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Surgical management of esophageal atresia with tracheoesophageal fistula in extremely low birth weight neonates: A systematic review.

BACKGROUND: Surgical management of esophageal atresia/tracheoesophageal fistula (EA/TEF) in extremely low birth weight (ELBW) neonates remains challenging and controversial. This study systematically reviews surgical strategies and outcomes in this population. METHODS: Following PRISMA guidelines, Cochrane, Embase, MEDLINE, Scopus, and Web of Science (2004-2024) were searched in February 2025 for studies on surgical management of ELBW neonates with EA/TEF (PROSPERO CRD42025636228). Fatal chromosomal abnormalities were excluded. Demographics, comorbidities, surgical techniques, and complications were analyzed descriptively. Risk of bias was assessed. RESULTS: Eleven publications (five case reports and six case series) comprising 30 patients (Gross type B/C = 1/29) met the eligibility criteria. Mean gestational age was 28.1 (23-34) weeks, and mean birth weight was 760.4 (422-995) g. Twelve primary repairs (PR) and 18 delayed primary repairs (DPR) were performed, including staged repair (n = 11), lower esophageal banding (n = 4), and other techniques (n = 3). Postoperatively, four anastomotic leaks were managed conservatively, six strictures and one recurrent TEF required endoscopic intervention, three fundoplications and two aortopexies were reported (follow-up: 1-198 months, n = 19). Overall mortality was 30% (PR: 8.3%; DPR: 44.4%). Mortality was 60% among neonates with major congenital heart defects (CHD) and 40% among those with VACTERL association. EA/TEF-related complications contributed to 33.3% of deaths. CONCLUSIONS: Mortality in this cohort remains high, particularly with major CHD, and is largely unrelated to EA/TEF-specific complications. In selected cases, PR appears feasible as an alternative to DPR, although conclusions are limited by the small sample size and heterogeneous studies.

Humans

Serum concentrations of 25-hydroxyvitamin D in rickets of extremely premature infants.

Nine premature infants developed radiographic and biochemical rickets at a mean +/- SD of 12.6 +/- 2.8 weeks of age. Serum 25-hydroxyvitamin D concentrations were all low, with a mean of less than 3.6 +/- 2.1 ng/ml. The mean average daily intake of vitamin D since birth had been 300 +/- 181 IU, and the mean average daily intake during the week of diagnosis was 587 +/- 313 IU. All of the infants were extremely premature (mean weight 948 +/- 153 gm, mean gestation 27.7 +/- 1.1 weeks), and were being fed either a low-calcium "human milk-like" formula or a soy formula. It is postulated that low-calcium intake may have increased 25-OHD utilization in the face of a decreased ability of the extremely premature infant to produce 25-OHD. Because of multiple factors leading to both decreased production and possible increased utilization of 25-OHD, such infants have an increased requirement for vitamin D to maintain normal serum 25-OHD concentrations, and daily intakes of at least 400 IU vitamin D orally must be assured. Serum 25-OHD measurements and radiographs may be important in following infants at risk.

Humans

[The estimation of thyroxine, triiodothyronine, thyro-binding-index, and free-thyroxine-index in the newborn (author's transl)].

Because of the importance of early diagnosis of hypothyroidism normal values of thyroxine (T4), thyro-binding-index (TBI), free thyroxine-index (FTI) and triiodothyronine (T3) in the serum of newborns were established. In extremely premature babies as in early fetal life the total thyroxine is relatively low. The lowest serum thyroxine in newborns without hypothyroidism was found in a premature infant with a birth weight of 750 g, i.e. 4.8 mug/100 ml on the 4th day of life. Otherwise the T4 values were quite high during the neonatal period, without signs of hyperthyroidism. Our hypothyroid patients scarcely had higher T4 values (0.8-5.1 mug/100 ml) within the first month of life than older hypothyroid patients. Healthy newborns had a mean T4 value of about 15 mug/100 ml during the first week of life (two standard deviations 6.4-23.6 mug/100 ml). Afterwards the T4 values slowly came down to a mean of about 12 mug/100 ml in the 4th week of life. During the first month of life the FTI of hypothyroid patients was below two standard deviations of normal newborn values, whereas TBI-values showed an overlap. During the first 3 days of life newborns with goiter had T4-values in the lower normal or hypothyroid range without obvious signs of hypothyroidism. FTI was quite low, too, and TBI relatively high (as in hypothyroidism). Within the second week of life all these values normalized mostly after treatment with KI ointment, occasionally without this treatment. Where these values did not normalize, hypohtyroidism was assumed. Triiodothyronine in cord blood was very low (0.47 ng/1.6 ng/ml) during the neonatal period (one to two days after birth almost 2.0 mg/ml). Values in our hypothyroid patients fluctuated widely (zero to slightly elevated values with a mean of 0.78 ng/ml). Therefore, T4 seemed more reliable than T3 for the diagnosis of hypothyroidism (the opposite was true for hyperthyroidism.

