Birth asphyxia is one of the leading causes of neonatal mortality worldwide. In Uganda, it accounts for 28.9% of all neonatal deaths. With a view to inform policy and practice interventions to reduce adverse neonatal outcomes, we aimed to determine the prevalence and factors associated with birth asphyxia at two referral hospitals in Northern Uganda.p-value < 0.05 was considered statistically significant.This was a cross-sectional study, involving women who gave birth at two referral hospitals. Women in labour were consecutively enrolled by the research assistants, who also attended the births and determined Apgar scores. Data on socio-demographic characteristics, pregnancy history and care during labour, were obtained using a structured questionnaire. Participants were tested for; i) malaria , ii) syphilis, iii) white blood cell counts (WBC), and iv) haemoglobin levels. The prevalence of birth asphyxia was determined as the number of newborns with Apgar scores < 7 at 5 min out of the total population of study participants. Factors independently associated with birth asphyxia were determined using multivariable logistic regression analysis and a A total of 2,930 mother-newborn pairs were included, and the prevalence of birth asphyxia was 154 [5.3% ]. Factors associated with birth asphyxia were; maternal age ≤ 19 years [adjusted odds ratio (aOR) 1.92 (1.27–2.91)], syphilis infection [aOR 2.45(1.08–5.57)], and a high white blood cell count [aOR 2.26 (1.26–4.06)], while employment [aOR 0.43 (0.22–0.83)] was protective. Additionally, referral [aOR1.75 (1.10–2.79)], induction/augmentation of labour [aOR 2.70 (1.62–4.50)], prolonged labour [aOR 1.88 (1.25–2.83)], obstructed labour [aOR 3.40 (1.70–6.83)], malpresentation/ malposition [aOR 3.00 (1.44–6.27)] and assisted vaginal delivery [aOR 5.54 (2.30–13.30)] were associated with birth asphyxia. Male newborns [aOR 1.92 (1.28–2.88)] and those with a low birth weight [aOR 2.20 (1.07–4.50)], were also more likely to develop birth asphyxia.The prevalence of birth asphyxia was 5.3%. In addition to the known intrapartum complications, teenage motherhood, syphilis and a raised white blood cell count were associated with birth asphyxia. This indicates that for sustained reduction of birth asphyxia, appropriate management of maternal infections and improved intrapartum quality of care are essential. Birth asphyxia is defined by the World Health Organization (WHO), as failure to initiate and sustain breathing at birth . It may Interventions to address newborn deaths around the time of birth include: i) promotion of maternal birth preparedness, ii) skilled attendance at birth, iii) essential newborn care, iv) basic and comprehensive obstetric care, and neonatal resuscitation , 11. AltThe literature describes several factors associated with birth asphyxia as an interaction between predisposing factors, infections and birth complications . While tWe hypothesized that in addition to the common intrapartum risk factors for birth asphyxia, maternal infections such as; malaria, syphilis and other bacterial infections, and socio-demographic factors, play an important role in this study setting. Therefore, we aimed to determine the prevalence and to describe the contextual factors associated with birth asphyxia in a post conflict region of Uganda, in order to support planning for targeted interventions.The study was conducted at Gulu Regional Referral Hospital (Gulu RRH), and St. Mary’s Hospital-Lacor, in the Acholi region, Northern Uganda. Gulu RRH is a public Regional Referral facility, with a 347-bed capacity. During the study period, it had a maternity unit of 6 delivery beds, and around 4,400 births in a year. St. Mary’s Hospital-Lacor is a large private not for profit facility at the level of a referral hospital, with a 482-bed capacity. The maternity unit had 8 delivery beds, and an average of 6000 births annually. Both hospitals have the capacity to perform caesarean sections and offer emergency obstetric and newborn care interventions. Preference for where to seek care depends on the referring facility, and the woman’s individual ability to pay user charges at the private facility. These facilities receive referrals from primary care facilities within the neighboring districts, and beyond. These districts include; Nwoya, Amuru, Kitgum, Lamwo, Pader and Omoro.A cross-sectional study design was used. Data was collected from March 2018 to March 2019 in Gulu RRH, and from November 2018 to March 2019 in St. Mary’s Hospital Lacor.Women in established labour, who delivered at one of the two hospitals during the study periods, were included. We recruited women in the active phase of the first stage of labour with a cervical dilatation of ≥ 4 cm. Women who came in the second stage of labour were not invited to participate in the study, since it would be difficult to obtain consent. Women who; 1) were critically ill, for example those with eclampsia, and unable to respond to the questions, 2) were less than 37 weeks of gestation, 3) had multiple pregnancy or 4) had stillbirths were excluded.To determine the factors associated with birth asphyxia, we calculated the sample size, using the Kelsey’s formula . A samplData collection was done by six trained research assistants, who were nurses/midwives. The training of the research assistants included both theoretical and practical aspects of screening participants for eligibility, obtaining informed consent, drawing blood, determining the Apgar score, and completing the questionnaires. Potential study participants were consecutively informed about the study, by the midwife on duty. Thereafter, informed consent was obtained by the research assistants, to collect maternal blood samples for complete blood count and malaria, at admission; and cord artery blood sample collection at birth . FurtherData was collected using paper-based questionnaires. Sections in the questionnaire included: socio-demographic characteristics, antenatal history, intrapartum events including laboratory tests and newborn characteristics. The socio-demographic characteristics and antenatal care history were obtained from the mother, while intrapartum events were abstracted from the mother’s maternity record. At birth, the research assistants were present, to score the newborn, using the Apgar scoring sheet.Two milliliters (2 ml) of venous blood were collected from all mothers. The blood was stored in EDTA vacutainers, and analyzed for a complete blood count and Rapid Plasma Reagin (RPR) test, for syphilis. Peripheral maternal blood was also taken by a finger prick, and placental blood was taken from the vein, to make a thick malaria smear on a slide. All samples were tested at MBN, a clinical laboratory that is certified by HuQAS External Quality Assessment Services, situated within a 10-km radius of the study hospitals. Samples were picked daily, and transported to the laboratory for analysis. Results were returned to the research assistants, who included the findings in the questionnaire. Participants who were positive for any of the infections were treated, according to hospital protocols. In case the results returned after the mother’s discharge, she was contacted by phone, and asked to seek care from a nearby health facility.The main outcome of this study was birth asphyxia, defined as a 5-min Apgar score, less than 7 . Apgar s3cells/mm3 was considered high as per the laboratory reference ranges. Syphilis was identified using the Rapid Plasma Reagin test. We did not conduct HIV testing, but used the results from the antenatal or maternity records of the mother. Information regarding complications during labour such as; obstructed labour, malpresentation, malposition, induction of labour and augmentation of labour, were reviewed from the maternity case records as per the diagnosis of the attending health care provider. Fetal distress was considered when the fetal heart rate at any time during labour was < 120 or > 160 beats per minute . At one minute, 476/2928[16.3% (95% CI: 14.9–17.6)] newborns had an Apgar score of < 7. One in 10 newborns with birth asphyxia had very low Apgar scores ≤ 3 at 5 min.A significant number of women, 1186/2928 (40.5%) were having their first birth. Nearly half of all participants 1399/2832 (49.4%) came from a distance within 5 Kms radius of the study sites and a higher proportion of women 79/923 (53.0%) with birth asphyxia came from a distance of more than 10 km. The proportion of women with hemoglobin levels < 11.0 g/dl indicative of anemia, was 18.2%. The majority 2917/2926 (99.7%) of women attended antenatal care visits with 57.3% of them completing four visits. Several socio-demographic characteristics were highly associated with birth asphyxia. The bivariable analysis showed that age ≤ 19 years, primiparity, mother’s educational level, being employed, and being in the lowest wealth quintile were significantly associated with birth asphyxia. Distance from home to hospital, place of birth, and having had fever during pregnancy, were also significantly associated with higher odds of birth asphyxia. Details are shown in Table Malaria infection during labour was higher in placental 61/2893 (2.1%), than in the peripheral blood samples 38/2893 (1.3%). Significantly, more 129/150 (86.0%) women with a high WBC count had newborns with birth asphyxia. In this population, the prevalence of HIV infection was 9.9%. There was no significant association between; placental malaria, syphilis, HIV, and birth asphyxia.Nearly a quarter 427/2921 (14.6%) of the women were referred from other health facilities and 38.6% of these had newborns with birth asphyxia. The commonest complication reported was prolonged labour 899/2916 (30.8%). Fetal distress was found among 8.9% of women and of these, 63.2% gave birth to newborns with birth asphyxia. At bivariable analysis, all maternal complications during labour including: fetal distress, obstructed labour, prolonged labour, induction/augmentation of labour, mal-presentation/malposition, and premature rupture of membranes, were associated with birth asphyxia. In addition, newborn characteristics such as