Preterm infants often have long hospital stays and frequent blood tests; they often develop anemia requiring multiple blood transfusions. Placental transfusion via delayed cord clamping (DCC) or umbilical cord milking (UCM) helps increase blood volume. We hypothesized umbilical cord milking (UCM), together with DCC, would be superior in reducing blood transfusions.To compare the effects of DCC and DCC combined with UCM on hematologic outcomes among preterm infants.One hundred twenty singleton preterm infants born at 280/7- 336/7 weeks of gestation at Thammasat University Hospital were enrolled in an open-label, randomized, controlled trial. They were placed into three groups (1:1:1) by a block-of-three randomization: DCC for 45 s, DCC with UCM performed before clamping (DCM-B), and DCC with UCM performed after clamping (DCM-A). The primary outcomes were hematocrit levels and number of infants receiving blood transfusions during the first 28 days of life. Intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC) were secondary outcomes. Analyses were performed with an intent-to-treat approach.p = 0.88), receiving blood transfusions 25%, 20%, and 12.5% (p = 0.24), incidence of NEC 7.5, 0 and 10% (p = 0.78) in the DCC, DCM-B and DCM-A groups, respectively. There were no preterm infants with severe IVH, polycythemia, maternal or neonatal death.One hundred twenty preterm infants were randomized. There was no statistically significant difference in neonatal outcomes; hematocrit on admission 54.0 ± 5.5, 53.3 ± 6.0, and 54.3 ± 5.8 (The placental transfusion techniques utilized, DCC and DCC combined with UCM, provided the same benefits for preterm infants born at GA 28 and 33 weeks in terms of reducing the need for RBC transfusions, severities of IVH and incidence of NEC without increasing comorbidity.TCTR20190131002. Registered 31 January 2019—Retrospectively registered. Currently, performing delayed cord clamping (DCC) is the standard care practice recommended for preterm infants by many professional organizations , 2. PretIn preterm infants, umbilical cord milking (UCM) has the same benefits as DCC in terms of red blood cell (RBC) transfusion requirements , 11. A mIn a study of preterm infants born by cesarean section, the DCC group had a blood volume greater than the early cord clamping group . However0/7- 33 6/7 weeks at Thammasat University Hospital, Pathumthani, Thailand, between July 1st, 2016, and December 31st, 2018 were enrolled in a randomized controlled trial by the delivery nursing team. We excluded infants who were multiples, diagnosed with severe disabilities, having chromosomal abnormalities, hydrops fetalis, intrauterine growth retardation, or from mothers with placenta previa with hemorrhage, abruption placenta, prolapsed cord, or having fetal distress before birth, as well as those mothers who were giving birth before or on arrival, or unable to give consent. Of note, after enrollment, no infant had fetal distress. This study was approved by the Human Research Ethics Committee No.1, Faculty of Medicine, Thammasat University. The informed consent was obtained before delivery by our research staff.Preterm infants born at GA 28Participants were divided into three groups (1:1:1) by a block-of-three randomization using sealed envelopes, performed by the research team. Envelopes were opened by the delivery nursing team, when mothers commenced preterm labor and had at least four regular uterine contractions in 20 min with cervix dilatation > 4 cm or when mothers had preterm birth scheduled due to severe preeclampsia.DCC means delaying cutting the umbilical cord after birth for 45 s. DCM-B is DCC for 45 s with an obstetrician then performing UCM on about 25 cm length of the cord three times, then cutting the umbilical cord. DCM-A is DCC for 45 s with the umbilical cord cut to around 25 cm length; after this, the pediatrician milks the umbilical cord toward the infant three times, and the cord is cut to standard. Digital clocks were used to time the procedure.During these interventions, infants born by cesarean section were placed on the maternal abdomen, and for those born by vaginal delivery, the obstetrician held the infant at the maternal vaginal level.After cutting the cord, the preterm infants were wrapped in a plastic bag and placed on a warm mattress under the radiant warmer. Neonatal resuscitation was decided by the attending physician at birth.st and 4th week of age. If an infant was discharged home before 28 days of life, there was an appointment to follow up and check hematocrit levels at the 4th week of age.All infants received our standard care. Our feeding protocol started when the infant had been stable for at least 24 h, then trophic feeds of 10–15 ml/kg/day were initiated for two days, and advanced in increments of 15–20 ml/kg/day. After the infant could tolerate 120 ml/kg/day of milk for two days at 12–14 days of age, a starter iron supplement of 4 mg/kg/day was given. In addition, an ultrasound brain screening was performed between 14 and 28 days of life by a pediatric radiologist who was blinded to the intervention. Jaundice was assessed using serum microbilirubin, and verification of hematocrit levels within one hour of birth was checked at 12O and/or needing fractional inspiratory oxygen ≥ 0.3, II. infants requiring mechanical ventilation with mean airway pressure < 8 cmH2O and/or needing fractional inspiratory oxygen ≤ 0.3 with significant apnea and bradycardia, tachycardia (> 180 beats per minute) or a respiratory rate of more than 80 breaths per minute, weight gain of less than 10 g/day over 4 days, or sepsis; or III. Infants who had a hematocrit of less than 25%.All outcomes were analyzed by blinded team researchers who did not know the code of the intervention. The primary outcome was preterm infants received RBC transfusions within 28 days of age. RBC transfusion was given 10–15 ml/kg for preterm infants who had one of these 3 conditions: I. infants requiring mechanical ventilation with mean airway pressure ≥ 8 cmHNeonatal outcomes such as IVH , NEC deAladangady N, et al. showed that preterm infants who received DCC for 30–45 s had increased blood volume 2–16 ml/kg and 10–28 ml/kg at cesarean and vaginal birth, respectively . Hence, Katheria AC, et al. had 52% of the preterm infants in their DCC group who received blood transfusions . We, theP < 0.05 is considered significant. Data analyses were performed using an intent-to-treat basis.Demographic data was reported using percentage (%), mean, and SD median. ANOVA test was used to compare continuous variables that were normally distributed; Kruskall-Wallis was used for continuous variables not normally distributed. Pearson chi-square and Fisher’s exact test compared categorical outcome variables. n = 24), diagnosis with severe disabilities (n = 3), chromosomal abnormalities (n = 1), hydrops fetalis (n = 1), intrauterine growth retardation (n = 8), mother with placenta previa with hemorrhage or abruption placenta (n = 3), prolapsed cord (n = 2), fetal distress before birth (n = 7), birth before or on arrival (n = 15), and absence of consent (n = 8)  as shown in Table p = 0.22) and NEC (p = 0.78) as shown in Table The primary outcome of the number of infants needing RBC transfusions during the first 28 days of life was not statistically significant in the DCC, DCM-B, and DCM-A groups (0/7- 36 6/7 weeks) than those in our study (GA 280/7- 33 6/7 weeks) [UCM combined with DCC; DCM-B or DCM-A should, theoretically, increase blood volume in preterm infants, compared to DCC alone. In our study, all three techniques showed no variations in hematocrit after intervention. Preterm infants in DCM-B (20%) and DCM-A (12.5%) groups requiring blood transfusion were fewer than those in DCC (25%) group but it was not significantly different. Our study had a lower rate of infants requiring transfusion compared to Jasani B et.al, a systematic review and network meta-analysis, which showed the rate of infants needing RBC transfusion in DCC group (38.3%) compared to immediate cord clamping (ICC) group (46.9%), and UCM (32.3%) compared to ICC group (46.9%) . There w7 weeks) . Second,7 weeks) . Our praPlacental transfusions also reduced the incidence and severity of IVH as well as NEC. Our study showed NEC incidence was 0—10%, averaging 5.8%, versus our previous report at 15%  and no iNo observable negative effects occurred; most importantly, there were no cases of polycythemia, or neonatal death, and no maternal postpartum hemorrhage or death. Another benefit was that hypothermia incidence was reduced by half, compared to our prior intervention period. Shirk SK, et al. reported that performing DCC or UCM in low birthweight infants made the infants warmer than immediate cord clamping as placental transfusion gives warm blood . As is g0/7- 33 6/7 weeks, requiring fewer transfusions than the preterm infants (GA 230/7- 316/7 weeks) in Katheria and colleagues’ study, who needed more transfusions overall because of their extreme prematurity. Other factors that may affect the volume of placental transfusion, including uterine contractions and the onset of infants’ ventilation, were not collected and may have contributed to our results. Our predetermined effect of DCC combined with UCM was unlikely to be detected in our small sample size. Hence, a larger population is required in future studies. Nonetheless, long-term follow up for neurodevelopmental outcomes should be future research.Our study was novel in comparing DCM-B and DCM-A to DCC in a randomized controlled trial. However, our outcomes lacked statistical significance because the sample size was small. Compared to previous studies, the number of preterm infants requiring transfusions in our study was also lower. This may be due to the difference in GA; the preterm infants in our study delivered at GA of GA 286/7 weeks in terms of reducing the need for RBC transfusions, severities of IVH and incidence of NEC without increasing comorbidity.All placental transfusion techniques, DCC and DCC combined with UCM, provided the same benefits for preterm infants born at GA of 28 and 33