Fetal Blood

[Population genetics approach to the problem of the nonspecific biological resistance of the human body. I. Statement of the problem and basis for the approach. Distribution parameters of anthropometric markers of normal and ill newborn infants and nurslings].

Distributions of two metrical characters-the weight and the body length at birth are considered in several groups of healthy, diseased and dead newborns and infants. Significant differences in statistical parameters of these distributions (mean, standard deviation, skewness and kurtosis) are demonstrated for normal and malformated children. The increased number of children with minimal deviations from the mean values of characters (adaptive norm) is observed among healthy newborns, while in groups of diseased and dead children the frequency of individuals with extreme (especially low) values is increased. The principle of classification of individuals based simultaneously on two characteris is suggested and the problem of "average phenotype" classification by the number of characters is discussed.

Birth Weight

Proteomic Profile in Retinopathy of Prematurity: A Secondary Analysis of the Mega Donna Mega Randomized Clinical Trial.

IMPORTANCE: Identifying early proteomic profiles in infants who develop severe retinopathy of prematurity (ROP) may reveal targets for preventive interventions to reduce retinal vessel loss and the subsequent risk of severe ROP. OBJECTIVE: To assess early longitudinal profiles of blood protein levels in preterm infants with or without severe ROP and the effect of arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory, post hoc analysis of serum proteome profiles in preterm infants in the double-masked Mega Donna Mega (MDM) randomized clinical trial using targeted Olink Proximity Extension Assay proteomics covering 538 analytes. The setting was 3 university hospitals in Sweden and included extremely preterm infants born before 28 weeks of gestational age (GA), from 2016 to 2019. Data were analyzed from January to March 2025. EXPOSURES: All infants received standard nutrition; additionally, half received enteral lipid supplementation with AA/DHA (100/50 mg/kg per day) from birth to term equivalent age. MAIN OUTCOMES AND MEASURES: Longitudinal protein profiles during the first month of life were examined using mixed models for repeated measures, adjusted for GA, study center, and AA/DHA supplementation, and tested for the interaction between severe ROP (stage &#x2265;3 and/or treated) and postnatal age. RESULTS: A total of 177 extremely preterm infants (mean [SD] GA, 25.6 [1.4] weeks; 100 male [56.5%]) were included, of whom 50 (28.2%) developed severe ROP. Of 538 longitudinal analyzed proteins, 109 protein profiles in the first month of life associated with severe ROP, proteins related to immune response, apoptotic processes, blood coagulation, and lipid metabolism. The most pronounced association with severe ROP was a fast rise in fibroblast growth factor 21 (FGF-21; &#x3b2;&#x2009;=&#x2009;0.68; 95% CI,&#x2009;0.39-0.97; Q =.002) and tissue plasminogen activator (tPA; &#x3b2;&#x2009;=&#x2009;0.21; 95% CI,&#x2009;0.13-0.29; Q <.001) during the first postnatal days. The increase in serum FGF-21 level in the first week of life was associated with lower GA, lower birth weight, low enteral energy intake, and more days receiving mechanical ventilation. No association was observed between AA/DHA supplementation and the proteome. CONCLUSIONS AND RELEVANCE: In this post hoc exploratory analysis of data from the MDM randomized clinical trial, a fast rise in FGF-21 levels, a metabolic stress-induced hormone, during the first postnatal days was strongly associated with the development of severe ROP in extremely preterm infants. These findings suggest that early interventions improving bioenergetic status may help prevent severe ROP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03201588.

Humans

Theophylline pharmacokinetics in premature infants with apnea.