low birth weight, male sex, assisted vaginal birth by vacuum extraction, were associated with birth asphyxia. Detailed findings are displayed in Table At multivariable analysis, the following factors were significantly associated with birth asphyxia: i) young maternal age , ii) syphilis infection , iii) a high WBC count , iv) referral , v) induction/augmentation of labour , vi) prolonged labour , vii) obstructed labour , viii) malpresentation/malposition  and, ix) assisted vaginal delivery  had higher odds of getting newborns with birth asphyxia. Women who were employed were 57% less likely to give birth to newborns with birth asphyxia. Newborn factors associated with birth asphyxia included being male  and having a low birth weight . Details are presented in Table Our large cross-sectional study, at two hospitals in a post conflict area in Northern Uganda, indicated that one in 20 newborns had birth asphyxia. Factors independently associated with birth asphyxia were; young maternal age, syphilis infection, a high WBC count, referral, obstructed labour, prolonged labour, induction or augmentation of labour, malpresentation or malposition, assisted vaginal delivery, male newborns and low birth weight.The prevalence of birth asphyxia at 5.3% is of major concern, considering that birth asphyxia causes more than a third of all newborn deaths in Uganda . Also, mYoung mothers < 19 years of age were twice more likely to give birth to newborns with asphyxia. Studies in other low-income countries have reported a similar association although with varying age cut-offs . Poor biThere was a significant relationship between birth asphyxia and women with syphilis infection. Maternal syphilis infection in pregnancy has been shown in other studies to lead to adverse birth outcomes including; spontaneous abortions, preterm birth, stillbirth and newborns who are small for gestational age . Importa3 was found to predict chorioamnionitis among women with premature rupture of membranes [In this study, a high WBC count was associated with birth asphyxia which could be a proxy indicator for bacterial or viral infections . Althougembranes . TherefoWe hypothesized that malaria would be one of the important predictive factors. However, there was no statistically significant relationship between placental malaria and birth asphyxia. Although normally, Northern Uganda is a high malaria endemic area, this study was done at a time following massive indoor residual spraying by the Ministry of Health , which eAs expected, there was a statistically significant association between birth asphyxia, and most intrapartum complications namely: prolonged labour, obstructed labour, induction or augmentation of labour, malpresentation/malposition, and assisted vaginal delivery. This is similar to findings in other studies in Africa and other low income countries , 57. TheLow birth weight and being male has been associated with poor health outcomes in many settings. It is therefore not surprising, that the risk of birth asphyxia was increased in the population. In a study among very premature infants, males were found to have poor neurological and respiratory outcomes, compared to their female counterparts . In anotOur large and comprehensive study in two hospitals is one of the few studies reporting the prevalence of birth asphyxia in a post-conflict region. Beyond the common indicators of socio-demographic and obstetric factors, we included infections such as syphilis, malaria, and WBC; to investigate the possible associations with maternal infections and birth asphyxia. A major strength of our study is the rigorous determination of the newborn Apgar scores, which was done by trained research assistants, who were not part of the hospital care. While excluding preterm newborns can be seen as a weakness, we know that the Apgar score used in this study is less valid in this group . We beliThe study also had some limitations. First, there could have been reporting bias on variables that were collected using the participant’s report for example; gestational age, history of fever, events during pregnancy, and duration of labour. Secondly, since this was a cross-sectional study, we were not able to ascertain a causal relationship with birth asphyxia. Lastly, we also found a low prevalence of placental malaria, which may have reduced our power to make conclusions on its association with birth asphyxia.There prevalence of birth asphyxia in this study was 5.3% which is comparable to some studies in low-income settings. Being referred, young maternal age, infections, intrapartum complications, male and underweight newborns, were associated with birth asphyxia. There is need for special attention to pregnant teenagers and women who have been referred in labour. Women with other complications such as prolonged labour, obstructed labour and malpresentations or malpositions and a high risk of infection should be prioritized for fetal heart rate monitoring and timely interventions to prevent birth asphyxia. Re-screening of pregnant women, and appropriate management of syphilis and other infections along the continuum of care for women should be prioritized.


Congenital upper limb deficiency care and management have undergone drastic changes over the past 50 years. Given the low incidence of this defect nationwide, this case report adds to the existing database to analyze the etiological investigations, descriptive epidemiology, and trend detection. We present a case of a 2-month-old male child with congenital upper limb deficiency and explore the possible etiologies and difficulties during early diagnosis of such rare disorders in a low and middle-income countrries and present implications at the primary health care level to improve the prognosis. Poor nutrition during pregnancy due to an unplanned pregnancy is a possible cause. The prognosis is unfavourable due to sociocultural barriers. To address these limitations, it is pertinent to address disability-adequate knowledge among communities, promote early diagnosis, and timely rehabilitation using a multidisciplinary approach. Further, we provide a framework to optimize care. We further discuss the difficulties during the early diagnosis of such rare congenital disorders in Low- or Middle-Income countries (LMIC) like Nepal and present implications at the primary health care level to improve the prognosis.Over the past 50 years, the clinical management of congenital upper limb deficiency has been drastically changed.A 2-month-old male child was born to Gravida 2, Para 1, and Abortion 1 (G2P1A1) at 39 weeks of gestation by cesarean section due to cephalo-pelvic disproportion. There was no history of consanguinity, and the prenatal course was uneventful. All prenatal ultrasounds were reported as "normal". The mother took iron and calcium tablets but no folic acid during the course of the pregnancy. She had no history of infection during pregnancy. There was no history of prenatal exposure to radiation or the consumption of any teratogenic drugs during the prenatal period. The cesarean delivery was uncomplicated. The child weighed 4.2 kgs at birth. The baby cried immediately after birth. His Apgar scores were 8/10 and 9/10 at 1 and 5 minutes, respectively. On physical examination, the head and neck were normal. However, it was noted that the baby had short upper limbs with only two digits on the left hand and an absent left forearm. In addition, the right forearm was short with two digits attached to the distal forearm .On further examination, his anthropometry was within the normal limit and he could move all his digits and limbs. All other systemic examination findings were unremarkable. Exclusive breastfeeding was started immediately after birth and he passed urine and meconium within the first 24 hours of life.The mother had no prior history of tobacco use or alcohol consumption. Furthermore, diabetes or hypertension was not documented prior to or during the course of the pregnancy. She had a history of spontaneous abortion at 8 weeks of gestational age a year back. There was no family history of similar defects. The baby's X-ray report suggested a type IV radial longitudinal defect in the right forearm and an intercalary defect in the left arm or distal phocomelia with two digits directly attached to the humerus .To rule out an association with other congenital diseases like vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association, Fanconi anaemia, and genetic syndromes like Holt-Oram Syndrome, a complete blood count panel, echocardiography, and ultrasonography (USG) abdomen were ordered and were found to be within the normal range. Other pertinent investigations could not be carried out owing to resource limitations. The baby and the mother were observed for a week and were discharged after proper genetic counselling in consultation with the pediatric neonatologist. The baby was advised of regular follow-ups and was referred to the orthopaedics department for further management and rehabilitation.4 Congenital limb malformations are defined as (I) failure of part formation, (II) failure of part differentiation (separation), (III) duplication, (IV) overgrowth, (V) undergrowth, (VI) congenital constriction band syndrome, and (VII) generalized skeletal abnormalities, according to the International Federation of Societies for Surgery of the Hand and the International Society of Prosthetics and Orthotics.1 Congenital abnormality affects between 1 and 2% of live births. Of these, around 10% have upper-limb deformities.5 A study conducted in Nepal, in 2015 pointed out that although genetic and environmental factors are major contributors to birth defects in Nepal, poor nutrition, low maternal body mass index (BMI), unplanned pregnancy, folic acid supplementation late in pregnancy, and general lack of awareness are causative of birth defects.6 In the case of unintended pregnancies, mothers typically seek medical help after the first trimester or not at all. The child of an unplanned conception is at greater risk of abortion, being underweight at birth, dying in the first year of life, being abused, and