Piglets experience a significant temperature drop soon after birth and the time taken to recover can impact their survival and growth. Rectal temperature is the best method currently used to monitor temperature change, however, it is invasive and requires handling which can be stressful. Infrared camera technology has improved and surface temperature has been suggested to be a good substitute for rectal temperature. A study was undertaken to investigate the utility of infrared measurements of piglets from immediately after birth to 24 h old. Results showed that surface temperature had a similar temperature pattern to rectal temperature but was highly affected by the environment and cannot be recommended as a substitute for rectal temperature measurement.The use of infrared cameras to record surface temperature has shown some promise in older pigs, but neonatal piglets are metabolically less mature and experience rapid temperature changes during their first 24 h. The present experiment aimed to compare rectal temperature to surface temperature at the base of the ear, measured using an infrared camera, for piglets of different birth weights. During farrowing, 48 multiparous sows were monitored, and rectal and surface temperatures were recorded for their lower-birth-weight (≤1.2 kg) piglets within 3 min of birth and at 0.25, 0.50, 0.75, 1, 1.25, 1.50, 2, 3, 4, and 24 h. Piglet birth weights were assigned to one of three categories (BWC): BWC1 (≤0.80 kg), BWC2 (0.81 to 1.10 kg), or BWC3 (1.11 to 1.20 kg). Piglet rectal temperatures at 1.25 h after birth were assigned to one of three categories: RC1 (≤32.0 °C), RC2 (32.1 to 35.0 °C), or RC3 (≥35.1 °C). Surface temperatures showed a similar recovery pattern to rectal temperatures in the first 24 h across all piglet birth weights, although large and variable differences seen in the current study militate against surface temperature being an appropriate replacement for neonatal rectal temperature for use in production. Piglets are born wet and into an environment that is significantly cooler than conditions in utero 38–40 °C) ,2, leadi8–40 °C ,Smaller piglets have a greater surface area to volume ratio than heavier piglets, and thus have a proportionately greater potential for heat loss and reduction in the ability to thermoregulate . ConsequRectal temperature is the gold standard for measuring the internal temperature of pigs as it is relatively unaffected by external factors. However, repetitive rectal thermometer readings to monitor temperature changes and to identify critical periods for the piglets is an invasive procedure which can become stressful for the piglet . This inA variety of different infrared thermometers and cameras can indicate core temperature, but are affected by factors such as distance from the animal . In thatThis experiment was conducted during September and October at a commercial piggery  and was approved by the Rivalea Animal Care and Ethics Committee (Protocol number 20R027) in accordance with the Australian Code for the Care and Use of Animals for Scientific Purposes .Multiparous Large White × Landrace sows  were moved into their farrowing accommodations at 110 d (±2 d) of gestation, being housed in individual farrowing crates equipped with sow- and piglet-level nipple drinkers and a heat lamp positioned centrally over one side (creep area). The sows were fed 2.5 kg/day of a standard lactation diet formulated to provide 15 MJ DE/kg, 16.7% protein, and 0.90% SID lysine from entry into the farrowing house until farrowing (116 ± 1.5 d of gestation). Farrowings were observed and measurements were recorded daily from 0600 h to 1900 h. Once farrowed, sows were fed to appetite via hand feeding twice per day until weaning (21 ± 2 d of lactation). The farrowing rooms were semi-enclosed with natural ventilation and a dripper cooling system was set to automatically activate at 28 °C. Additional portable evaporative coolers were placed in the shed at sow entry and used until 2 weeks after farrowing to aid in temperature control.Piglets weighing ≤ 1.2 kg at birth and born during normal working hours over a 3-day farrowing period were included in this trial. Based on these constraints, 67 piglets  born to 48 sows were included in the experiment. Piglet birth weights were assigned to one of three categories: BWC1 (≤0.80 kg), BWC2 (0.81 kg to 1.10 kg), or BWC3 (1.11 to 1.20 kg). Within 3 min of birth (0 h), piglet surface and rectal temperatures were recorded after they were moved into a semi-enclosed container positioned over a scale and were individually ear tagged, weighed, and their sex recorded. Rectal temperatures were measured using a standard digital thermometer with a lowest possible reading of 32 °C (0.3 °C sensitivity). Surface temperature was measured at the base of the right ear  using a All statistical analyses were performed using SAS version 9.4 . There were 737 piglet-related data point observations available for analysis. After bootstrapping the data at a root of 24 possibilities per piglet ID, 11,196 piglet observations were available for analysis. For the data analysis:Piglet birth weights were assigned to one of three categories: BWC1 (≤0.80 kg), BWC2 (0.81 kg to 1.10 kg), or BWC3 (1.11 to 1.20 kg).Piglet rectal temperatures at 1.25 h after birth were assigned to one of three categories: RC1 (≤32.0 °C), RC2 (32.1 °C to 35.0 °C), or RC3 (>35.0 °C).r) and the respective 95% confidence intervals. Correlation was deemed very high if r ≥ 0.90, high if r was between 0.70 and 0.89, moderate if r was between 0.50 and 0.69, low if r was between 0.30 and 0.49, and negligible if r < 0.30 [p < 0.05.The correlation between the rectal and surface temperatures across body weight categories were estimated using PROC CORR, with the output being the Pearson correlation coefficient p < 0.001), although the initial surface temperatures recorded were at least 4 °C lower than the rectal temperatures  that suBirth weight significantly influenced the rectal and surface temperature profiles of piglets during their first 24 h of life. None of the smallest piglets BWC1) had rectal temperatures above 35 °C at 1.25 h. However, if they did have a relatively higher temperature, <35 °C, their rate of survival increased. A relationship between temperature (and hypothermia) and birth weight has been established for piglet preweaning survival [ had rectSimilar to previous research, piglet temperatures had decreased by 0.25 h post-birth, although the start of recovery was evident from 0.5 h rather than 1 h as previously documented . This waThese findings, along with the physiology of the piglet, highlight the importance of good management from early life to ensure optimal survival. Providing an optimal environment from birth is critical to support this; however, arguably the most important strategy to improve survival is to ensure fast and adequate access to colostrum, particularly for low-birth-weight piglets. Colostrum intake is positively related to rectal temperature and provides the critical energy required to thermoregulate and build an immune response, thus setting the piglets up for survival ,26. BeinOther studies which have focused on the use of infrared thermal technology in piglets have concluded that this technology has the potential to be an effective, less invasive tool for temperature measurement, albeit not identical to rectal temperature . There aSurface temperature measured using infrared thermal camera technology at the base of the ear produces large variations compared to rectal temperature, although the recovery pattern was similar. Therefore, these devices cannot be recommended for use in commercial settings at this stage. Birth weight and temperature are directly related and should be considered together when monitoring piglets.