The pharmacokinetics of theophylline were examined in eight low-birth-weight infants (gestation: 26-32 weeks: birth-weight: 887-1,480 gm), who received the drug for treatment of primary apnea. The drug was assayed by high pressure liquid chromatography. The final dosage was 1 to 3 mg/kg/6 hour at 25 to 37 days of age. At the time, theophylline had a prolonged half-life ranging from 13 to 29 hours, a relatively large volume of distribution of 0.65 to 2.86 1/kg, and a small body clearance of 23 to 68 ml/hr/kg. The extremely slow and variable elimination of theophylline must be considered in treatment of apneic infants. The initial dosage regimen suggested is a loading dose of 6 mg/kg and a maintenance dose of 2 mg/kg/ 12 hours, with adjustments made based on monitoring of the serum concentration and on an increased biotransformation capability as maturation occurs.

Apnea

[Parenteral nutrition and nitrogen balances in low birth weight newborns in the adaptation period (author's transl)].

Nitrogen balance studies were performed in the course of parenteral nutrition in the first 5 days of life in three groups of low birth weight newborns (I. group = 12 premature, 27.--30. gestational week, b. w. M = 1298 g, II. group = a) 7 prematures, 27.--31.g.w.,b.w.M = 1295 g,b) 5 small for date prematures, 29.--32.g.w.,b.w.M = 1208 g, III. group = 10 prematures, 31.--36.g.w.,b.w. M = 1751 g). Losses of nitrogen via urine in extreme prematures during the adaptation period are higher than in full term or moderate prematures. Increased volume of parenteral nutrition (glucose, fat emulsion) and increased caloric quotient did not produce a significant restriction of N-losses via urine. No difference was found in N-losses between extreme prematures and small for date prematures of similar birth weight/group IIa): IIb)/. Aminoacids (cca 500 mg N/kg body weight/24 hrs) given on the second day of life were well retained; increased losses of N represented about 20% of N infused.

Amino Acids

Intraventricular haemorrhage in the preterm infant without hyaline membrane disease.

The clinicopathological associations of 33 singleton infants who died with intraventricular haemorrhage (IVH) without hyaline membrane disease (HMD) ('IVH only') were compared with those of 39 infants who died with IVH+HMD over the same gestation range in order to determine what factors other than those related to HMD may contribute to the pathogenesis of IVH. The incidence of 'IVH only' was inversely related to gestational age in the Hammersmith birth population, whereas the incidence of IVH+HMD rose to a peak at 28-29 weeks' gestation. Infants with 'IVH only' lived longer on average than those with IVH+HMD despite a lower birthweight and shorter gestation. Infants who died in the first 12 hours from 'IVH only' had suffered severe birth asphyxia but in those who died later the main symptom was recurrent apnoea. Fewer infants with asphyxia but in those who died later the main symptom was.recurrent apnoea. Fewer infants with 'IVH only' were given alkali therapy or were connected to the ventilator as compared to those with IVH+HMD, but there were no differences in alkali therapy in those who lived for 12 hours or more. In the 'IVH only' group there was a high incidence of haemorrhage from other sites and of bacterial infections. It is suggested that, in the absence of HMD, extreme immaturity is the main factor determining the occurrence of IVH. Birth asphyxia, apnoeic attacks, haemorrhage, and infections may play subsidiary roles, possibly through development of metabolic acidosis.

Cerebral Hemorrhage

Failure of indomethacin to close persistent ductus arteriosus in infants weighing under 1000 grams.

Six preterm infants with a persistent ductus arteriosus, who failed to improve with conventional medical management, received indomethacin in an attempt to close the duct pharmacologically. All infants weighed less than 1000 g when the drug was administered. All showed a transient response to indomethacin; however, no infant demonstrated a permanent response, even though 5 of the 6 received multiple doses. One of the patients developed a severe episode of anuria, uraemia, and gastrointestinal bleeding. Of the 6 infants, 3 underwent subsequent successful surgical ligation of the ductus. It is suggested that the extremely preterm infant may be a 'poor responder' to indomethacin. Since the side effects of indomethacin may be life-threatening, it may be wise to consider surgical ligation in lieu of indomethacin administration in these infants.

Anuria

Results of the Inter-American Investigations of Mortality relating to reproduction.