receiving insufficient resources for healthy development.7 In our case, the mother had a prior abortion pointing to the consequence of an unplanned pregnancy. Consequently, the unborn and newborn children were at an added risk. A study done in China found that folic acid supplementation leads to a reduction in limb defects. The mother in our case also had poor nutrition and did not take folic acid supplements, thus adding value to this study's findings.8The phenotypic symptoms of congenital limb malformations are diverse.2 Infectious agents like toxoplasmosis, rubella, cytomegalovirus, herpes, and human immunodeficiency virus (HIV) virus (TORCH) during embryogenesis play a vital role; however, the use of the Rubella vaccine has reduced the risks of major congenital anomalies by 85%.2 In contrast to contributing factors of congenital limb defects, the mother in our case did not take any teratogenic medications and had no pre or postnatal infections and was vaccinated as per guidelines led out by the Nepalese government. Thus, poor nutrition and an unplanned pregnancy is a possible hypothesis for the baby's congenital limb defect. A central limitation to tying in these findings was that we could not carry out molecular and/or genetic investigations because of inadequate resources in the LMIC setting. As per one study, congenital limb defects require early diagnosis and prompt rehabilitation to gain optimum limb function while improving the cosmetic appearance.9 The medical and financial costs of congenital abnormalities are enormous.10 A thorough assessment is henceforth necessary to promote age-specific mental and physical development. The treatment is multidisciplinary, requiring reconstruction of digits while preserving sensory and motor functionality. Further, fitting prosthetics for cosmetic purposes along with long-term occupational therapy and physiotherapy ought to be the primary care consideration in similar cases. In our child, we made referrals to the orthopaedic surgeon team, to probe for timely surgical intervention and genetic counselling.A one-year review study from 2003-2004 done in Maternity Hospital (Prasuti Griha), Nepal found 14 cases of musculoskeletal anomalies upon deliveries. The study further concluded that congenital defects of both the upper (3.4/10000) and lower limbs (1.1/10000) may occur mainly due to teratogen exposure during the 4th-5th weeks of gestation.11 As illustrated in the preliminary framework to optimize care in LMICs, it is necessary to promote awareness using public health messages, pursue action plans for improved surveillance, prevention of anomalies using improved diagnostic testing facilities, research trends in the country, and optimize care for children affected by birth defects.In the context of early diagnosis and prompt rehabilitation, Nepal lags behind in speciality services, especially in the rural setting where individuals, particularly pregnant females, are unaware of congenital anomalies or internalize them as a consequence of their wrongdoings. This is a pertinent socio-cultural issue as mothers link their child's congenital limb defects to their sins, with other religious themes. Children are often socially ostracized and deprived of basic needs in the name of faith and religion. Comprehensive fetal ultrasonography enables an early prenatal diagnosis of congenital limb defects and offers critical information to the parents, assisting them in making decisions about the pregnancy's fate.12 Similarly, it is important to consider ethnicity to the incidence of congenital abnormality due to economic inequalities that may modify exposures; advantageous ethnic groups like Brahmin and Chettri are comparatively less likely to be connected with birth abnormalities than non-advantageous ethnic groups and this was supported by the findings of a multicenter study done in Nepal.13Randomized trials and several observational studies have indicated that folic acid supplementation during pregnancy, either alone or in combination with other vitamins, is beneficial in preventing neural tube abnormalities. The question of whether this holds true for other congenital defects is a complicated one, and it is the subject of this study. It's vital to assess the data not just for individual birth problems, but also for all birth defects taken together.The age of the mother also should be considered because of the known link between maternal age and poor pregnancy outcomes. Furthermore, given the known association between gastroschisis and amelia in newborns of younger mothers, it's likely that a vascular disruption is at the root of the congenital limb abnormality.Congenital limb deficiency is a rare genetic disorder. Besides genetic and chromosomal abnormalities, poor nutrition during pregnancy as a consequence of unplanned pregnancy could be one of the contributory factors. To address these limitations, it is important to take into consideration various reasons for a disability such as lack of adequate knowledge among communities, promoting early diagnosis, and timely rehabilitation using a multidisciplinary approach and informed framework. One way is to have a birth defects surveillance system. The birth defects surveillance system contains a large database of infants with major and minor exterior structural malformations, as well as the unique characteristic of a photographic record in the majority of instances. These data can be used for etiological investigations, descriptive epidemiology, and trend detection.


To study changes in heart function and hemodynamics during the transitional period in small for gestational (SGA) infants and appropriate (AGA) healthier counterparts.A hospital based prospective observational study was performed at a perinatal center. Echocardiograms were performed on the first postnatal day and again at 48 h age. Term SGA infants were compared with those AGA newborns matched for the GA and mode of delivery.p > 0.05 and birthweight 2331 ± 345 vs. 3332 ± 405 grams, p < 0.05, respectively]. Maternal weight and body mass index was higher among non-affected pregnancies, 61% infants were born vaginally, and no differences in cord blood pH at birth were noted. SGA infants had higher systolic and mean blood pressure at both time points, lower indices of right ventricular (RV) performance , lower pulmonary acceleration time (PAAT) suggestive of elevated pulmonary vascular resistance  and higher left ventricular (LV) ejection fraction .Eighteen SGA infants were compared with 18 AGA infants [gestation 38 ± 1.5 vs. 38 ± 1.2 weeks, SGA infants had evidence of higher pulmonary vascular resistance, and lower RV performance during the postnatal transition. The relevance and impact of these changes to hemodynamic disease states during the postnatal transition requires prospective investigation. Vasoconstriction of the peripheral vascular bed  less than 10th percentile are at increased risk of adverse outcome such intrauterine death , and mecnd shape , arteriand shape , metabolnd shape , and perular bed  and vasoular bed , 13.After birth, experimental studies on animals demonstrated a progressive decrease in pulmonary vascular resistance (PVR) , concomiWe conducted a prospective cohort study of pregnant women detected during the first to second trimester of pregnancy with EFW < 10th centile and group of matched for gestational age (GA) healthy pregnant (control group). This study was performed at a Level II neonatal intensive care unit (NICU) at Maternity Department of County Hospital, Târgu Mures Romania between June 2021, and January 2022. The total annual birth rate in this center is approximately 1,500 cases; of these, 5% are SGA newborns leading to 75 potential eligible infants/year. Pregnant women during the first to second trimester of pregnancy, in whom EFW < 10th centile, were examined closely during the third trimester of pregnancy as part of routine care until spontaneous labor or delivery. A control group, consisting of healthy pregnant women with EFW between 10 and 90th centile, were matched one-to-one according to GA. Mothers were approached again at term (37–41 weeks) and asked to participate in the study. The informed consent process took place before active labor, and only those who agree to participate and signed a consent form were included. The study was approved by the Ethics of Research of University of Medicine, Pharmacy Science, and Technology George Emil Palade of Targu Mures, Târgu Mureș, Romania . Pregnancies where absent or reversed diastolic flow on UA and MCA Doppler was detected were excluded, as these babies usually are delivered prematurely.The health care providers who attend the pregnant women at birth were blinded to the subject's participation into the study. In addition, data abstractors were blinded to group allocation. To minimize operator dependency error, the maternal scans were performed by a single experienced obstetrician (C.M) and the neonatal scans were performed by a single sonographer (L.M.S). The sonographers were not blinded to group allocations and echo order; however, all 72 neonatal scans used for this study were de- identified, digitally stored and all the measurements were performed off-line in a random order at the completion of recruitment. To ensure blinding, clinical data were collected separately and were merged with echocardiography data prior to statistical analysis.Eligibility Criteria:(i)Birth Weight (BW) ≤ 10th percentile on Fenton growth charts(ii)Evidence of EFW ≤ 10th percentile in first to second trimester(iii)Born after 37 completed weeks GA and clinically asymptomatic(iv)Singleton pregnancy with documented GA based on the LMP date and first trimester ultrasound examAppropriate for Gestational Age (AGA) controls were included if they satisfied the following eligibility criteria:(i)AGA infant with BW > 10–90th centile on Fenton growth charts at birth(ii)Evidence of EFW > 10th centile in first to second trimester(iii)Low-risk singleton pregnancy with documented GA based on the LMP date and first trimester ultrasound exam and were followed up until spontaneous or induced labor and delivery(iv)Born at term gestation and clinically asymptomatic(v)All eligible fetuses had documented umbilical artery (UA) and middle cerebral artery (MCA) Doppler tracings prior to birthExclusion criteria were as follows:(i)Maternal age < 18 years(ii)Fetuses with structural anomalies.