TSH level of neonatal plantar blood within a week of birth between the two groups, and the mean neonatal TSH level was lower in the LT4 supplementation group than in the control group. The whole neonatal birth weight was significantly lower in the LT4 supplementation group than in the control group (3292 g P=0.014) (P=0.019)  or in the adjusted model (P=0.004). Interestingly, maternal TSH levels had a significant positive association with neonatal birth weight when maternal TSH was roughly in the normal range, which transformed to a slight negative association for high TSH levels .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.


We aimed to explore associations between maternal psychosocial risk factors and deviation in child gestational EA at birth  in a South African birth cohort study—the Drakenstein Child Health Study. Maternal psychosocial risk factors included trauma/stressor exposure; posttraumatic stress disorder (PTSD); depression; psychological distress; and alcohol/tobacco use. Child gestational EA at birth was calculated using an epigenetic clock previously devised for neonates; and gestational EA deviation was calculated as the residuals of the linear model between EA and chronological gestational age. Bivariate linear regression was then used to explore unadjusted associations between maternal/child risk factors and child gestational EA residuals at birth. Thereafter, a multivariable regression method was used to determine adjusted associations. Data from 271 maternal-child dyads were included in the current analysis. In the multivariable regression model, maternal PTSD was significantly and negatively associated with child gestational EA residuals at birth , controlling for study site, sex of the child, head circumference at birth, birthweight, mode of delivery, maternal estimated household income, body mass index (BMI) at enrolment, HIV status, anaemia, psychological distress, and prenatal tobacco or alcohol use. Given the novelty of this preliminary finding, and its potential translational relevance, further studies to delineate underlying biological pathways and to explore clinical implications of EA deviation are warranted.Accelerated epigenetic aging relative to chronological age has been found to be associated with higher risk of mortality in adults. However, little is known about whether and how  Maternal exposure to psychosocial risk factors during pregnancy—including traumatic stressors, psychiatric disorders and symptoms, and substance misuse – constitute a notable public health concern; and may be associated with poor birth outcomes and adverse health and development in affected children –3. GivenAccelerated epigenetic aging—i.e., greater DNAm gestational age relative to chronological age—has been found to be associated with increased risk of mortality in adults –14 , an ongoing, interdisciplinary, longitudinal birth cohort study investigating determinants of maternal-child health in a poor, peri-urban South African community –22. We hPregnant women were recruited at 20–28 weeks’ gestation from two primary care clinics in the Drakenstein sub-district in Paarl, Western Cape, South Africa—one (TC Newman) serves a predominantly mixed ancestry community; while the other (Mbekweni) serves primarily a black African ancestry community. Within the DCHS, mothers are followed throughout pregnancy and childbirth until the index child is at least 5 years old –22. GeneStatistical Analyses, below).For this analysis, samples of mothers with complete and accurate sociodemographic, biomedical and psychosocial phenotype data; with recorded maternal informed consent; and with non-contaminated Illumina Infinium HumanMethylation450K or MethylationEPIC BeadChip umbilical cord blood data were eligible for inclusion   or MethylationEPIC  BeadChip cord blood data , 29% of the study sample reported symptoms of psychological distress on the SRQ-20. Similarly, a quarter scored above threshold for depression on the BDI-II (25%) ). Alcohol consumption during pregnancy was reported in 17% of participants, and prenatal tobacco use in 29%. A notable site-specific difference was evident, with the prevalence of tobacco use significantly higher among mothers from TC Newman.More than half (55%) of children in this study sample was male; and the median (IQR) gestational age at birth was 39  weeks, Table β = 1.87; p = 0.026), newborn head circumference at birth , birth weight  and weight-for-age z-score at birth , each was found to be significantly positively associated with gestational EA residuals at birth, using the conventional p-value < 0.05 cut-off. When accounting for potential trend-level relationships (p < 0.1), positive associations with the outcomes of interest were also noted for estimated household monthly income of less that ZAR 1000 (≈USD 70) , maternal body mass index  at enrolment  and maternal anaemia .In bivariate unadjusted analyses, mode of delivery  and low infant birthweight  were found to be significantly negatively associated with gestational EA residuals at birth; while maternal HIV  and PTSD  showed trend-level negative associations , when controlling for study site, sex of the child, head circumference at birth, birthweight, mode of delivery, maternal estimated household income, BMI at enrolment, HIV status, anaemia, psychological distress, prenatal tobacco use and alcohol