Maternal age and parity, according to the findings of the Inter-American Investigation of Mortality in Childhood, have a direct relationship to the health and survival of the infant. Among the results of this broad undertaking are data suggesting that babies born close in succession, especially within large families and as birth order ascends, are at greater risk of dying. Also, the offspring's future is increasingly threatened as the mother's age tends toward the extremes of the childbearing years. Compromise of the mother's health, in turn, was indicated in the earlier Investigation, a study of deaths in adults, which revealed unexpectedly high maternal mortality in the Latin American cities that it covered. Immaturity, or low birthweight, and malnutrition emerged as the two major underlying or associated causes of death in the Latin American projects of the Inter-American Investigation of Mortality in Childhood. Despite the marked variations in the data available from the different areas, there appeared to be some correlation between these two indicators of deficits in growth and development. Mortality due to immaturity was especially high for babies of young mothers, with increases occurring as the birth order rose. Not only are the risks greater for mothers having low-weight babies when they are young (under 20), but they increase even more with the second, third, and fourth products when the birth intervals become shorter. Maternal age, birth order, and birthweight are factors that must be considered in combination in the programming of protective health measures.

Adolescent

Transepidermal water loss in newborn infants. I. Relation to ambient humidity and site of measurement and estimation of total transepidermal water loss.

Insensible water loss (IWL) is an important factor in the thermoregulation and water balance of the newborn infant. A method for direct measurement of the rate of evaporation from the skin surface has been developed. The method, which is based on determination of the vapour pressure gradient close to the skin surface, allows free evaporation. From measurements performed on 19 newborns placed in incubators, a linear relation was found between the evaporation rate (ER) and the humidity of the environment at a constant ambient temperature. A 40% lower ER was recorded at a high relative humidity (60%) than at a low one (20%) in the incubator. At measurements on different sites of the body, a high ER was observed on the face and peripheral parts of the extremities, while ER at other sites was relatively low. By determining ER from different parts of the body and calculating the areas of the corresponding surfaces, the total cutaneous insensible water loss for the infant in question could be obtained. The transepidermal water loss (TEWL) for the whole body surface area was calculated to be 8.1 g/m2h. On the basis of measurements performed it was found that the total cutaneous insensible water loss can be estimated with a reasonable degree of accuracy by recording ER from only three easily accessible measurement points.

Birth Weight

Observations on intrauterine growth in urban Ethiopia.

A total of 3144 deliveries comprising a wide range of socio-economic groups in Addis Abeba were investigated. A positive correlation was found between family income and birth weight, with a difference of nearly 500 g between the extremes of socio-economic classes. A seasonal variation in mean birth weight was also observed. The mean length of gestation was 7.4 days shorter, and the anthropometric measures at birth were significantly lower in the Ethiopian infants as compared with the Swedish norm. The median weight and length development in relation to gestational age in the Ethiopian newborns was similar to the Swedish standard up to approximately 34--35 weeks of gestation. After that time there was very little further intrauterine growth in Ethiopian infants. The possible reasons for the observed pattern of growth are discussed.

Birth Weight

Leucocyte ascorbic acid and pregnancy.

1. Leucocyte ascorbic acid concentrations have been measured in 1147 females during early pregnancy and in smaller numbers of women before conception, throughout pregnancy and at 6 months post partum. 2. The leucocyte concentration in the 1st trimester was found to be affected by season, social class and smoking. Selecting individuals by extremes of social class, season and smoking produced two small populations with almost separate ascorbic acid distributions and mean concentrations of 21.7 and 45.1 microgram/10(8) leucocytes. 3. Early pregnancy had little effect on leucocyte ascorbic acid concentrations but values decreased in the second trimester. However, this was associated with a leucocytosis so that the total leucocyte ascorbic acid content of blood was unchanged. 4. Low ascorbic acid concentrations during the 1st trimester were not associated with subsequent spontaneous abortions, still-births or neonatal deaths, but there was an increased frequency of low values in women who gave birth to infants smaller than 3250 g. 5. The adequacy of ascorbic acid reserves in early pregnancy is discussed.

Adult

Transient hypothyroidism associated with prematurity, sepsis, and respiratory distress.

Serial TSH and T4 determinations were performed in sixty neonates admitted to our hospital for neonatal intensive care within a period of three months. Seven patients (12%) showed transient hypothyroidism on the basis of low T4 and high TSH values. Only one of these patients, who had meconium aspiration and pneumonia, did not have the respiratory distress syndrome. In addition, 4 of these patients had sepsis. All of the patients were born before 37 gestational weeks and had birth weights under 2200 g. In addition, two patients of this gestational age and birth weight group had a progressive fall of T4 to extremely hypothyroid values without simultaneous elevation of TSH. Two of the 5 patients who died had histological studies of their thyroids. These revealed colloid-depleted vesicles, desquamated epithelium, and prominent vascularisation of the thyroid. The results of this study show that early recognition and therapy of transient hypothyroidism may be live saving.

Birth Weight