(iii)Infants detected with genetic or dysmorphic abnormalities(iv)Infants born less than 37 weeks GA(v)Evidence of perinatal hypoxia-ischemia (vi)Evidence of significant congenital heart disease EFW was calculated from measurements of the biparietal diameter, head circumference, abdominal circumference and femur length using Hadlock formula . Immediately after birth, the clinical status of newborn infants was evaluated by the attending neonatologist according to the Apgar score at 1 and 5 min. Other data including birthweight, cranial perimeter and length were assessed.Arterial blood pressure was measured at two different time points , prior to each echocardiographic evaluation exam was performed, using a noninvasively oscillometric method  with the infant in a calm state. An appropriate size cuff for the arm was used. An average of two consecutive measurements were included in analysis. We choose to report this parameter because it is widely used to define hypotension; however, there are a number of factors that can affect interpretation , 24.2) was measured because several studies reported SpO2 screening of critical congenital heart disease (CCHD) to be feasible and cost effective  and 48-h (Echo 2) postnatal age. These two time points were specifically chosen because healthy term newborns are usually discharged after 2 complete days of hospitalization. Exams were performed with the Versana active ultrasound system using a 12-MHz neonatal transducer . Each echocardiogram was performed with the infants in the supine position, either asleep or in a resting state, without prior sedation, and lasted less than 40 min. Small volumes (2–5 ml) of Glucose 10% were administered by mouth and/or swaddling techniques to help the infant reach a quiet state. Image acquisition was conducted in accordance with the guidelines for targeted neonatal echocardiography . ComprehRight ventricular systolic function was assessed using both tricuspid annular peak systolic excursion (TAPSE) and fractional area change (FAC) measured from the RV 3-chamber view. Abnormal RV systolic function was defined be TAPSE <8 mm  value <55% was used as a threshold abnormal LV systolic function (Pulmonary Acceleration Time (PAAT) and Right Ventricular Ejection Time (RVET) were measured from Doppler spectral flow velocity envelope obtained by placing a pulsed Doppler sample volume at the pulmonary valve annulus. PAAT is defined as the interval between the onset of systolic pulmonary arterial flow and peak flow velocity. RVET is measured from the interval between the onset of RV ejection to the point of systolic pulmonary arterial flow cessation. Pulmonary Vascular Resistance index (PVRi) was calculated by dividing RVET to PAAT to account for the impact of heart rate of time-dependent indices. Mean PAAT and RVET, from three well-defined waveforms, were used for data analysis. A RVET: PAAT ratio > 4 was considered abnormal . Right vSE <8 mm  and FAC SE <8 mm  based onfunction  Diastolifunction . In addifunction .primary outcome was pulmonary vascular resistance index (PVRi = RVET: PAAT), an echocardiography parameter of the pulmonary vascular disease. Secondary outcomes included echocardiography indices of pulmonary hemodynamics , LV systolic performance , RV systolic performance , left heart diastolic function  and systemic hypoperfusion .The p value less than 0.05 was considered statistically significant. We used SPSS 21 to conduct the analysis. A predefined sample size of 25 pregnant women was selected for convenience purposes.Values were presented as mean (standard deviations) unless stated otherwise. Independent sample T test was used to assess the differences between SGA and AGA groups. Continuous data were reported as mean (SD) and categorical data are presented as n (%). Changes in variables with repeated measurements were assessed using two-way repeated measures analysis of variance. A In total, 25 pregnant women were serially assessed for eligibility during the study period and closely examined during the third trimester of pregnancy. Subsequently, 7 newborns with low Apgar score, preterm birth, and prolonged echocardiography examination were excluded. Ultimately, 36 patients were allocated into two groups of 18 cases (SGA Group) and controls (AGA Group).  The finaMaternal baseline characteristics (p < .001).eristics : MaternaNeonatal cardiorespiratory variables (p < .05) but no differences in APGAR score at 1- and 5-min and cord pH at birth were noted. Systolic and mean blood pressure were higher in SGA infants at both time points (p < 0.05), but no intergroup differences in either pre- or post -ductal oxygenation were noted (ariables : Neonatare noted .Right ventricular function (p < 0.05); specifically, RV-FAC and TAPSE were lower at both time-points. The rate of abnormal TAPSE or RV-FAC, suggestive of RV systolic dysfunction were 44% and 27.8% respectively in SGA infants. None of the AGA group reached abnormal thresholds of RV systolic function. In addition, tricuspid E/A ratio was also lower in the SGA group compared to AGA infants (p < 0.05). Although the incidence of abnormal tricuspid E/A ratio <1 was higher, this did not reach the statistical significance (p > 0.05).function , 4: IndiLeft ventricular function (p < 0.01), 22% satisfied the criteria for LV systolic disfunction (EF < 55%). Indices of LV diastolic function were also different between groups; specifically, IVRT was longer and mitral valve peak E and A wave velocity was lower in SGA infants. No difference in mitral E/A ratio, however, was noted (p > 0.05). A strong trend towards higher rate of abnormal mitral E/A peak velocity ratio <1.0 and IVRT >50 msec were noted in SGA group (p = 0.06).function , 4: AlthPulmonary and systemic hemodynamics (p < 0.01), lower RVO (p < 0.05) and higher rate of abnormal PVRi (>4) threshold compared to AGA infants. Similarly, the rates of bidirectional atrial and PDA shunt were higher in SGA infants at both time-points (p < 0.01 vs. time and group) indicating different loading condition of the RV in the SGA group (p < 0.01), no differences in LVO were noted. No differences in systemic blood flow velocities, resistance and pulsatility indices were noted between groups over time , and a lesser drop in PVR after birth were noted compared to AGA counterparts –35. In tin utero. The exact mechanisms of these associations are yet unknown, but evidence from recent studies indicates that impaired growth in utero triggers an adaptative process of arterial wall remodeling caused by increased pressure on fetal circulation in context of placental insufficiency  and Speckle tracking echocardiography (an angle independent technique) or a combination of high frame color Doppler data with speckle tracking analysis blood speckle imaging (BSI) were not used in this study.Strengths of our study is that study subjects were included in fetal life, they had a close prenatal care and monitoring until birth and followed up during the immediate transition to extrauterine life up to 48 h age when the major changes in cardiopulmonary physiology occur. Second, all variables were recorded prospectively in a cohort of infants, detected to be SGA before 32 weeks of gestation, born at term and matched according to mode of delivery with healthy term infants. Furthermore, primary, and secondary outcomes were evaluated based on comprehensive TnECHO, which is an essential tool to facilitate diagnostic precision and to provide physiologically appropriate treatment choices . There aependent , 63. Howependent . This woCharacterization of the cardiovascular adaptative changes during transitional period is important among SGA infants for appraising disease susceptibility. Our study showed that SGA infants had higher PVR, lower RV performance and impaired LV diastolic function. The clinical relevance and impact of these changes to hemodynamic disease states during the postnatal transition requires prospective investigation.


Preterm birth is serious public health worldwide, and early prediction of preterm birth in pregnant women may provide assistance for timely intervention and reduction of preterm birth. This study aimed to develop a preterm birth prediction model that is readily available and convenient for clinical application.Data used in this case-control study were extracted from the National Vital Statistics System (NVSS) database between 2018 and 2019. Univariate and multivariate logistic regression analyses were utilized to find factors associated with preterm birth. Odds ratio (OR) and 95% confidence interval (CI) were used as effect measures. The area under the curve (AUC), accuracy, sensitivity, and specificity were utilized as model performance evaluation metrics.Data from 3,006,989 pregnant women in 2019 and 3,039,922 pregnant women in 2018 were used for the model establishment and external validation, respectively. Of these 3,006,989 pregnant women, 324,700 (10.8%) had a preterm birth. Higher education level of pregnant women , pre-pregnancy overweight  and obesity , and prenatal care  were associated with a reduced risk of preterm birth, while age ≥ 35 years , black race , pre-pregnancy underweight , pregnancy smoking , pre-pregnancy diabetes , pre-pregnancy hypertension , previous preterm birth , and plurality  were related to an increased risk of preterm birth. The AUC and accuracy of the prediction model in the testing set were 0.688  and 0.762 , respectively. In addition, a nomogram based on information on pregnant women and their spouses was established to predict the risk of preterm birth in pregnant women.The nomogram for predicting the risk of preterm birth in pregnant women had a good performance and the relevant predictors are readily available clinically, which may provide a simple tool for the prediction of preterm birth.The online version contains supplementary material