Objective To investigate the association between prenatal care (PNC) adequacy indexes and the low birth weigth (LBW) outcome.Methods A total of 368,093 live term singleton births in the state of Rio de Janeiro (Brazil) from 2015 to 2016 were investigated using data from the Brazilian Live Birth Information System . Seven PNC adequacy indexes were evaluated: four developed by Brazilian authors  and three by authors from other countries . Adjusted odds ratios were estimated for the PNC adequacy indexes by means of multivariate logistic regression models using maternal, gestational and newborn characteristics as covariates.Results When the PNC is classified as “inadequate”, the adjusted odds ratios to the LBW outcome increase between 42% and 132%, depending on which adequacy index is evaluated. Younger (15 to 17 years old) and older (35 to 45 years old) mothers, those not married, of black or brown ethnicity, with low schooling (who did not finish Elementary School), primiparous, with preterm births, as well as female newborns had increasing odds for LBW. The models presented areas under the receiver operating characteristic (ROC) curve between 80.4% and 81.0%, and sensitivity and specificity that varied, respectively, between 57.7% and 58.6% and 94.3% and 94.5%.Conclusion Considering all PNC adequacy indexes evaluated, the APNCU had the best discriminatory power and the best ability to predict the LBW outcome. Low birth weight LBW, < 2,500 g) is considered an important risk factor for neonatal and postnatal mortality. Neonates with LBW have an increased risk of death during the first months and years of life, and a higher risk of health-related issues, such as hindered growth and development, damage to vision, learning difficulties, hyperactivity, and increased risk of developing chronic diseases in adulthood.,500 g isLow birth weight is directly caused by preterm births (pregnancy duration < 37 weeks), fetal growth restriction, or by both processes simultaneously (resulting in the most severe cases).The importance of PNC during pregnancy is well documented in the literature. Observational studies showed lower maternal and perinatal mortality when PNC was performed.On the other hand, the influence of PNC on birth weight is not a consensus among authors.The relationship between PNC and the occurrence of unwanted pregnancy outcomes remains unclear and requires further studies. Therefore, the present study aims to investigate the association between different levels of adequacy of PNC and LBW, using data of singleton live births in the state of Rio de Janeiro (RJ), Brazil, between 2015 and 2016.Several countries maintain large databases with information on live births that provide subsidies for health system interventions, such as public policies on mother and newborn health. In Brazil, this information is recorded in the Live Birth Information System , which compiles obstetric, demographic and social characteristics of women in addition to date regarding the utilization of PNC. Nevertheless, the number of studies using data from the SINASC addressing LBW indexes is small.The present research is based on SINASC data pertaining to the state of RJ.The adequacy of PNC was assessed using indexes developed in Brazil , the pregnancy ,Unreported or implausible cases were excluded, based on the following criteria: Robson classification > 10; number of PNC consultations > 42; mother's age ≤ 16 years and complete higher education; mother's age ≤ the sum of 12 plus the total number of previous births (live or still). The APNCU index  was recalculated based on the information provided by the database, and was called recalculated APNCU. The categorization of the variables is shown inp < 0.20 in the preliminary bivariate analysis.The association between the PNC adequacy indexes (independent variable) and LBW (dependent variable) was investigated using logistic regressions controlled by the following covariates: maternal age , marital status (with or without partner), schooling (incomplete or complete Elementary School), ethinicity (white or non-white), parity , gestational age  and newborn gender . We followed the categories originally proposed by the PNC adequacy indexes. For each independent variable, a simple logistic model was initially performed, with “birth weight” as a dependent variable . The aforementioned covariates were preselected from the literatureAdjusted Odds Ratios (ORs) for each index were calculated based on multiple regression models with the independent variables that showed statistical significance. Modeling was also carried out considering the interactions between the PNC adequacy indexes and the control variables, as well as the interactions between the mother's age and the parity variables.The significance and predictive capacity of the models were assessed using the Global Significance Test (Omnibus test), model sensitivity and specificity.During the study period, 64% of live births in RJ referred to mothers aged between 21 and 34 years, 65% without a partner, 97% with complete Elementary School, 56% without an occupation (unemployed or NA), 54% self-declared brown, and 42% primiparous . As forRegarding birth weight, it was normal in 87% of the cases, and low in 7.44%. The prevalence of LBW was higher in mothers aged 15 to 17 and 35 to 45 years, without a partner, with lower schooling, self-declared black, and primiparous or with more than four previous deliveries. It was also more frequent in preterm pregnancies and in female newborns. Most births were classified as having undergone “adequate PNC” in the indexes. The highest frequency of LBW was in the category “inadequate” on the Ciari Jr. et al.The adequacy of the PNC proved to be a significant variable with adjusted ORs of 1.34 and 2.52 for the “no PNC” category APNCU. In addThe models presented areas under the ROC curve between 80.4% and 81.0%, and sensitivity and specificity that varied, respectively, between 57.7% and 58.6%, and 94.3% and 94.5%. The optimal cutoff value for the prediction score was 0.30. All models were statistically significant according to the global significance test used (data not shown).Although there are several indexes to assess the adequacy of the PNC, their use actually lacks concrete epidemiological evidence. The present study used a large birth database from the state of R, from January 2015 to December 2016, in order to access the level of adequacy of the PNC and to investigate it as a risk factor for the outcome of LBW. Moreover, the proportion of LBW was calculated according to characteristics pertaining to the mother, , the pregnancy, the delivery, and the newborn.The rate of LBW in RJ was similar to that of other Brazilian studies,The frequency of cases with adequate PNC according to the Kessner et al.Adequacy of the PNC was an important risk factor for LBW, appearing as a significant variable in all models. Among the Brazilian indexes , the TaWith regard to the international indexes , the APThe maternal age categories in the present study were used to identify a possible influence of early (adolescent women) or late (women over 35 years of age) maternity on the outcome. This influence was detected for the 15 to 17 and 35 to 45 age groups, with the exception to the TakedaParity was also significant in the models pointing to a protective effect of previous pregnancies.The average chance of a non-white mother to give birth to a LBW newborn was greater than that of white mothers . This variable was significant in all models, and is convergent with other studies.The present study used the mother's schooling as a proxy variable, in order to capture the socioeconomic risk factor of LBW, and this variable appeared as statistically significant in all models. The mother's schooling is crucial to her ability to understand the importance of the PNC, so women with higher schooling tend to start PNC earlier and use it more than mothers with lower schooling.These present results highlight the importance of the adequacy of PNC on the LBW outcome. Among the evaluated indexes, the APNCUThe present study had as limitations the lack of information regarding the risk factors relevant to the aLBW outcome, such as smoking and alcohol consumption, drug use and malnutrition during pregnancy,Finally, the results suggest that special attention should be given to the APNCU


Extremely low birth weight (< 1000 g) still influences postsurgical prognosis in the neonatal and infantile periods. Additionally, the life expectancy of neonates with trisomy 18 is extremely poor owing to various comorbidities. Therefore, it takes courage to perform laparotomy for the purpose of treatment of congenital multiple intestinal atresia in a baby with an unpredictable life prognosis.Fetal ultrasonography revealed cardiac malformation, intestinal dilation, and physical characteristics suggestive of a chromosomal abnormality in this case. The patient was diagnosed with trisomy 18 after birth, with an extremely low birth weight. An atrial septal defect, ventricular septal defect, dilated jejunum, and a very thin collapsed small intestine were found on ultrasonography. With a diagnosis of congenital small intestinal atresia, a challenging laparotomy was done at 3 days of age, with jejunal atresia and multiple distal small intestinal atresia were observed. The jejunal end and distal small intestinal stump were separated into stomas at the wound edge. Hypertrophic pyloric stenosis developed at the age of 3 months and resolved with medication. The patient gained weight (2 kg) by daily stool injection into anal side of the intestine and decompression against poor peritonitis of dilated jejunum using enteral feeding tube for the long period. Finally, we could perform intestinal reconstruction safely and successfully at the age of 9 months.Tracheotomy was performed due to difficulty in extubation associated with chronic lung disease. The patient was discharged at the age of 1 year and 3 months, and no major problems were noted at the age of 2 years.We treat congenital intestinal atresia in extremely low birth weight infants with severe chromosomal abnormalities and severe cardiac malformations as follows: Stoma creation is performed quickly to avoid deterioration of the patient's hemodynamics. After that, while continuing enteric management, palliative cardiovascular surgery is performed as necessary, and the patient's body weight and intestinal tract status are determined to allow safe intestinal reconstruction. Extremely low birth weight (ELBW) influences the life prognosis after surgery in the neonatal and infantile periods , 2. AddiA male baby with a gestational age of 29 weeks and 6 days was delivered by emergency cesarean section with a birth weight of 699 g because of HELLP syndrome. Fetal ultrasonography revealed cardiac malformation, intestinal dilation, and physical characteristics suggestive of a chromosomal abnormality. After birth, rocker’s bottom foot and overlapping fingers were observed Fig. .Fig. 1ApThe patient was diagnosed with trisomy 18 based on G-band karyotyping. Atrial septal defects (ASD) and ventricular septal defects (VSD) were identified using echocardiography. The dilated jejunum and collapsed small intestine were detected using abdominal ultrasonography Fig. .Fig. 2AbWith a preoperative diagnosis of congenital jejunal atresia, we decided to perform a laparotomy at 3 days of age after discussing the patient’s life prognosis with the family and NICU staff. Jejunal atresia  was developed Fig.  and resoConsequently, intestinal reconstruction was delayed until body weight gain was achieved.When his body weight reached 2 kg, intestinal reconstruction was performed safely and successfully at the age of 9 months Fig. .Fig. 6WoHe underwent tracheotomy due to difficulty in extubation associated with chronic lung disease, and despite careful surgery, lymphorrhoea developed immediately after surgery and required sedation for several days. Eventually he was discharged from the hospital at the age of 1 year and 3 months. He has been living using a home respirator without any major problems.Recent advances in perinatal and neonatal care have increased survival rates of infants admitted to the neonatal intensive care unit (NICU), but extremely low birth weight (ELBW) or extremely lower operative weight is still associated with postoperative mortality , 2. RegaAssociation of HPS with Trisomy 18 has been previously reported . We suspWe wondered whether surgery should be performed for an extremely low birth weight neonate with trisomy 18, because he may suffer from severe mental retardation and require extensive nursing care even if he survives long term.After discussing with the patient’s family and NICU staff, we decided to perform a laparotomy to preserve the patient's life because the VSD and ASD were not symptomatic.A high survival rate was described for extremely low birth weight infants with congenital small intestinal atresia by primary anastomosis . HoweverAlthough there is some discussion to limit life-sustaining treatment for neonates with trisomy 18 , we opteHere, we encountered a rare case of trisomy 18 in a patient with ELBW, multiple congenital small intestinal atresia, and congenital heart malformations. We treat congenital intestinal atresia in extremely low birth weight infants with severe chromosomal abnormalities and severe cardiac malformations as follows: Stoma creation is performed quickly to avoid deterioration of the patient's hemodynamics. After that, while continuing enteric management, palliative cardiovascular surgery is performed as necessary, and the patient's body weight and intestinal tract status are determined to allow safe intestinal reconstruction. The family's opinion should also be considered.