consumption, Table In the final multivariable regression model, maternal PTSD was significantly and negatively associated with gestational EA residuals at birth  deviation at birth in the index children, we found a negative association with EA residuals in children born to mothers with PTSD (compared to those without such exposure), when controlling for a number of relevant covariates.n = 96), assessing pre- and post-deployment EA reported that the development of PTSD symptoms was associated with a relative decrease in EA over time  [These findings are comparable to emerging—albeit mixed—evidence of trauma-/PTSD-associated EA deviation in adult combat veterans. For example, recent work has demonstrated a positive association each between lifetime PTSD severity  and PTSDs study) .N = 101) reported a positive correlation between age acceleration  and direct exposure to neighbourhood violence in children aged 6–13 years [Work in paediatric study samples has yielded similarly varied findings. For example, one recent study , we also included study site as a covariate in the multivariable regression model. Fifth, gestational age estimation (including by ultrasound) may be prone to notable measurement error –68, whicThese limitations notwithstanding, our study provides a unique preliminary exploration of associations between maternal psychosocial risk factors and child gestational EA deviation at birth in a high-risk LMIC environment. To the best of our knowledge, an association between maternal PTSD and gestational EA deviation in the index children has not previously been reported. Future studies—incorporating larger samples sizes and cross-tissue analyses—are warranted in order to explore such associations further; and to delineate underlying neurobiological mechanisms. In addition, work is needed to understand the implications of EA deviation at birth. For example, it is currently unknown whether and how EA deviation may also be associated with adverse neurodevelopmental outcomes in the affected children, although interest in this field is growing . FurtherSupplementary Table A


Early life factors influence the number of nephrons a person starts life with and a consequence of that is believed to be premature kidney ageing. Thus, we aimed to identify early life factors associated with cystatin C and creatinine-based estimated glomerular filtration (eGFR) rate equations and urine -albumin-to-creatinine ratio after a follow-up of 46–67 years.The study included 593 Swedish subjects without diabetes mellitus from the Malmo Diet Cancer Cohort. Perinatal data records including birth weight, gestational age, placenta weight and maternal related risk factors were analysed. eGFR was determined by Chronic Kidney Disease Epidemiology (CKD-EPI), the Lund-Malmö revised and Caucasian, Asian, Paediatric, and Adult (CAPA) equations. Postnatal growth phenotypes were defined as low (≤ 0) or high (> 0) birth weight z-score, or low (≤ median) or high (> median) body mass index at 20 years of age.p = 0.04). Men with high birth weight z-score and high BMI at 20 years had lower risk for albuminuria .In women, lower birth weight was associated with lower eGFR . Birth weight z-score predicted adult albuminuria specifically in men . Women with high birth weight z-score and low BMI at 20 years had lower eGFR (CAPA; CKD-EPI cystatin C; Lower birth weight, prematurity and postnatal growth curve have a potential sex- specific effect of early exposure to an adverse environment on lower cystatin C-based eGFR and albuminuria later in life. Cystatin C compared to creatinine -eGFR equations shows a higher ability to detect these findings. Kidney senescence, dependent on predicted anatomical and structural changes, is a separate process from kidney disease  and maniRenal functional capacity is influenced by factors acting early in life, such as intrauterine environment, maturity, birth weight, length at birth, placental weight, etc. –9. EarlyIn a recent meta-analysis  the stroThe evaluation of kidney function is based on glomerular filtration rate (GFR) that can be measured (mGFR) or estimated (eGFR) from equations based on creatinine or cystatin C which are used worldwide . During We aimed to identify how early life factors affect adult kidney function, by introducing cystatin C-based GFR equations and kidney damage, determined by urine albumin-to-creatinine ratio (UACR), in a cohort with very long follow-up, i.e., more than 40 years. We hypothesize that in middle-aged and elderly Swedish subjects, changes in kidney function capacity, represented as lower eGFR, and albuminuria, are influenced by early life factors such as low birth weight, prematurity, discrepant birth weight to placental weight ratio, and postnatal growth mismatch phenotype.. Furthermore, a random 50% of MDCS participants were invited to participate in carotid artery disease epidemiological analysis (the cardiovascular arm of MDCS (MDCS‐CC)). Due to lower response rate a total of 6,103 participants completed the MDCS-CC study , high-birth weight-z-score/lowBMI20—OR 0.73, 95% CI .The odds of albuminuria (adjusted for age and pulse pressure) were significantly This observational, population-based study supports our hypothesis that in middle-aged and elderly Swedish subjects sex-specific associations exist between early life factors and kidney function, defined as cystatin C-based