available at 10.1186/s12887-022-03591-w. Preterm birth, defined as delivery of less than 37 completed gestational weeks , 2, may Previous studies have reported that the risk of preterm birth was associated with age, race, smoking, economic status, and previous preterm birth , 8. A siIn this study, we aimed to establish a model to predict maternal preterm birth using baseline information that can predict preterm birth with the information readily available in clinical trials. Furthermore, external validation was conducted to assess the prediction ability of the model.Data used in this case-control study were extracted from the National Vital Statistics System (NVSS) database between 2018 and 2019 . The NVSData of pregnant women were collected including age (< 35 years and ≥ 35 years), race , education , pre-pregnancy body mass index (BMI) , prenatal care (yes or no), pregnancy smoking (yes or no), pre-pregnancy diabetes (yes or no), gestation diabetes (yes or no), pre-pregnancy hypertension (yes or no), gestation hypertension (yes or no), hypertension eclampsia (yes or no), previous preterm birth (yes or no), infection (yes or no), plurality (yes or no), and preterm birth (yes or no). In addition, the age, race, and education of the pregnant spouse were also collected. The outcome of this study was preterm birth.Preterm birth means births occurring before 37 completed weeks of gestation are preterm for purposes of classification consistent with the ICD-9  and ICD-10  definitions.Educational status was divided into three categories, high school or below, bachelor, and master or above. 8th grade or less, 9th through 12th grade with no diploma, high school graduate or GED completed, some college credit, but not a degree, associate degree  combined into high school and below. Master’s degree  and doctorate  or professional degree  merged into master’s degree and above.Pre-pregnancy BMI was calculated as: [mother’s pre-pregnancy weight (lb) / [mother’s height (in)]2] * 703 . Pre-preInformation on the timing and number of prenatal care visits was collected from the items “Date of first prenatal visit”  and “Total number of prenatal visits for this pregnancy.”All entries reporting packs of cigarettes are converted to the corresponding number of cigarettes (1 pack = 20 cigarette). If the mother reported smoking in any of the three trimesters of pregnancy she was classified as a smoker (smoked anytime during pregnancy).Infections include gonorrhea, syphilis, chlamydia, hepatitis B and hepatitis C.Plurality was defined as twin, triplet, quadruplet, and quintuplet and higher-order births.The 2019 data were randomly divided into the training set and testing set with a ratio of 1:1. Univariate and multivariate logistic regression analyses were conducted. Variables that were statistically significant in univariate analysis were included in multivariate analysis using backward stepwise regression. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the effect of the variable on preterm birth. Characteristics of the pregnant women and their spouses  and variables that were statistically significant in the multivariate regression analysis were included in the prediction model. The 2018 data were utilized for external validation of the predictive model. The performance of the predictive model was assessed by area under the curve (AUC), accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). A nomogram used to predict whether a pregnant woman had a preterm birth was drawn.The sample size was calculated using the PASS 15.0.5 software . Calculations of sample size and model power were shown in Supplement Fig. 2 tests or Fisher’s exact tests. SAS 9.4 software  was used for analysis. R 4.02 software  was used to draw logistic prediction model nomogram. Python 3.7.3 software  was utilized to calculate the AUC, accuracy, sensitivity, specificity, NPV, and PPV values. All statistical tests were used two-sided tests, and P < 0.05 was considered the difference to be statistically significant. Statistical power testing was performed using G*Power 3.1.9.7.Categorical variables were described in numbers and percentages [n (%)] and the groups were compared using χData of 3,757,582 pregnant women were extracted in 2019, and after excluding 750,593 pregnant women with incomplete information, a total of 3,006,989 women’s information were used for analysis , race (P < 0.001), education (P < 0.001), age of spouse (P < 0.001), race of spouse (P < 0.001), education of spouse (P < 0.001), pre-pregnancy BMI (P < 0.001), prenatal care (P < 0.001), pregnancy smoking (P < 0.001), pre-pregnancy diabetes (P < 0.001), gestation diabetes (P < 0.001), pre-pregnancy hypertension (P < 0.001), gestation hypertension (P < 0.001), hypertension eclampsia (P < 0.001), previous preterm birth (P < 0.001), previous cesareans (P < 0.001), infections (P < 0.001), and plurality (P < 0.001) between women with and without preterm birth.Table P < 0.05), and higher education level of pregnant women and their spouses and prenatal care may have a lower risk of preterm birth (P < 0.05). The multivariate analysis presented that higher education level of pregnant women  and their spouses , pre-pregnancy overweight  and obesity , and prenatal care  were associated with a decreased risk of preterm birth, while age ≥ 35 years , the black race of pregnant women  and their spouses , pre-pregnancy underweight , pregnancy smoking , pre-pregnancy diabetes , gestation diabetes , pre-pregnancy hypertension , gestation hypertension , hypertension eclampsia , previous preterm birth , previous cesareans , infections , and plurality  were related to an increased risk of preterm birth.Table Variables such as age, race, education of pregnant women and their spouses, pre-pregnancy BMI, prenatal care, pregnancy smoking, pre-pregnancy diabetes, gestation diabetes, pre-pregnancy hypertension, gestation hypertension, hypertension eclampsia, previous preterm birth, previous cesareans, infection, and plurality were included to develop a prediction model. Table In this study, we established a prediction model based on a large-sample database to predict preterm birth. Our results demonstrated that bachelor or above education level of pregnant women and their spouses, pre-pregnancy overweight and obesity, and prenatal care were linked to a reduced risk of preterm birth, while age ≥ 35 years, the black race of pregnant women and their spouses, pre-pregnancy underweight, pregnancy smoking, pre-pregnancy diabetes, gestation diabetes, pre-pregnancy hypertension, gestation hypertension, hypertension eclampsia, previous preterm birth, previous cesareans, infections, and plurality were associated with an increased risk of preterm birth. In the preterm birth prediction model constructed by these variables, the AUC of the model was 0.688 in the testing set. In addition, the model still performed well in the external validation set.Black ethnicity and advanced maternal age may be indicators of preterm birth in some studies , 20. In There were some studies focused on prediction models related to preterm birth, such as preterm birth prevention, cesarean delivery during the preterm period, or nulliparous women with a short cervix –14. ManyFrom the perspective of genetics, the neonatal father and mother were responsible for fetuses. Many parents were associated with maternal outcomes directly and indirectly . Sparse This study used a lot of demographic information which can obtain easily from clinical data. Because there were many restrictions on pregnancy and medical resources, such as in rural areas or low-income families. Using this prediction model can filter some pregnant who may have a preterm birth. Then the doctor can provide some suggestions or give preventions for pregnant to prevent them from preterm birth. This prediction model can save humans, material resources, and time. There were some limitations in this study. Firstly, the external validation group was still from the United States. Preterm birth was a global public health problem. This external validation may ignore the different countries pregnant. Because in different countries, pregnancy may have various characteristics, this prediction model may have different effects to predict preterm birth. Secondly, although our data source was easy to obtain, the effect of prediction model performance was not accurate because there was no gold standard in this prediction model. If there were some other information such as blood test information, and mid-term cervical length value, the predictive ability may increase. Third, 98.8% of the included population had prenatal care, and the predictive effect of the model on preterm birth in the population without prenatal care may need further verification.A nomogram for predicting the risk of preterm birth in pregnant women was established. The prediction model had good performance in the testing set and external validation set. In addition, the relevant predictors of the prediction model are readily available clinically, and the nomogram may provide a simple tool for the prediction of preterm birth.Additional file 1: Supplement Fig. 1. Calculations of sample size and model power.