The World Health Organization recommends universal vaccination of medically stable infants with Hepatitis B vaccine within 24 hours of birth to prevent mother-to-child transmission of Hepatitis B virus (HBV) infection. However, the proportion of infants who receive a timely birth dose is extremely low in Nigeria. We reviewed the implementation of an infant HBV vaccine schedule at a single center and identified factors affecting the receipt of a timely birth dose of HBV vaccine. We conducted a retrospective cohort study utilizing data from the INFANT study, a 2013–2017 prospective cohort study of pregnant women with and without HIV and their infants We utilized bivariate and multivariable logistic regression to assess if maternal characteristics, or the day of the week on which the infant was born were significantly associated with timely receipt of a birth dose of HBV vaccine. Receipt of HBV vaccine on the day of birth or the following calendar day were considered a timely birth dose. Among 409 infants in our cohort, 133 infants (33%) received a timely birth dose of HBV vaccine. Only the day of the week on which infants were born was significant (p<0.0001): when compared to Friday, infants born Monday through Thursday had significantly higher odds of receiving a timely birth dose, while infants born on a Saturday or Sunday had similar (low) odds. We found no association between maternal age, education, marital status, HIV status, parity and mode of delivery, and infant receipt of a timely birth dose of HBV vaccine. National immunization programs could improve timely HBV birth dose rates by providing access to vaccine immediately following birth at all infant delivery venues on all days of the week. Where not possible, there should be rapid linkage to the nearest facility where HBV vaccination is immediately available. Globally, approximately 257 million people are chronically infected with hepatitis B virus (HBV) . ChronicSeveral strategies and interventions have been recommended to prevent MTCT of HBV –13. ThesOf the 46 countries in sub-Saharan Africa, Nigeria is one of only 11 offering a vaccine schedule that includes a birth dose of HBV vaccine . HoweverWe conducted a retrospective cohort study utilizing data from the INFANT  study. INFANT was a prospective cohort study of mother-infant pairs at a tertiary hospital in North-Central Nigeria enrolled between 2013 and 2017 .Approval for the use of de-identified data from the INFANT study was provided by the University of Maryland Baltimore Institutional Review Board, and the Plateau State Specialist Hospital in Nigeria. For this study, consent was waived because it had been obtained previously during the parent study for the storage and use of stored samples in subsequent studies. Contacting patients to obtain additional consent would have been the only reason to utilize patient identifying information. Linking identifying information and contacting patients to obtain consent is associated with a risk of breach of confidentiality. This was avoided by obtaining a waiver of consent.Additional information regarding the ethical, cultural, and scientific considerations specific to inclusivity in global research is included in .Nigeria added HBV vaccine to its National Programme of immunization in 1995, but the vaccine was not widely available until 2004 . At the Pregnant women living with and without HIV were offered enrollment into the INFANT study as they attended antenatal clinic. At the time of registration for antenatal care, all pregnant women were tested for HIV as part of standard of care . For womParticipating pregnant women were to be at least 18 years of age, to have voluntarily chosen to breastfeed their infants and able to meet the study assessment schedule.Prospective participants were excluded if they had complications during pregnancy or delivery , if the subsequently delivered infant had neonatal asphyxia, seizures, or sepsis; if infant gestational age was less than 36 weeks at birth, or if infant birth weight was less than 2.5 kg. All infants were tested for HIV via DNA polymerase chain reaction at birth per study protocol, and between 4–6 weeks of life per standard of care, and any infants found to be HIV-infected were also excluded from the study .Questionnaires detailing maternal socio-demographic, clinical and obstetric factors, and infant birth, feeding, clinical and vaccination data were completed by research personnel via maternal participant interviews and medical record abstraction. Physical examinations of infants were performed by pediatricians and pediatric nurses on the research team, and blood, stool, saliva and breast milk collected by laboratory personnel on the research team at each study visit. The blood samples were processed and plasma aliquoted and stored in -80°C freezers within six hours of blood collection.All participants enrolled in the INFANT study were eligible for inclusion in our study. A de-identified data set containing maternal demographic information, maternal obstetric history, infant anthropometric and vaccination data from the INFANT study was obtained in line with the ethical provisions for such transfers.We excluded all second twins (n = 10) from our analysis.We determined the proportion of infants who received each of the birth, six-, and 14-week HBV vaccines  and the timing of HBV1 vaccine. The primary outcome measure was the proportion of infants who received a timely birth dose of HBV1 vaccine. We described the birth dose as a dose received within the first seven calendar days of life and a timely birth dose, as a dose given on the day of birth or the following calendar day.We conducted bivariate analysis using Pearson’s chi-square, Fisher’s, and t-tests as indicated to determine the association between covariates of interest and a timely birth-dose of HBV1 vaccine. We used this to identify variables to evaluate in multivariable logistic regression but adjusted for all variables identified a priori as potential confounders. Covariates included maternal factors thought to influence a mother’s decision to vaccinate her child or affect her ability to present her child for HBV vaccination at the clinic. These factors included maternal age, education, marital status, HIV status and parity. We also analyzed factors that may have incapacitated a mother and rendered her unable to present her child for vaccination soon after delivery, such as her mode of delivery; cesarean or vaginal. In view of the immunization clinic schedule of services (Tuesdays and Thursdays only), we evaluated the effect of the day of the week the infant was born on receipt of a timely birth dose. All analyses were conducted using SAS version 9.4.A total of 409 pregnant women and 419 infants had been recruited into the INFANT study. For our analysis, we included 409 mother-infant pairs from the INFANT study after excluding one infant each from ten pairs of twins. Nearly all infants  received HBV1; 95% (390/409) received HBV1 and HBV2 and 94% (384/409) received HBV1, HBV2 and HBV3 vaccines. Among the 404 infants that received HBV1, 91% (366) received a birth dose (within seven days of birth), yet only 33% received a timely birth dose of HBV1 vaccine.Maternal and infant factors associated with infants who received of a timely birth dose of HBV1 vaccine as compared to those that did not are summarized in In our study cohort, the proportion of infants who received the full 3-dose regimen of HBV vaccine was very high; much higher than the Nigerian national coverage for infant HBV in 2019, which were, 52% for birth dose and 57% for all three doses . This waSeveral factors could influence the timely receipt of an infant’s birth dose of HBV1 vaccine. Maternal factors such as marital status may reflect availability of (partner) support following delivery. Another important factor is if the index pregnancy was the mother’s first pregnancy. In such cases, the new mother may be unaware of all the services required for her newborn and may miss some services or obtain them late. Mothers who delivered by cesarean section are more likely to be incapacitated post-delivery, and thus may not obtain newborn services in a timely manner. However, in our study, none of the maternal factors we considered were significantly associated with the timely receipt of an infant’s birth dose of HBV1. Other studies identified maternal educational status to be associated with the odds of receipt of HBV1 vaccination within the first week of life , 26. TheOn evaluating infant factors, the day of the week the infant was born was significantly associated with the odds of receiving a birth dose of HBV1 vaccine. Infants born on Friday, Saturday and Sunday had similar (low) odds of receiving a timely birth dose of HBV1 vaccine; however, infants born on Monday, Tuesday, Wednesday, and Thursday had much higher odds of receiving a timely birth dose of HBV1 vaccine when compared to infants born on Fridays. This is not surprising, considering HBV vaccine was administered to infants only on Tuesdays and Thursdays at the study facility. This reinforces findings from previous studies in other African countries that sought to identify barriers to the receipt of a timely birth dose of HBV1 vaccine. These studies identified that the lack of daily vaccination services played a significant role in timely receipt of a birth dose of HBV1 vaccine , 26. FacWe were unable to utilize the standard definition for a timely birth dose of HBV vaccine (a dose given within 24 hours of birth)  because Even though 91% of infants received a birth dose of HBV vaccine, only 33% received a timely birth dose, which is key to preventing MTCT of HBV. The availability of daily child vaccination services seems to be an obvious requirement for improving access to the birth dose of HBV vaccine. However, this study provides evidence of how, and to what extent this affects vaccine uptake. In the absence of daily services, infants in our cohort faced vastly different odds of HBV vaccine uptake simply based on the day of the week on which they were born. National immunization programs could likely improve timely HBV1 birth dose rates by providing access to vaccine immediately following birth at all infant delivery venues on all days of the week. Where not possible, there should be rapid linkage to the nearest facility where HBV vaccination is immediately available.S1 Checklist(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Very early-life conditions are recognized as critical for healthy brain development. This study assesses early-life risk factors for developing dementia. In the absence of historical medical birth records, we leverage an alternative full population approach using demographic characteristics obtained from administrative data to derive proxy indicators for birth complications and unfavorable birth outcomes. We use proxy variables to investigate the impact of early-life risk factors on dementia risk.We use administrative individual-level data for full cohorts born 1932–1950 in Sweden with multigenerational linkages. Records on hospitalization and mortality are used to identify dementia cases. We derive 3 birth risk factors based on demographic characteristics: advanced maternal age, narrow sibling spacing, and twin births, and apply survival analysis to evaluate long-term effects on dementia risk. We control for confounding using multiple indicators for socio-economic status (SES), including parental surnames, and by implementing a sibling design. As comparison exposure, we add low education from the 1970 Census.The presence of at least 1 birth risk factor increases dementia risk . The occurrence of twin births poses a particularly heightened risk .Improvements to the very early-life environment hold significant potential to mitigate dementia risk. A comparison to the influence of low education on dementia (the largest known modifiable risk factor) suggests that demographic birth characteristics are of relevant effect sizes. Our findings underscore the relevance of providing assistance for births experiencing complications and adverse health outcomes to reduce dementia cases. In light of the limited progress regarding disease-modifying medical treatments for Alzheimer’s disease and related dementias (ADRD), the Lancet 2020 commission underscores the importance of prevention targeting modifiable risk factors . ExistinN = 35,191) and identify an inverse association between birth weight and dementia risk, as well as a positive association between smaller head circumference and dementia risk. However, caution should be exercised in generalizing these findings to the broader population due to the specific characteristics of the study sample relying on twins only. In sum, evidence linking very early-life characteristics to dementia risk remains sparse.The objective of this paper is to assess early-life risk factors for developing dementia. Research on this topic is limited. First, there are studies examining the observational relationship between birth characteristics and later-life cognitive abilities. This research relies on small sample sizes and is often of limited generalizability, due to reliance on birth records from specific health care centers. There are several reasons as to why birth characteristics may exert an influence on the development of dementia in later life. Birth characteristics, such as birth weight, length, or head circumference, are all indicators of intrauterine fetal growth and development. Thus, one reason for a relationship with dementia may be that slow fetal growth and intrauterine development lead to differences in