eGFR, as well as with albuminuria. This study also confirms that cystatin C compared to creatinine is a more sensitive marker for demonstrating these associations.Despite the growing evidence that low birth weight together with developmental exposure to an adverse environment acting on the kidney might result in lower nephron/podocyte endowment , 34, thelower adult eGFR as determined by the CKD-EPI cystatin C equation, but not by eGFR creatinine equations. In women this association was even more pronounced, revealing a significant association between low birth weight and low eGFR acquired by both cystatin C equations (CAPA and CKD-EPI cystatin C).Previous studies, including those listed in two recent meta-analyses, , 35 havehigher eGFR based on creatinine (LMrev equation). In contrast, a decreased birth weight to placenta weight ratio has been previously reported to be related to worse perinatal outcome [Interestingly, we found that in men a decreased birth weight to placenta weight ratio, reflecting suboptimal fetal growth, when adjusted for age, gestational age, parity and pulse pressure, was related to  outcome  and both outcome . This co outcome  that sho outcome  and init outcome .Lower cystatin C-based eGFR  was observed in adult women with high-birth weight-z-score/lowBMI20 phenotype indicating slowed postnatal growth. We could not find that in men. However, adult men with high-birth weight-z-score/highBMI20 phenotype, indicating subjects with normal to high birth weight who had higher than median BMI at 20 years of age (> 21.7 kg/m2), had a lower risk of albuminuria. These findings highlight the importance of postnatal risk factors, e.g. over-nutrition [mismatch phenotype), did not have lower eGFR compared to the reference group. The mismatch phenotype has been previously linked to hypertension [Furthermore, to the best of our knowledge we are the first to report that different postnatal growth mismatch phenotypes affect human adult kidney function. utrition , for thertension  and therlower risk of albuminuria in adults born with normal to higher birth weight, also evident in men. A 2008 report of the National Kidney Foundation's Kidney Early Evaluation Program [Albuminuria, an unfavourable marker of renal outcomes , has bee Program  stated tFurthermore, our findings could be explained by several possible pathways. First of all, early life factors are associated with hypertension , 49 and The strength of this study is that we report data after a long follow-up period, on average 58 years, which means current middle-aged and elderly Swedish subjects. Another strength is that we report kidney function measured by cystatin C and that we use different up-to-date cystatin C and creatinine eGFR equations against a background of different early life factors. Cystatin C is a more sensitive marker of kidney function compared to creatinine, as reported elsewhere . It is wLimitations include that the study was restricted to people born in Sweden between 1926 and 1945, and that the study sample was relatively small. Our results could be biased due to the unequal sex distribution in the study sample, reflecting the source study (MDCS) , and theIn summary, here we report that a history of prematurity, irrespective of sex, and lower birth weight in women, are factors associated with lower cystatin C-based eGFR, while in men a history of lower birth weight (z score) is a risk marker for adult albuminuria. Cystatin C-derived eGFR equations show a higher ability to detect these findings compared to creatinine eGFR equations. A postnatal growth catch-up phenotype is not related to lower eGFR per se. The introduction of cystatin C in modern research has made it easier to describe these associations. We identified the protective phenotype (high-birth weight-z-score/highBMI20) for albuminuria in men and the unfavourable phenotype (high-birth weight-z-score/lowBMI20) for lower cystatin C-based eGFR in women. The observed association in men between birth weight to placenta weight and creatinine based eGFR (LMrev equation) could possibly indicate hyperfiltration and needs further investigation. The findings in general suggest that lower birth weight and postnatal growth phenotypes have a potential sex-specific influence on kidney function in middle-aged and elderly Swedish subjects. Our findings suggest that women seem to be more affected by early life factors when compared to men. Further studies are warranted to address the prognostic value of early life factors for adult kidney function and risk of renal disease across the life course.


Over the past decade, electric vehicles (EVs) have been considered in a growing number of models and methods for vehicle routing problems (VRPs). This study presents a comprehensive survey of EV routing problems and their many variants. We only consider the problems in which each vehicle may visit multiple vertices and be recharged during the trip. The related literature can be roughly divided into nine classes: Electric traveling salesman problem, green VRP, electric VRP, mixed electric VRP, electric location routing problem, hybrid electric VRP, electric dial-a-ride problem, electric two-echelon VRP, and electric pickup and delivery problem. For each of these nine classes, we focus on reviewing the settings of problem variants and the algorithms used to obtain their solutions.