Intensive care is of great significance for very low birth weight infants (VLBWI). The Yangtze River Delta is the most ecomonically developed area in China. However, there are few data on the care practices and survival of VLBWI in this region.To investigate the prevalence, care practices and motality of VLBWI in Yangtze River Delta in China.A multi-center retrospective investigation study was conducted at five tertiary hospitals within the Yangtze River Delta in China from January to December 2017. Clinical data included the general characteristics of the infants and the mothers, clinical prognosis, care practices in NICUs was collected by trained research members.During the study period, 1059 VLBWIs were included. Infants with birth weight < 750 g, 750-1000 g, 1000-1250 g and 1250-1500 g accounted for 2.3, 14.9, 34.8 and 47.8%, respectively. Premature rupture of membranes (17.8%) was the main cause of premature delivery. The catheterization rates of umbilical vein catheterization (UVC) and peripherally inserted central catheter (PICC) were 25.0 and 64.4%, respectively. The duration of parenteral nutrition was 27.0 ± 19.5 d, the meantime of feeding tube indwelling was 36.2 ± 24.2 d. The corrected gestational age of the infants who reached full oral feeding was 35.8 ± 2.7 weeks. The breast feeding rate in the investigated infants was 61.9%. The mortality rate of preterm infants was 3.4%. The incidence of main complications BPD, PDA, ROP, NEC and sepsis were 24.9, 29.9, 21.7, 9.4 and 13.3% respectively.Maternal and infant care practices need to be improved in the very preterm births. This study provides a baseline for the improvement in the further study. Very low birth weight infants (VLBWI) are defined as neonates with birth weight of less than 1500 g. VLBWI accounted for 20% of total hospitalized infants in the neonatal intensive care units (NICU), while extremely low birth weight infants (ELBWI) with a birth weight of less than 1000 g accounted for 15.1%  with theWith the rapid development of perinatal medicine and neonatal intensive care in China, more VLBWI have been admitted and treated in Chinese NICUs. Several epidemiological studies have been conducted aiming to describe the prevalance and prognosis of VLBWI in NICU. These data were widely used to assist clinical decision-making, evaluate the quality of neonatal treatment, and carry out quality improvement of NICU , 3, 7. TA multi-center cohort observational study was conducted in NICUs at 5 tertiary hospitals within the Yangtze River Delta in China. The Yangtze River Delta region incorporate Shanghai District, Jiangsu Province and Zhejiang Province. It is one of the most densely populated regions on earth, with over 150 million registered residents living in more than twenty developed cities including Nanjing, Hangzhou, Suzhou, Ningbo, Wuxi, and Changzhou. All the participating hospitals were tertiary neonatal care centers. The data came from the care database of VLBWIs in the Yangtze River Delta. All preterm infants with a weight of less than 1500 g who were younger than seven days at admission were included and the data from admission to discharge or death were all in the database. The data of all stillbirths and infants who were not discharged or died in these hospitals were not in the database. The data of infants discharged from January 1, 2017, to December 31, 2017 were analyzed in this study. Infants’ guardian signed informed consent. The study was approved by Ethics committee of Children’s Hospital of Fudan University ([2018]-211).The collected data included the general characteristics of the infants and the mother, clinical prognosis, conditions of nursing related care in NICU. Each unit designated a special data collector  who was responsible for data collection. All data collectors were trained before the study. The data of each unit was uploaded to the special database established for the VLBWI project in the Yangtze River Delta. The research group located at Children’s Hospital of Fudan University (CHFU) was responsible for checking the integrity and quality of the data. In addition, members of different research centers traveled to other centers for data audit. All data for this study were collected from the electronic medical record system of each hospital.The important data involved in the study were defined as follows: (1) gestational age: defined as the gestational age evaluated by early pregnancy ultrasound, obstetric examination, and obstetric history. If the difference between obstetric gestational age and neonatal gestational age assessment in NICU was more than 2 weeks, the neonatal simple gestational age assessment form was used for the assessment. The New Ballard score was used to evaluate the gestational age of preterm infants less than 28 weeks . (4) Int2 tests and continuous data using analysis of variance (ANOVA). A p-value < 0.05 was considered to be statistically significant with two-tail test.SPSS Version 22.0 software was used for statistical analysis of all data. For the objective of this study, the status of care measures, mortality & morbidity of neonatal outcome were described and summarized among VLBWIs. Continuous variables with normal distribution were expressed as means ± Standard deviation while those with highly-skewed distribution were represented by the median (p25-p75). Categorical variables were expressed as number of case (percentage). The denominator for percentages was the total number of infants with no missing data for each variable analyzed. Missing data were not imputed. For formal statistical analyses, we examined categorical variables using χA total of 1059 VLBWIs with an average gestational age of 29.8 ± 2.3 weeks and an average birth weight of 1216.6 ± 198.0 g were included in the study. Infants with birth weight < 750 g, 750-1000 g, 1000-1250 g and 1250-1500 g accounted for 2.3% (25 infants), 14.9% (158 infants), 34.8% (369 infants) and 47.8% (507 infants), respectively. Among them, 183 infants (17.2%) were ELBW, while 126 infants (11.9%) were infants with multiple pregnancies. Of total mothers of 1059 infants, 86.0% (911 mothers) had a regular prenatal examination, 21.1% (223 mothers) received prenatal glucocorticoids. Among the causes of preterm delivery, preterm rupture of membranes, fetal distress, placental abruption, and placenta previa accounted for 17.9, 4.4, 3.1, and 14.5%, respectively. The proportion of Apgar score in 1 min less than 3 reduced as the increase of birth weight, see Tables Rate of pulmonary surfactant use increased with decreased birth weight, from 64% at < 1000 g to 43% at 1251-1500 g. The top three utilization of respiratory support modes were CPAP (59.8%), conventional mechanical ventilation , and nasal tube oxygen inhalation (39.7%). Of total VLBWI, 688 (65.0%) infants, 536 (50.6%) infants, 207 (19.6%) infants were treated with caffeine, PS and aerosol inhalation respectively, see Table Umbilical vein catheterization  and Peripheral central venous catheterization PICC, 64.4%) were the most commonly used for vascular accesses in VLBWI. Among VLBWIs undergoing UVC, the mean indwelling time was 6.7 ± 4.8 days. The mean catheterization time of VLBWIs with PICC was 23.7 ± 16.2 days. See Table .4% were The duration of parenteral nutrition was 27.0 ± 19.5 days and the average duration of feeding tube indwelling was 36. 2 ± 24.2 days. The corrected gestational age of the VLBWI who reached full oral feeding was 35.8 ± 2.7 weeks in this study. The exclusive breast feeding rate was 61.9% among VLBWI (Table Hypothermia occurred in 11.7% of study population during hospitalization. The incidence of Hypothermia decreased significantly with the increase of birth weight: 28% at infants < 750 g, 19% at 750-1000 g, 13.3% at 1250-1500 g and 7.5% at 1250-1500 g. The proportion of VLBWI undergoing EEG monitoring, continuous glucose monitoring and percutaneous partial pressure of oxygen monitoring was 16.8, 15.8 and 20.9% respectively (Table The smaller of the birth weight, there was a greater risk of mortality due to prematurity. The mortality rate of VLBWI was 32% at < 750 g, 6.3% at 750-1000 g, 3% at 1000-1250 g and 1.4% at 1250-1500 g. There was significantly reduction of incidence of Sepsis with the increase of birth weight: 28% at < 750 g, 19.6% at 750-1000 g, 15.2% at 1000-1250 g and 9.3% at 1250-1500 g. The incidences of BPD, PDA, ROP and NEC were 24.9, 29.9, 21.7 and 9.4%, respectively. There were significant differences in the incidence of BPD, ROP and NEC among different birth weight groups (Table There are many factors causing preterm delivery, , 16 suchPrevious studies have also suggested a protective effect of noninvasive ventilation in preterm infants. CPAP is recommended as the preferred noninvasive ventilation mode after birth . Early CIn addition to noninvasive ventilation, caffeine administration also played major roles on promotion of neonatal morbidity. Caffeine can help VLBWIs wean earlier, reduce the incidence of BPD, and improve the prognosis of neurodevelopment –27. In tAdequate nutrition supply is the key for the survival of preterm infants. Proper vascular access is the key to parenteral nutrition but limited studies focus on the vascular choices in the NICU. UVC and PICC are the most commonly used vascular accesses for VLBWIs. In this study, UVC and PICC were used in 25.0 and 64.4% infants, respectively. Meanwhile, smaller birth weight was associated with the longer indwelling time of UVC and PICC, which was consistent with previous study . In thisIn terms of enteral nutrition, breast milk is the first choice for VLBWIs, and it is related to the prognosis and survival rate , 31. AccThe management of body temperature is very important for preterm infants, in this study, hypothermia was observed in 19.3% of cases during hospitalization. We concluded that the smaller birth weight was associated with a higher incidence of hypothermia. Some researchers have suggested that bundles of golden hour temperature management including plastic bags usage, pre-warming the linens could significantly reduce the incidence of hypothermia in VLBWIs , 39. In EEG monitoring, brain or intestinal oxygen monitoring, and transcutaneous oxygen partial pressure monitoring are very important noninvasive monitoring methods in clinic. However, our results revealed that these monitoring methods were not frequently applied in VLBWIs, which also indicated that this kind of monitoring was not taken as routine monitoring in clinic. Infants with smaller birth weight and the more serious diseases were associated with the higher the proportion of such kind of monitoring.The mortality rate of VLBWIs included in this study was 2.4%. Lower birth weight was associated with a higher mortality rate. Compared with other domestic studies,  the mortThis study described the care practices of VLBWIs in the NICU of the Yangtze River Delta region, thus providing baseline data for the care of VLBWIs in the future. Our results also showed that the care strategies of VLBWIs in the Yangtze River Delta region needed to be improved.