brain structure and function that persist into old age. For example, men who experienced undernutrition in early gestation following exposure to the Dutch famine during World War II had smaller total brain volumes  and worsRecently, it was also reported that birth weight shows a remarkably consistent spatial pattern to cortical volumes across children, middle-aged, and older adults, but no consistent relations to brain change . Part ofBirth characteristics like weight and length at birth are also associated with an increased risk of preterm birth and birth complications. A systematic review and meta-analysis of studies on humans demonstrates that preterm birth is associated with volumetric, morphologic, and microstructural alterations in the brain in adulthood . The stun = 1,568,049) that is representative of the elderly population in Sweden, resulting in more generalizable and precise estimates. Furthermore, we have sufficient power to investigate potential nonlinear effects of maternal age with dementia and can control for a comprehensive set of parental SES characteristics, which may confound the relationships of interest. We address potential confounding caused by biological or sociodemographic factors (or both), using a large set of background variables from multigenerational registers, and employing a sibling design.A key hindrance faced by prior research efforts investigating the link between early-life risk factors and dementia was the lack of comprehensive historical data on birth outcomes for larger populations. The present study presents new insights into the intricate interplay between early-life factors and dementia risk, using an alternative approach that extends to a full population analysis to answer the research question of whether early-life risk factors have an impact on dementia. We use administrative data and demographic variables to assess very early life. Specifically, we examine three demographic risk factors—maternal age, birth spacing, and twin births. These birth-related characteristics were either previously examined in the literature or are closely linked to characteristics studied in smaller samples using data from health care centers. We hypothesize that the three risk factors, which are associated with lower birth weight, length, and birth complications, are associated with higher dementia risk. The present study advances prior research by using a sizeable sample  covering the total population born 1930–1985 and their parents, linking several population registers including the Educational Register (1985–2016), the 1950, 1960, and 1970 Censuses, the Cause of Death Register , and the Inpatient Hospitalization Register (1964–2016). Individuals are linked to their parents through the multigenerational Register, available for cohorts born in 1932 or later.Following register-based research on dementia risk , dementiLeveraging health administrative data to identify dementia cases enables the analysis of large sample sizes, required when applying proxy indicators. However, a trade-off exists in terms of moderate sensitivity, with the cohorts studied herein detecting only 70% of all dementia cases . The truActual birth characteristics data for the full population is only available from 1973 in Sweden. We derive risk factors for birth complications and adverse birth outcomes using demographic family links. Our choice of characteristics is driven by empirical evidence from pediatrics and epidemiological research. Using linked multigenerational data, we identify the following risk markers for pregnancy and birth complications:≥35) or in 3-year age intervals,Advanced maternal age proxied by a binary indicator of high maternal age  spacing to the next oldest sibling, andShort inter-pregnancy interval for an index sibling, capturing a narrow  is associated with a 45% increase in preterm births  in the 1960 Census. Based on SEI, we further construct an indicator for the household head being a farmer. Parental education is also derived from the 1960 Census and refers to whether the household head has at least upper secondary education. Finally, we include an indicator of patronymic surnames, which captures low socioeconomic status . ResearcN = 1,924,191). We exclude individuals without proper linkage to a biological mother  as this information is necessary to construct the demographic birth risk factors of interest. We also exclude individuals with unreasonably short birth spacing of less than 10 months (N = 286) and individuals who died or emigrated before the age of 65 . Our final sample consists of N = 1,568,049 observations. The baseline population consists of all individuals born in Sweden 1932–1950, excluding individuals emigrating or dying before 1961  and where Zi represents a very early-life risk factor. λ0(t) represents the baseline hazard. As the occurrence of a birth risk factor does not necessarily imply birth complications nor adverse birth outcomes, we interpret γ1 analog to an intent-to-treat parameter as a lower bound for the association between birth complications or adverse birth outcomes on dementia risk. Testing proportional hazards assumption reveals violations for some birth cohort indicators and sex, but no violations for any of the exposures. We run proportional hazard models stratified by birth cohort and sex which deliver identical results without violations of the proportional hazards assumption.where To mitigate possible omitted variable bias, we estimate Cox proportional hazards models with sibling-fixed effects as an additional analysis. These models can control for unobserved confounding factors that are commonly shared among siblings, such as family background, genetics, and upbringing. In these models, the baseline hazard is stratified by the biological mother. As discussed by bad control variables for our exposures by controlling for a mediator and introducing an overcontrol bias , with low education being regarded as the single largest, modifiable risk factor in preventing dementia . Educatirol bias .We make complementary analyses and test the sensitivity of the baseline results, including adding parity as a risk factor, using an alternative definition of dementia, estimating the relationship of interest using logistics regressions, and testing the relationship between risk factors and infant and child mortality, respectively. We also provide evidence to show that our proxy variables strongly are associated with birth complications and adverse health outcomes at birth for younger cohorts.p < .01, relative risk 1.043). Descriptive statistics in Panel A in Panel B in Panel C in When restricting our endpoint to individuals with dementia diagnosis only from inpatient registers, excluding mortality cases, the results barely change, see Finally, we also examine the impact of parity as a risk factor. Research suggests an impact of parity on dementia risk for parents , but medWe examined the relationship between proxy measures of pregnancy complications and adverse birth health outcomes—advanced maternal age, short inter-pregnancy interval, and twin birth—on dementia risk in a population sample of Swedish individuals. Our main results indicate substantial associations between very early-life risk factors and the risk of dementia, with 5%–16% increased risk, mirroring substantial potential for reducing dementia burden. It is important to acknowledge that our risk proxies serve as indicators of potential adverse outcomes rather than direct targets for intervention. The focus of intervention should be on enhancing ante and postnatal care to mitigate the consequences associated with elevated levels of risk.The interpretation of the magnitude of our estimates is challenging for two reasons. First, the presence of a demographic birth risk factor according to our definition does not automatically lead to adverse birth outcomes or complications. This also indicates that the potential role of adverse health outcomes at birth and complications is indeed larger than what is indicated by our estimates. The interpretation of our results thus analogs the interpretation of an intent-to-treat parameter. Second, we rely on dementia diagnosis from Inpatient and Cause-of-death administrative data which exhibit a certain lag with respect to the onset of dementia and where there is a potential for misclassification, further attenuating our estimates.To gain a better understanding of the magnitude of our estimated effects, we apply two strategies. First, we compare our results to the role of low education, which is the largest single modifiable risk factor for later-life dementia . The assSecond, we can compare our estimates to the study from Previous literature shows that the demographic birth risk factors used in this study correlate with socioeconomic background . ControlWe interpret our results for demographic birth characteristics as effects arising from pregnancy complications and adverse birth health. At the same time, we do now know how frequently these characteristics lead to birth complications or adverse birth events for our study population. In fact, a major advantage of our design is that we estimate the effects on dementia risk in the absence of detailed historical data on birth outcomes. To determine the frequency at which pregnancy complications and adverse birth health outcomes are associated with our proxy variables to help interpretation in case of an intent-to-treat parameter, we investigate the relationship using current birth records pertaining to cohorts born between 1973 and 1985. As an alternative approach to examining the validity of our exposures, we examine the association between one of our identified risk factors with childhood mortality. If the identified exposures are good proxies for insults to fetal development, this exercise should reveal an association with infant and, possibly, child mortality. For twins, we can combine the complete 1950 Population Census and the Swedish Death Registry, including all deaths in Sweden 1901–2013, which allows us to identify all twins. As the data cover the whole universe of the population (minus emigrants), we can estimate the effect of being a twin on infant and child mortality, respectively, for the cohorts born 1932–1950. A major strength of our study is that we can assess the role of very early-life factors in dementia in late life in the absence of detailed historical birth records by exploring full administrative population data and using proxy measures of pregnancy complications and adverse birth health outcomes. These proxies  are further measured without any substantial error in the registers. Our findings suggest that administrative demographic data, available in many countries, can be used in future research to further provide insights into the complex interplay between very early-life factors and dementia. Another key strength of our study is that we have access to a broad set of control variables and also address confounding by a sibling-fixed approach.Our study naturally has several weaknesses. First, our analysis cannot separate between the suggested underlying reasons for why the examined risk factors relate to dementia. For example, while twin birth is predictive of birth complications, twins also have more restricted fetal growth, whereby our estimates on dementia risk may reflect both these mechanisms. The exact causal chain between very early-life factors and dementia remains unknown. Our study can only draw conclusions regarding the association between birth risk factors and dementia in old age. Second, while leveraging administrative data enables an analysis of large sample sizes, our dementia measure based on the cause of hospitalization and death has moderate sensitivity and likely primarily captures more severe cases of dementia.Finally, we need to discuss the external validity of our study. Clearly, given medical and scientific progress, the risk factors identified are likely less problematic today than during 1930–1950. For instance, in modern maternal-fetal health care, older pregnant women generally undergo systematic monitoring, while specialized programs address twin pregnancies, involving structured fetal growth assessments and amniotic fluid measurement . The fulExternal validity is also relevant for our sibling design effects, especially regarding the estimation of twin effects. Families in sibling design need at least three children to identify a twin effect, which may threaten their representativity. We find that the families are larger and that non-twin siblings are more often older. This suggests some expected adjustment of birth parity when parents receive twins. The within-family twin sample further has a 0.36% points higher dementia risk and lower SES . If greater family size and lower SES are associated with an increased risk of dementia, then the within-family estimates can be expected to be larger due to a higher baseline risk. This is also what we find. Time may also constitute a threat to the external validity of our twin results. Earlier research showed that twins are vulnerable early in life for cognitive development for cohorts born before 1950, an effect that might be less relevant today . The magIn conclusion, our study suggests that improvements to the very early-life environment hold significant potential to substantially mitigate the risk of developing dementia. Our findings underscore that providing assistance for births experiencing complications and adverse health outcomes can be of relevance to reducing the number of dementia cases.gbad142_suppl_Supplementary_AppendixClick here for additional data file.


Background and Objectives: Vasa previa (VP) is a significant perinatal complication that can have serious consequences for the fetus/neonate. Velamentous cord insertion (VCI) is a crucial finding in prenatal placental morphology surveillance as it is indicative of comorbid VP. Assisted reproductive technology (ART) has been identified as a risk factor for VCI, so identifying risk factors for VCI in ART could improve VP recognition. This study aims to evaluate the displacement of umbilical cord insertion (CI) from the placental center and to examine the relationship between the modes of conception. Materials and Methods: We conducted a retrospective study at the Obstetrics Department of Osaka Metropolitan University Hospital in Japan between May 2020 and June 2022. The study included a total of 1102 patients who delivered after 22 weeks of gestation. They were divided into three groups: spontaneous pregnancy, conventional in vitro fertilization (cIVF), and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). We recorded patient background information, perinatal complications, perinatal outcomes, and a numerical “displacement score”, indicating the degree of separation between umbilical CI and the placental center. Results: The displacement score was significantly higher in the cIVF and IVF/ICSI groups compared with the spontaneous conception group. Additionally, the IVF/ICSI group showed a significantly higher displacement score than the cIVF group. Conclusions: Our study provides the first evidence that the methods of ART can affect the location of umbilical CI on the placental surface. Furthermore, we found that IVF/ICSI may contribute to greater displacement of CI from the placental center. Vasa previa (VP) is a rare and serious condition that can result in fetal/neonatal hemorrhage due to the laceration of vulnerable fetal vessels that run through the membrane . The recIn the prenatal surveillance of the placental morphology, velamentous cord insertion (VCI) is a key finding to presume comorbid VP . PlacentThe identification of risk factors of VCI in ART conceptions may offer opportunities for improved recognition of VP. The current study aimed to evaluate the deviations of umbilical CI from the center of the placenta using our original formula and to depict the association of cIVF and IVF/ICSI with VCI.The medical records of women with a singleton pregnancy who delivered at Osaka Metropolitan University Hospital after 22 weeks of gestation between May 2020 and June 2022 were retrospectively reviewed. All patients gave their informed written consent, and the study protocol was approved by the Institutional Review Board . The women studied were divided into three groups: the spontaneous conception group, the cIVF group, and the IVF/ICSI group. Intrauterine fetal death, multiple pregnancies, unknown method of conception, multiple-lobed and/or accessory placentas, undelivered placentas due to adhesion, and incomplete entry were excluded from the study. We also excluded the cases conceived by fresh embryo transfer since frozen embryo transfer is often chosen to improve pregnancy rates.After the delivery of the placenta, midwives and/or obstetricians examined the placental morphology and recorded the long/short diameters of the placenta and the longest/shortest distance from CI to the margin. Using this formula, the score will decrease where the CI is near the center of the placenta; on the other hand, the score will approach 1 where the CI is located near the margins of the placenta. It becomes greater than 1 if the CI attaches directly to the membrane away from the placental margin.MCI was defined as CI with Wharton’s jelly attached 2 cm or less from the margin of the placenta, and VCI was defined as vulnerable umbilical vessels without Wharton’s jelly running through the fetal membrane .For the comparison of birth weight, an examination between the two groups was performed by comparing the difference in the standard deviation (SD) between the two groups in terms of how much their birth weight deviated from the mean of their birth week. Birth weight SD was calculated using the “Japanese Birth Weight SD Score Table” based on the number of weeks of delivery, nulligravida/multigravida, sex of the infant, and birth weight . Furtherp-value < 0.05.Median comparisons between the two groups were made using the Mann–Whitney U test, and median comparisons between the three groups were made using the Kruskal–Wallis test. Categorical data were expressed as frequencies and percentages, and the Pearson χ-square test was used for these variables. Linear regression models were used for multivariate analysis of continuous variables. Logistic regression models were used for multivariate analyses of binary variables, and R version 4.2.2, EZR version 1.55, and a Microsoft Excel (2018) spreadsheet were used for statistical analyses. Statistical significance was defined as a two-sided p < 0.001). Moreover, the proportion of multiparous women was significantly higher in the spontaneous conception group than that in the ART group .p < 0.01). Blood loss at delivery in the ART group was significantly more frequent , and the SD of birth weight was also significantly higher . Moreover, the rate of VCI in the ART group was significantly higher , and the rate of VP was also significantly higher . The rate of placenta previa in the ART group was found to be significantly higher as well .p < 0.05/0.032–0.639, p < 0.05, respectively).p = 0.172) and 1.919 , respectively, compared with spontaneous conception. There were no statistically significant differences in this study.The present study first demonstrated that IVF/ICSI has a striking impact on the umbilical insertion site into the placenta when compared with placentas from spontaneously conceived pregnancies. Furthermore, we also quantitatively clarified that the significant deviations of CI on the placental surface may be caused by IVF/ICSI, even in the placentas without VCI.Clinical features of placentas and CI regarding the mode of conception have been reported in previous studies ,10. EnglJauniaux et al. speculated in their previous study that the artificial placement of the embryo in the uterine cavity could impede the normal process of blastocyst orientation during its implantation period, which might thus cause VCI . BlastocOur study showed that VCI was more commonly observed in cases conceived by IVF/ICSI. The procedures for IVF/ICSI involve removing the cumulus cells around the retrieved oocyte, puncturing the zona pellucida, and then injecting the sperm directly into the cytoplasm in order to inseminate the oocyte . These tThe zona pellucida prevents multisperm fertilization and protects the early embryo prior to implantation, and it is composed of oocytes and a small number of egg-specific glycoproteins zona pellucida 1–4, which, like other somatic extracellular matrix (ECM) cells, are thought to influence cell adhesion and migration, intercellular communication, gene expression, differentiation, and morphogenesis . RegardiIssues on the relationship between IVF/ICSI and embryo hatching have been discussed previously . RegardiIn terms of birth weight, our study confirms a trend toward larger birth weights with ART compared with spontaneous conception. Many papers have reported on the birth weight of infants born via ART versus spontaneous conception; however, there are differences in the timing of the reports, and there are no consistent views. A previous study of over 2 million births reported a 13% increase in the frequency of small for gestational age (SGA) children born via ART  . Qin et Our study has some limitations. The first one is the relatively small number of subjects. The second is that our study lacks a comparison of the outcome depending on the mode of conception, such as fresh or frozen embryo transfer. The last one is that the present study did not contain a detailed consideration of the development of ART devices and techniques over the last few decades.Our study first demonstrated that the umbilical CI on the placental surface could be affected by the methods of ART; furthermore, it clearly showed that IVF/ICSI might further displace the CI from the center of the placenta. With these findings, close information sharing between fertility practitioners and obstetricians, as well as careful observation of the fetus and the placenta in early pregnancy, will improve the prognosis for fetuses and newborns from disastrous outcomes caused by cord troubles, especially vasa previa. In addition, by obtaining prior information on VCI, obstetricians will be more vigilant in the management of pregnant women in labor or with rupture of the membranes, when attempting a vaginal delivery. Further research should be undertaken to determine whether fresh embryo transfer or frozen embryo transfer has a greater impact on the umbilical CI site, considering the physiology of the zona pellucida and the remarkable progress of reproductive techniques.