Advanced maternal age at birth is considered a risk factor for adverse birth outcomes. A recent study applying a sibling design has shown, however, that the association might be confounded by unobserved maternal characteristics.N = 580 133; 90% population coverage), Norway (N = 540 890) and Sweden (N = 941 403) and from 2001–2014 in Finland (N = 568 026), we test whether advanced maternal age at birth independently increases the risk of low birthweight (LBW) (<2500 g) and pre-term birth (<37 weeks gestation). We estimated within-family models to reduce confounding by unobserved maternal characteristics shared by siblings using three model specifications: Model 0 examines the bivariate association; Model 1 adjusts for parity and sex; Model 2 for parity, sex and birth year.Using total population register data on all live singleton births during the period 1999–2012 in Denmark (The main results (Model 1) show an increased risk in LBW and pre-term delivery with increasing maternal ages. For example, compared with maternal ages of 26–27 years, maternal ages of 38–39 years display a 2.2, 0.9, 2.1 and 2.4 percentage point increase in the risk of LBW in Denmark, Finland, Norway and Sweden, respectively. The same patterns hold for pre-term delivery.Advanced maternal age is independently associated with higher risk of poor perinatal health outcomes even after adjusting for all observed and unobserved factors shared between siblings. Key MessagesAdvanced maternal age at birth is linked to an increased risk of adverse birth outcomes, but the evidence of whether the association is independent of maternal characteristics is inconclusive.Using total population registers from Denmark, Norway, Sweden and Finland, we test whether advanced maternal age at birth independently increases the risk of adverse birth outcomes using sibling models to reduce confounding by unobserved maternal characteristics shared by siblings.We employ a more careful application of the sibling design approach than prior studies.Advanced maternal age is associated with a higher risk of poor perinatal health outcomes even after adjusting for all observed and unobserved factors shared between siblings.The postponement of childbearing has been one of the most prominent demographic developments in high-income countries in recent decades, with mean maternal age at childbearing rising to >30 years in the 2010s across most member countries of the Organization for Economic Co-operation and Development (OECD).et al.Although most studies report that an advanced maternal age is associated with poor perinatal outcomes and pregnancy complications, whether this association is directly attributable to the consequences of reproductive ageing, or some combination of factors that confound the association between maternal age and perinatal outcomes, is not yet clear. A recent study has cast doubt upon whether maternal age is an independent or important determinant of perinatal health outcomes.et al.et al.The findings reported by Goisis In this study, we use population register data from Denmark, Finland, Norway and Sweden covering birth cohorts from 1999 to 2012 in Denmark, Norway and Sweden, and birth cohorts from 2001 to 2014 in Finland. All data are drawn from each country’s Medical Birth Registers, including information on the linked children and mothers. Each of these data sets is considered to be of exceptionally high quality.N = 580 133). We access the Finnish Medical Birth Register through the National Institute for Health and Welfare of Finland (N = 568 026). Access to the Norwegian Medical Birth Register is provided by the Norwegian Institute of Public Health (N = 540 890). We access the data for Sweden through the Swedish Interdisciplinary Panel, administered by the Centre for Economic Demography at Lund University (N = 941 403). Our data sources for Finland, Norway and Sweden provide data on all births recorded in the birth cohorts that we study. The Danish data that we have access to are a 90% random sample of the full population.We access the Danish Medical Birth Register via the Danish Health Data Authority through Statistics Denmark . Multiple births were excluded from the analyses , because multiple births have higher risks of LBW and PTB, and are more common at later maternal ages.We study two binary birth outcomes: whether a child was born with LBW (<2500 grams at birth) and whether the child was delivered with PTB (<37 weeks of gestation).The main explanatory variable was maternal age at childbirth. We divided maternal age into the following categories: <18, 18–19, 20–21, 22–23, 24–25, 26–27, 28–29, 30–31, 32–33, 34–35, 36–37, 38–39, 40–41 and 42+ years. This categorical approach allows us to capture potential non-linearities in the association between maternal age and LBW and PTB. The age group 26–27 years is used as the reference category.,,The sibling fixed-effects model adjusts for all time-invariant observed or unobserved factors that are shared by siblings. In terms of time-varying characteristics that vary from sibling to sibling, we included controls for parity  and child’s sex. We control for parity because within families later births always occur at higher maternal ages and births at parities two and above have a lower risk of LBW than first births.We estimate the association between maternal age and birth outcomes by fitting three different linear probability models (LPMs) for each of our two binary outcomes for each country separately, with fixed effects specified at the level of the sibling group. We compare siblings born to the same mother at different ages. This approach allows us to adjust for all unobservable maternal factors that are shared between siblings, including social background, pre-childbearing health behaviours, maternal age at first birth, unobserved aspects of maternal health and some genetic factors. Sibling fixed-effects models do not, however, adjust for factors that vary between siblings unless they are explicitly modelled.We rely on LPMs over nonlinear models such as the logit specification because only the former allow direct comparisons of coefficients across models and groups,et al.Model 0 is a bivariate fixed-effects model, estimating the association between LBW, PTB and maternal age in the absence of any further control variables. Model 1 controls for parity  and child sex. Model 2 introduces an additional control for year of birth using individual-year dummy variables and is comparable to the main estimation model presented in Goisis ,We conducted two sensitivity analyses. First, in Model 3, we estimate sibling fixed-effects models adjusting only for sex in order to investigate the influence of parity on the model estimates . Second, we estimate Model 4, adjusting for inter-pregnancy interval (IPI) in addition to sex and parity. IPI is included as a categorical variable for the number of months between pregnancies for Finland and Norway (month of birth was not provided with the Danish or Swedish data deliveries). This exercise was done since IPI and maternal age are associated and IPI or its determinants  may affect the outcome.IJE online) show trends in maternal age at childbearing and fertility across the four countries.Denmark: –0.009; 95% CI: –0.012, –0.006), 0.6 , 0.7  and 1.2  percentage-point lower risks of LBW relative to the reference category in the respective countries. This corresponds to ∼27%, ∼20%, ∼20% and ∼38% lower risks of LBW relative to the baseline probability in each country, respectively. On the other hand, mothers aged 38–39 years displayed 2.2 , 0.9 , 2.1  and 2.4  percentage-point higher risks of LBW relative to the reference category in Denmark, Finland, Norway and Sweden, respectively, corresponding to 66%, 30%, 61% and 75% higher risks of LBW relative to the baseline probability in each country.The results from Model 2 are shown for illustrative purposes. The results from Model 2 show an attenuated gradient in all four countries and a decrease in precision leading to a lack of differences between most of the age groups relative to the reference group. However, due to perfect collinearity between maternal age and birth year in a sibling comparison model, it is not possible to separate the relative contribution of each factor to the risk of LBW.The results from analyses examining PTB are presented in Denmark: –0.006; 95% CI: –0.010, –0.003), 0.8 , 0.7  and 1.1  percentage-point lower risks of experiencing a PTB compared with the reference group in Denmark, Finland, Norway and Sweden, respectively. This corresponds to 13%, 17%, 13% and 20% lower risks of PTB relative to the baseline probability in each country, respectively. An elevated risk of PTB was observed among mothers older than the reference category. For example, mothers aged ≥38–39 years experience 2.0 , 1.4 , 1.6  and 2.4  percentage-point higher risks of PTB in Denmark, Finland, Norway and Sweden, respectively. This corresponds to 41%, 32%, 30% and 44% increases relative to the baseline probability, respectively. The Model 2 results are once again shown for illustrative purposes and, in line with the results for LBW, they show that there is an attenuated gradient and a loss of precision of the estimates.The results from Model 1 for PTB are similar to the results for LBW, with a monotonic increase in the probability of PTB with increasing maternal age across all four countries, with the exception of births to mothers <18 years of age in Norway, Denmark and Finland. Mothers aged 22–23 years of age display 0.6 (βIJE online). Specifically, model estimates from these sensitivity analyses were nearly identical to those from Model 0. Similarly, results from sensitivity analyses adjusting for IPI in Norway and Finland only slightly weakened the relationship between maternal age and the risk of LBW, and had no impact on the relationship between maternal age and PTB (IJE online).The sensitivity analyses examining the association between maternal age and LBW and PTB adjusting only for sex highlight the important role that the birth order adjustment plays  show a clear and substantial positive association between maternal age and the probability of both LBW and PTB. These results were obtained after controlling for parity, but not for birth year.et al.et al.et al.et al.,Our study builds upon Goisis IJE online), we nevertheless cannot be certain about the extent to which our results are being driven by birth year. In addition, the results from Model 1 highlight the important role of parity adjustments when estimating the effect of maternal age on LBW and PTB. Since first-born children experience an elevated risk of LBW and PTB and occur, on average, at younger maternal ages, the maternal age association with LBW and PTB becomes positive in sibling fixed-effects models after adjustment for parity; in fact, the maternal age association entirely reverses in comparison to Model 0, which indicates that the net beneficial effect of higher parity or the time-varying processes it reflects more than outweighs the net detrimental effect of increasing maternal age on birth outcomes. Nevertheless, it is the net effect of maternal age that is of interest to couples planning when to have a child of a certain birth order or to those advising on such matters. Note also that the beneficial effect of higher birth order is consistent with the existing research showing large parity differences in perinatal health.Our preferred estimation model (Model 1) includes controls for parity and child sex, but not birth year due to the collinearity between maternal age and birth year when comparing births to the same mother. By excluding a control for birth year, our models are estimating the joint effect of maternal age and birth year. We would prefer to obtain estimates for maternal age net of the effect of birth year, but this is not possible when applying the sibling comparison design. Although we have restricted our analyses to a period over which the prevalence of LBW and PTB hardly varied in the Nordic region  are highly similar to those presented in the main text.The results from our study complement previous work by Lawlor and colleaguesThis study has several strengths. First, we use total population data of equally high quality and coverage from four Nordic countries, each of which allows us to identify siblings. Second, the data are not prone to self-selection since they come from administrative population registers. Third, we are able to account for all unobserved maternal characteristics that are shared between siblings. To the best of our knowledge, no previous study has been able to analyse such a large geographic region with this degree of precision.a priori reason for believing this should be different for women who have only one child. Furthermore, research using cousin comparisons that adjust for some family characteristics but include only children produce similar results.This study also has limitations specifically attributable to the sibling fixed-effects model that we employ. First, our analyses are based upon a subset of women who had at least two live births, because the sibling fixed-effects model exploits variation between siblings. Although the fixed-effects models reduce confounding from unobserved factors shared by siblings, the exclusion of one-child sibling groups means that we cannot generalize our results to this population. However, our results show that advanced maternal age increases the probability of LBW and PTB, and we have no Second, the sibling comparison does not adjust for all factors that may vary over time within the family, such as changes between births in maternal health status, socio-economic status and health behaviours.Third, it is known that sibling model estimates can be severely biased if the outcome for one child affects subsequent fertility and thus the maternal age ‘exposure’ for a younger sibling.The mean age at childbearing has risen steadily across high-income countries since the 1970s, with the mean age at first birth nearing age 30 years across high-income countries and even exceeding age 30 years in countries such as Italy, Japan, Spain and Switzerland. This study sheds additional light on the potential public health consequences of this secular demographic trend. In contrast to recent work, our study suggests that childbearing at older maternal ages does increase the risk of LBW and PTB. Moreover, the consistency of our results across these four countries suggests that it may be reasonable to generalize this finding to other countries with similar fertility regimes and welfare systems.Ethical approval for the Danish data was provided by Statistics Denmark (Project FAMC706980). Data access to the Danish data was provided through a collaboration between the Centre for Economic Demography, Lund University and The Danish Institute for Human rights. Ethical approval for the Finnish data was provided by Statistics Finland (TK-53–1121-18) and Findata (THL/2179/14.02.00/2020). Ethical approval for the use of the Norwegian data was obtained from the Regional Committees for Medical and Health Research Ethics . Ethical approval for the Swedish data analysis was approved by the Swedish ethical-vetting authority, Dnr 2012/627 and 2017/813.dyac211_Supplementary_DataClick here for additional data file.