To examine associations of birth weight with clinical and imaging indicators of cardiovascular health and evaluate mechanistic pathways in the UK Biobank.Competing risk regression was used to estimate associations of birth weight with incident myocardial infarction (MI) and mortality , over 7–12 years of longitudinal follow-up, adjusting for age, sex, deprivation, maternal smoking/hypertension and maternal/paternal diabetes. Mediation analysis was used to evaluate the role of childhood growth, adulthood obesity, cardiometabolic diseases and blood biomarkers in mediating the birth weight–MI relationship. Linear regression was used to estimate associations of birth weight with left ventricular (LV) mass-to-volume ratio, LV stroke volume, global longitudinal strain, LV global function index and left atrial ejection fraction.–5) and attenuation to the null above this threshold. The birth weight–MI effect was mediated through hypertension (8.4%), glycated haemoglobin (7.0%), C reactive protein (6.4%), high-density lipoprotein (5.2%) and high cholesterol (4.1%). Birth weight–mortality associations were statistically non-significant after Bonferroni correction. In participants with cardiovascular magnetic resonance (n=19 314), lower birth weight was associated with adverse LV remodelling .258 787 participants from white ethnicities  years) were studied. Birth weight had a non-linear relationship with incident MI, with a significant inverse association below an optimal threshold of 3.2 kg (subdistribution HR: 1.15 (1.08 to 1.22), p=6.0×10Lower birth weight was associated with greater risk of incident MI and unhealthy LV phenotypes; effects were partially mediated through cardiometabolic disease and systemic inflammation. These findings support consideration of birth weight in risk prediction and highlight actionable areas for disease prevention. Previous studies have linked prematurity and small-for-gestational age (SGA) with increased lifetime cardiovascular risk. It is unclear whether similar risks are associated with low birth weight outside of these specific contexts.We demonstrate association of lower birth weight with higher risk of incident myocardial infarction and adverse left ventricular remodelling in a large population-based cohort of middle-aged adults. Associations were partially mediated through cardiometabolic diseases and systemic inflammation.Our findings indicate that the adverse cardiovascular effects of low birth weight described in preterm/SGA cohorts may extend significantly outside of these contexts. Further research is required to determine whether inclusion of birth weight may improve existing risk stratification tools and if preventative strategies targeted at individuals with lower birth weight have a role in improving clinical outcomes.The fetal origins hypothesis proposes intrauterine undernutrition as a key driver of increased susceptibility to later ischaemic heart disease (IHD) and associated mortality.While several studies have reported the association between low birth weight and a range of intermediary cardiometabolic factors, including insulin resistance,Cardiovascular imaging phenotypes reflect organ-level remodelling in response to a wide range of exposures and provide reliable indicators of cardiovascular health. The links between birth weight and cardiovascular image-derived phenotypes in large population-based cohorts have not been previously reported. Such analyses may provide new insights into the cardiovascular impact of birth weight, allowing capture of effects both independent of, and acting through, potential cardiometabolic mediators .We examined the association of birth weight with disease-specific mortality outcomes and incident acute myocardial infarction (AMI) in 258 787 UK Biobank participants. We accounted for potential confounders and evaluated the mediating role of childhood growth, cardiometabolic diseases, and blood markers of lipid profile, glycaemic control, and systemic inflammation. Finally, we assessed the association of birth weight with cardiovascular magnetic resonance (CMR) measures of cardiovascular structure and function.The UK Biobank comprises half a million participants recruited aged 40–69 years between 2006 and 2010. The research protocol is publicly available.Birth weight was self-reported at baseline assessment. We included singleton births with birth weights between 1 and 5 kg. Given known ethnic variations in birth weight,The following mortality outcomes were extracted from death register records documented per International Classification of Disease codes: any cardiovascular disease (CVD) (IX), IHD (I20–I25). Fatal AMI comprised of cases with AMI as the primary cause of death. Incident AMI was obtained from algorithmically defined outcome data; participants with a record of AMI at baseline were excluded from the analysis for this outcome. Outcomes occurring from baseline to the latest available censor dates were included  giving 7–12 years of follow-up.CMR was performed according to a predefined protocol and analysed using an automated pipeline.https://www.R-project.org/) and Stata V.17 . Descriptive statistics are presented as mean (SD) or median  depending on skew for continuous variables and number (percentage) for categorical data. We first estimated the association of birth weight with the incident outcomes. All-cause mortality models were fitted using Cox regression. Other outcomes were analysed using competing risk regression with proportional subdistribution hazards fitted as per Fine and Gray. Any mortality outcome occurring in patients without the outcome of interest was treated as a competing event. Sensitivity analysis was conducted using cause-specific Cox regression. Models were adjusted for age, sex, deprivation, maternal smoking, maternal diabetes, maternal hypertension and paternal diabetes . R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. diabetes . We repo10.1136/heartjnl-2022-321733.supp1Supplementary dataet alWe selected potential biological mediators of the birth weight–outcome relationships based on knowledge of potential causal pathways. A directed acyclic graph sets out the causal framework assumed by our models . The folWe estimated the association of birth weight with CMR metrics using linear regression, adjusting for confounders as before. We report change in CMR measure per 1 kg increase in birth weight with corresponding 95% CIs and p values. We used Bonferroni correction for multiple testing based on number of outcomes with significance thresholds indicated in table footnotes.The analysis sample comprised 258 787 individuals (100 540 men and 158 247 women) with median age of 56  years . The meaDuration of follow-up from baseline to the censor dates gave total person time of 2 304 749 years  years) for mortality outcomes, and 2 069 086 years  years) for incident AMI. The absolute number of outcomes and the rate of outcomes per 1000 person-years are presented in In fully adjusted models testing the linear association, higher birth weight was associated with reduction in hazard of all outcomes tested. After multiple testing correction, only association with incident MI remained statistically significant . There wWe considered mediation of the birth weight–AMI relationship. Multiple mediation analysis was used to calculate independent indirect effects for each mediator; this represents the effect of birth weight on incident AMI acting through individual mediators expressed as HRs and also, for ease of interpretation, as percentages . We deteIn fully adjusted linear regression models, lower birth weight was associated with more concentric pattern of LV remodelling (higher LVM/LVEDV) and poorer LV function (lower LVSV index). Associations with LVGFI, GLS and LAEF were not statistically significant in fully adjusted models .In this population-based study of 258 787 middle-aged and older-aged adults, birth weight had a non-linear relationship with incident AMI, with a significant inverse association below an optimal threshold of 3.2 kg and attenuation to the null above this threshold. Mediation analysis identified five independent mediators of the birth weight–AMI relationship, which together explained around one-third of the total effect. These comprised indicators of poor glycaemic control (HbA1c 7.0%), adverse lipid profile , hypertension (8.4%) and systemic inflammation (CRP 6.4%). Among 19 314 participants with CMR performed as part of the UK Biobank Imaging Study, lower birth weight was linked to adverse LV structure (higher LVM/LVEDV) and function (lower LVSV).et alet alet alInverse associations between birth weight and prevalent and incident IHD, and IHD mortality have been widely reported. In a study of 1394 post-menopausal women, Lawlor et alOur analysis demonstrates a convincing significant inverse relationship between birth weight and incident AMI. Characterisation of the non-linearity of the birth weight–AMI relationship in our study demonstrated a negative linear association for birth weights below 3.2 kg and no clear association with risk for birth weights above this threshold. The cut-off identified by our model approximates the population average birth weight,et alet alet alet alPrevious studies have linked low birth weight to adverse cardiometabolic disease. In a study of 72 healthy children, Hofman Several large cohort studies from the UKWe identified a significant mediating effect from higher CRP levels. Previous work has demonstrated inverse association of birth weight and serum CRP in both childrenFinally, although birth weight is the exposure of interest in our analysis, birth weight is a proxy indicator for intrauterine exposures that affect growth. That is, birth weight is a downstream manifestation of other ‘root’ exposures . Evaluation of such factors may provide new perspectives into the underlying causal mechanisms of the associations observed between birth weight and cardiovascular health.Previous studies of the association between birth weight and cardiovascular imaging phenotypes are limited to preterm birth or SGA individuals. There is heterogeneity within and across these study samples with multiple factors potentially influencing birth weight and subsequent cardiovascular risk. As such, direct comparison across cohorts is not possible.et alet alet alet al.et alIn an analysis of the Cardiovascular Risk in Young Finns Study participants, Arnott In our study of 19 314 population-based participants, we demonstrate a similar pattern of associations of lower birth weight with adverse CMR phenotypes. Specifically, we note association of lower birth weight with greater concentric LV remodelling and lower LVSV. These findings suggest that the adverse cardiovascular remodelling patterns related to lower birth weight are not limited to individuals with a history of preterm birth or SGA, but rather extend to a much larger proportion of the general population who have lower birth weight outside of these specific contexts.The birth weight variable was based on self-report and may be subject to recall bias, which may add noise or bias to observed associations. Some of the other covariates were also ascertained from self-report. Misclassification in these variables may be non-differential with individuals with higher education and health status more likely to accurately recall their birth weight and parental medical history. The unavailability of gestational age precludes definitive distinction between preterm, SGA and small but term births. We were also unable to consider the impact of adverse pregnancy outcomes, such as pre-eclampsia or gestational diabetes. We were underpowered to study ethnicities other than white. There is an interval of several years between baseline recruitment and the imaging visit, which may have led to survival bias in the associations with CMR metrics. The nature of the study precludes causal inference, and we cannot exclude residual confounding.In this large population-based cohort of middle-aged adults, lower birth weight was associated with significantly increased risk of incident MI below a threshold of 3.2 kg (approximating population average birth weight), independent of socioeconomic, parental and childhood factors. Poor glycaemic control, adverse lipid profile, hypertension and systemic inflammation were significant independent mediators of this relationship. However, these factors explained less than one-third of the birth weight–AMI effect, indicating important influence of other biological pathways. Lower birth weight was linked to an unhealthy pattern of cardiovascular remodelling indicating greater concentricity and poorer LV function.Our findings indicate that the adverse cardiovascular effects of low birth weight described in preterm/SGA cohorts may extend significantly into the general population. Further research is required to determine whether inclusion of birth weight may improve risk stratification and if preventative strategies targeted at individuals with lower birth weight have a role in improving clinical outcomes.


Epidemiological studies have linked various circulating cytokines to cardiovascular disease (CVD), which however remains uncertain whether these relationships represent causality or are due to bias. To address this question, we conducted a Mendelian randomization (MR) analysis to systematically investigate the causal effects of circulating cytokine levels on CVD development.cis-quantitative trait locus (cis-QTL) definition, derived from a GWAS meta-analysis comprising 31,112 participants of European descent, served as instruments for cytokines. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results.This study leveraged the summary statistic from respective genome-wide association study (GWAS) of 47 cytokines and four types of CVD. The cis-protein QTL (cis-pQTL) instruments, showed the causal effects of four cytokines  on the risk of coronary artery disease (CAD). We also identified causal relationships between two cytokines  and heart failure (HF), as well as two cytokines  and atrial fibrillation (AF), after controlling for false discovery rate (FDR). The use of cis-expression QTL (cis-eQTL) revealed additional causal associations between IL-1a, MIF and CAD, between IL-6, MIF, and HF, as well as between FGFBasic and AF. No significant sign was survived for stroke with FDR applied. Results were largely consistent across sensitivity analyses.The results of inverse-variance weighted method using The present study provides supportive evidence that genetic predisposition to levels of certain cytokines causally affects the development of specific type of CVD. These findings have important implications for the creation of novel therapeutic strategies targeting these cytokines as a means of preventing and treating CVD. Cardiovascular disease (CVD), a cluster of disorders that impact the heart and/or blood vessels, is a foremost cause of death and disability worldwide. In 2019, it is estimated that 17.9 million deaths were attributed to CVD, ranking the first leading cause of all global death  is a robust technology that can address the limitations accompanying observational studies mentioned above and provides the highest level of evidence hierarchy other than randomized controlled trials by leveraging genetic variants as instrumental variables (IVs) . This meThe flowchart of the current work is outlined in The present study relies on publicly available summary statistics from published studies, and therefore no additional ethical approval from the institutional review board was required. The characteristics of data used in this study are shown in For the cytokines as exposures, we acquired the IVs from the most up-to-date GWAS meta-analysis of three independent sources  [i.e., tFor the outcomes, the summary-level data for CAD , HF , AF , and stroke  were derived from CARDIoGRAMplusC4D Consortium , a GWAS cis quantitative trait locus (QTLs) as IVs to enhance instrument strength, including cis-protein QTLs  and cis-expression QTLs . These cis-QTLs, located at or close to the gene of origin, naturally have a stronger correlation with the gene expression and thereafter protein concentrations than other variants. For our main analysis, we used cis-pQTLs as the IVs, and for complementary analysis, we used cis-eQTLs since cis-eQTLs may capture the effects of pQTLs through gene expression, although not all pQTLs are represented by eQTLs  greater than 0.05 and performed clumping by setting a pairwise linkage disequilibrium (LD) cutoff of r2 < 0.1. The alleles of the QTLs were harmonized between the exposure and the outcome to ensure proper alignment of effects. Detailed information on the characteristics of the QTLs used as IVs can be found in the MR relies on three IV assumptions to ensure the accuracy of causal inferences (1): IVs must truly be associated with exposures (2), independent of confounders, and (3) affect outcomes solely through exposures, not through any other pathways. To better ensure that the selected IVs satisfy the above three assumptions, especially for the first and the third, we here used by eQTLs . Specificis-pQTL and cis-eQTL) to assess the links between genetically predicted circulating cytokine levels and the risk of each CVD outcome. For cases where there exists only one single QTL, the classic Wald ratio was adopted to gain MR estimates. Otherwise, the random-effects IVW model using a meta-analysis approach was performed to combine the Wald ratios of multiple QTLs to obtain overall MR estimates  that each cytokine has explained by the QTLs and F-statistics that quantified the strength of the IVs (F-statistics and an F-statistic > 10 was considered to avoid weak instrument bias (https://shiny.cnsgenomics.com/mRnd/)  . Lastly,P-value separately for each CVD outcome , “MendelianRandomization” (version 0.6.0), and “MR-PRESSO” (version 1.0) packages in R (version 4.1.2). To address the issue of multiple comparisons for the numerous cytokines, we performed the stratified false discovery rate (FDR) approach using Benjamini-Hochberg procedure for IVW analysis, i.e., estimating adjusted  outcome . Additiocis-pQTL instruments, explaining 0.1% to 28.9% of the phenotypic variance, and 27 cytokines possessed cis-eQTL instruments, explaining 0.04% to 13.0% of the phenotypic variance. Cumulative F-statistics of cis-pQTL for 29 out of 31 cytokines were greater than 10, proving the good strength of genetic instruments , MCSF , MIF , SeSelectin , while one cytokine, SCF , to a lower risk of CAD. After stratified FDR correction, the significance of MIF results was not remained. As expected, when using the cis-eQTL instruments and similarly estimated by IVW, most of findings from our main analysis including IL-1ra, MCSF were replicated, yet the MIF  maintained notable significant relationship with CAD risk. In addition, we observed the novel evidence regarding IL-1a .Using the cis-pQTL instruments, six cytokines  showed suggestive association with the risk of HF, six cytokines  with AF, and three cytokines  with stroke. When considering the stratified FDR of 10% or less, only two cytokines, IL-2ra  and IP-10 , reached a statistical significance (stratified FDR < 10%) for HF, as well as two cytokines, MCP-3  and SeSelectin , for AF. No significant sign was survived for stroke after stratified FDR correction. With cis-eQTL instruments and stratified FDR adjustment applied, the additional associations between IL-6 , MIF  and HF, as well as FGFBasic (basic fibroblast growth factor) and AF  were captured.Likewise, tested by IVW method using the Focused on the associations that withstand multiple comparison correction (stratified FDR < 10%), their corresponding sensitivity analyses indicated roughly the same estimates although several methods yield wide CIs due to less statistical power refer to Figure 3cis-pQTL and cis-eQTL instruments . More studies are needed to further explore. Notably, our study offered some novel insights regarding MCP-3, MCSF, and SeSelectin, which have not been previously found or minimally explored in direct relation to CVD.Our findings strengthened or extended existing observational evidence, pointing to an essential role played by certain cytokines, including IP-10, IL-6, IL-1ra, and SCF, in the development of CVD. A study combining data from two prospective cohorts suggested that higher concentration of IP-10 was related to the elevated risk of HF but not CAD or stroke, which largely aligns with our own results . In addiCytokines may have both direct and indirect effects on the cardiovascular system. Direct effects include alterations in the function of the heart and blood vessels such as increased heart rate, reduced blood flow, and changed blood pressure regulation , 34. Thecis-instrument definition approach, may result in a less statistical power, especially for MR sensitivity analysis which requires a higher number of instruments. Additionally, because of the high correlation between cytokines, particularly within a category, such as the ILs family, as well as correlations among four types of CVD, the naive multiple comparison adjustment may be excessive, further affecting the false negative. We hereby reminded that even in cases of negative results, complete exclusion of causality cannot be ensured and thus such results should be interpreted with caution. Secondly, the expression of certain cytokines can be influenced by age and the changing external setting, such as a bimodal curve that has been described for IL-1ra expression throughout the life stage  . Anotherfe stage . The estfe stage  and IL-1fe stage , known fTo conclude, based on innovative IVs that incorporate gene expression relevance and large genetic association data, this MR study comprehensively examined the causal influence of circulating cytokine levels on four major CVDs. Our MR study provides robust evidence that the levels of certain cytokines were associated with the development of CVD and highlights the importance of considering cytokines as potential targets for the prevention and management of CVD. Further research, if possible, clinical trials, are necessary to validate these findings and delve into the underlying biological mechanisms specifically at the specific cytokine level.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.RZ and TW were the major contributors in conceptualisation. TW, ZZ and LL analyzed the data. ZZ, BL, MW, WZ, QC, and FL verified the correctness of the data. TW, ZZ and RZ were major contributors in writing the manuscript. All authors contributed to the article and approved the submitted version.