Introduction: The World Health Organization (WHO) recommends all newborn infants receive the first dose of the hepatitis B vaccine within 24 h of birth irrespective of maternal hepatitis B carrier status. However, the physiological immaturity of the immune system in preterm infants may influence the immune responses to the vaccine particularly in the first few days and weeks of life, and adverse events may occur following vaccination that are not observed in infants born at term. Objectives: To review existing published guidelines surrounding timing of the first dose of the hepatitis B vaccine in preterm infants born to hepatitis B surface antigen negative (HBsAg-negative) mothers. Methods: A search was performed for relevant papers and guidelines published between January 2002 and July 2022 on the Ovid MEDLINE and Embase databases and through targeted searches. Two authors independently reviewed the search results to identify relevant sources, which were then analysed and described through narrative synthesis. Results: Twenty-seven relevant papers and guidelines regarding 15 countries and regions were included. Of these, 13.3% of guidelines, which represented 16.8% of the overall population of 4.1 billion people covered by the identified guidelines, recommended a nationwide birth dose of the hepatitis B vaccine to all preterm infants. In 40.0% of guidelines , the birth dose was only recommended for infants with a birth weight of more than 2000–2200 g. Another 33.3% of countries and regions (covering 4.4% of the population) recommended no universal birth dose for all infants, including preterm infants, whilst 13.3% (1.0% of the population) had guidelines that varied between jurisdictions and hospitals within their country/region. Conclusions: Existing guidelines surrounding the timing of the first dose of the hepatitis B vaccine in preterm infants vary substantially between countries and regions. Further research comparing the immunogenicity and safety of different hepatitis B vaccine schedules is needed to provide concrete evidence to provide guidance regarding the timing of vaccination against hepatitis B in preterm infants. Hepatitis B is a viral infection of the liver caused by the hepatitis B virus (HBV) and remains a serious public health concern worldwide. One of the most common routes of transmission is vertically, i.e., through mother-to-child transmission at birth . PerinatHaemophilus influenzae type B [Limited research exists regarding optimal timing of the first dose of the hepatitis B vaccine specifically in preterm infants. Compared to term infants, premature neonates are at an increased risk of serious illness from diseases preventable by vaccines; besides hepatitis B, these include diphtheria, pertussis, and e type B . Howevere type B . This ane type B . This reA search was performed for peer reviewed publications to identify guidelines specifically related to hepatitis B vaccination in preterm infants. The search strategy is outlined in The inclusion criteria were articles and guidelines that discussed the timing of the first dose of the hepatitis B vaccine in preterm infants born to HBsAg-negative mothers. Eligible sources were government and national immunisation program guidelines, and studies that referenced relevant national guidelines. Guidelines were only included if they specifically discussed preterm infants.Studies were excluded if they met any of the following criteria: included animal subjects or published prior to 1 January 2002.The search results from all databases were imported to the Covidence systematic review software , where duplicate articles were automatically removed. Two authors independently screened all articles based on their title and abstract to determine their eligibility, based on the inclusion and exclusion criteria. Findings from the relevant guidelines were then analysed and presented through narrative synthesis.Our search strategy through Ovid MEDLINE and Ovid Embase identified a total of 1386 papers, of which 471 duplicate records had been removed. A total of 1317 articles were excluded after title and abstract screening because they did not discuss hepatitis B vaccinations in infants, and we were unable to access the full text of nine studies. A further 51 studies were excluded due to the following reasons: not outcome of interest or guideline (27), full text not in English (16) or did not discuss preterm infants (8). An additional 18 sources were identified by reviewing the bibliographies of relevant articles and by conducting targeted internet searches. In total, 27 papers and guidelines were eligible for inclusion in this review . These 2Our results show that, despite WHO’s recommendation for all infants to receive their first dose of the hepatitis B vaccine as soon as possible after birth , guideliOf the 15 countries/regions for which we were able to identify relevant guidelines, two  have guidelines stating that all infants, including preterm infants, should receive their first dose of the hepatitis B vaccine within 24 h of birth. These are Australia ,11,12 anSix countries  have national guidelines that recommend a birth dose of the hepatitis B vaccine subject to the infant having reached a particular birth weight. These countries are China , India ,18,19, IEach of these six countries outlines similar recommendations regarding when infants born below the birth weight threshold can receive their first dose of the hepatitis B vaccine. In general, these guidelines consist of three main criteria: the infant reaching a predefined weight or age, or being discharged from hospital. In China, infants with a birth weight of less than 2000 g are recommended to receive their first dose of the hepatitis B vaccine once their weight reaches ≥ 2000 g or just before discharge from hospital , whilst Haemophilus influenzae type b and hepatitis B [Of the 15 countries/regions identified, five  have nationwide guidelines which do not include a universal birth dose. These countries instead recommend the first dose of the hepatitis B vaccine to be given during the first six to nine weeks of life to all infants, including preterm infants, as part of the routine hepatitis B vaccination series. These countries are Germany , Irelandatitis B .Of the relevant sources identified, our data indicated that two 13.3%/1.0%) countries/regions have guidelines regarding timing of the first dose of the hepatitis B vaccination in preterm infants that vary between jurisdictions .3%/1.0%  or hospiThe types of guidelines surrounding the timing of the first dose of the hepatitis B vaccine in preterm infants are summarised in p = 0.0004; odds ratios were similar for the same comparison at weeks 1 and 2 of life, e.g., OR 28.5, 95% CI 3.0–273, p = 0.004) [Evidence from a recent longitudinal study in preterm infants and accompanying animal data revealed that type 2-polarised inflammation underpins the neonatal chronic lung disease, bronchopulmonary dysplasia (BPD) . This tyThis variability in recommendations is at least in part justified by variations in hepatitis B prevalence and transmission rates, and therefore cost-effectiveness of different vaccination schedules. For example, hepatitis B vaccination for infants in the UK was not introduced until 2017, when the combination vaccine became available, for HBs-Ag negative mothers due to the low prevalence and low rates of vertical transmission  of hepatIn contrast, Australia and Latin America  have guidelines recommending a nationwide birth dose of the hepatitis B vaccine for all infants. The Australian Department of Health recommends that premature infants should receive vaccines in line with the recommended scheduling at chronological age without prematurity correction, provided they are medically stable with no contraindications to vaccination.Administration of a birth dose reduces the risk of hepatitis B transmission in infants by up to 90% and is also associated with high seroprotective levels of > 95% especially when a four-dose schedule is used ,42. In pA further 33% of countries/regions  had guidelines recommending no universal birth dose and instead the first dose at six to nine weeks of chronological age. One of the major benefits of later vaccination is that the hepatitis B vaccine can be provided as part of a combination vaccine to protect against other childhood illnesses that is only available to infants ≥ 6 weeks old . CompareThe most common type of guideline  recommended a nationwide birth dose of the hepatitis B vaccine subject to infants being born with a birth weight of approximately 2000 g. These guidelines reflect existing literature, which shows high seroprotective levels of > 90% in preterm infants when the first dose of the hepatitis B vaccine is delayed until a weight of 2000 g is reached postnatally ,49,50. FThe main limitations of our study were that we were only able to include countries with guidelines published online and in English and those that had specific recommendations for preterm infants. Compiled country-level data may not include details about preterm-specific guidance and not all individual country guidelines were reviewed. This circumstance limited our ability to describe patterns in timing of the first dose of the hepatitis B vaccination in preterm infants more widely. Where possible, dosing regimens of the hepatitis B vaccines were researched and outlined in Future research should focus on weighing the risks and benefits of different approaches regarding timing of the first dose of the hepatitis B vaccine in preterm infants, including comparing the immunogenicity and safety of different schedules.Guidelines relating to the timing of the first dose of the hepatitis B vaccine in preterm infants born to HBsAg-negative mothers show considerable variation between countries and regions. The guidelines most commonly adopted by countries/regions include a birth dose that is subject to infants being born with a birth weight of at least 2000–2200 g, or no universal birth dose and instead the first dose at six to nine weeks of age for all infants. The large variability between guidelines is at least in part justified by factors specific to countries and regions, such as the prevalence of hepatitis B infection. However, we argue that new safety concerns regarding the birth dose in preterm infants should be considered going forward, particularly in regions in which have comprehensive maternal hepatitis B screening programs.