Necrotizing enterocolitis (NEC) is a severe multifactorial disease in preterm neonates associated with high morbidity and mortality. Better insight into prognostic values of the many reported factors ...associated with NEC is needed to enable identification of neonates at risk for NEC. The aim was to systematically review the literature to identify independent risk factors for NEC from the literature.
Medline, Cochrane, Embase, Pubmed and Google Scholar were searched systematically for cohort studies reporting prognostic factors for NEC in neonates using multivariable analysis. Studies were scored with the Quality In Prognosis Studies tool (QUIPS).
From 5154 initial hits, 14 prognostic studies were included, with various designs. Study quality was rated high in three studies, moderate or low in the 11 others. Significant prognostic factors for NEC reported in at least two studies were: low birth weight, small for gestational age, low gestational age, assisted ventilation, premature rupture of membranes, black ethnicity, sepsis, outborn, hypotension (all increased risk), surfactant therapy (conflicting results) and cesarean section (lower risk). Meta-analysis was considered not feasible.
High quality studies on prognostic factors for NEC are rare. Several prognostic factors, that are not necessarily causal, are associated with NEC. High quality prognostic research is necessary to establish the predictive values of these factors.
Objective To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. ...Study design VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg−1 ·d−1 (control group), or 2.4 g AA kg−1 ·d−1 plus 2-3 g lipids kg−1 ·d−1 (AA + lipid group), or 3.6 g AA kg−1 ·d−1 plus 2-3 g lipids kg−1 ·d−1 (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. Results The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. Conclusions In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.
Breastfeeding is considered the most optimal mode of feeding for neonates and mothers. Human milk changes over the course of lactation in order to perfectly suit the infant's nutritional and ...immunological needs. Its composition also varies throughout the day. Circadian fluctuations in some bioactive components are suggested to transfer chronobiological information from mother to child to assist the development of the biological clock. This review aims to give a complete overview of studies examining human milk components found to exhibit circadian variation in their concentration.
We included studies assessing the concentration of a specific human milk component more than once in 24 h. Study characteristics, including gestational age, lactational stage, sampling strategy, analytical method, and outcome were extracted. Methodological quality was graded using a modified Newcastle-Ottawa Scale (NOS).
A total of 83 reports assessing the circadian variation in the concentration of 71 human milk components were included. Heterogeneity among studies was high. The methodological quality varied widely. Significant circadian variation is found in tryptophan, fats, triacylglycerol, cholesterol, iron, melatonin, cortisol, and cortisone. This may play a role in the child's growth and development in terms of the biological clock.
In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of ...the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother–child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.
Objective To test the hypothesis that an initial fraction of inspired oxygen (FiO2 ) of 30% during resuscitation of preterm infants results in less oxidative stress and is associated with improved ...clinical outcomes compared with an FiO2 of 65%. Study design Preterm infants of gestational age <32 weeks (n = 193) were randomized to start resuscitation with either 30% oxygen (low-oxygen group) or 65% oxygen (high-oxygen group), after which the FiO2 was adjusted based on oxygen saturation values. The primary outcome was bronchopulmonary dysplasia (BPD) assessed at 36 weeks postmenstrual age. Secondary outcomes included major neonatal illnesses and markers of oxidative stress. Results The median gestational age of included infants was 286 /7 weeks (IQR, 265 /7 -303 /7 weeks). The incidence of BPD was not significantly different between the low-oxygen and high-oxygen groups (24% vs 17%; P = .15). The FiO2 in both groups was adjusted to a mean of 40% by 7 minutes in the low-oxygen group and by 11 minutes in the high-oxygen group. No differences in markers of oxidative stress were noted between groups. Conclusion Initial supplementation of preterm infants with 30% oxygen during the fetal-to-neonatal transition is as safe as 65% oxygen, with no differences in oxidative stress markers or BPD.
Dysregulation of iron homeostasis is associated with cardiac alterations in a sex-dependent manner in adults. It is unknown whether iron status during pregnancy has long-term impact on cardiovascular ...health, and if this association is influenced by sex. Therefore, this study aimed to evaluate sex-specific association between maternal iron status during early pregnancy and cardiac outcomes in children aged 10 years.
In a population-based cohort study among 1972 mother–child pairs, hemoglobin and ferritin were measured in early pregnancy (<18 weeks) and categorized into anemia (hemoglobin<11 g/dL), elevated hemoglobin (hemoglobin≥13.2 g/dL), iron deficiency (ferritin<15 μg/L), and iron overload (ferritin>150 μg/L). At 10 years of age, cardiac MRI was performed to measure right and left cardiac outcomes of function (ventricular end-diastolic volume (RVEDV and LVEDV) and ejection fraction (RVEF and LVEF)), and structure (left ventricular mass (LVM), and left ventricular mass-to-volume ratio (LMVR)). Results are presented for boys and girls separately and models were adjusted for confounders and multiple testing.
In boys, one standard deviation score (SDS) increase in maternal hemoglobin was associated with lower RVEDV and LVEDV (difference (95%CI) −0.10 (−0.17, −0.03) SDS and −0.09 (−0.16, −0.03) SDS, respectively). In boys, maternal anemia, as compared to normal hemoglobin levels, was associated with higher LVEDV (difference 0.34 (0.10, 0.59) SDS).
No associations were observed for other cardiac outcomes and for ferritin in boys. No associations were observed in girls.
In boys, dysregulated iron status during early pregnancy might permanently alter cardiovascular RVEDV and LVEDV function. Underlying mechanisms need further study.
In nonpregnant populations, higher serum ferritin, which reflects high iron stores, is associated with an increased risk of hypertension. We hypothesized that a dysregulated maternal iron status in ...early pregnancy may lead to impaired gestational hemodynamic adaptations, leading to an increased risk of gestational hypertensive disorders.
We examined the associations of maternal iron status with maternal blood pressure, placental hemodynamic parameters, and the risks of gestational hypertensive disorders.
In a population-based prospective cohort study among 5983 pregnant women, we measured maternal serum ferritin, transferrin saturation, serum iron, and transferrin concentrations at a median of 13.2 weeks gestation (95% range, 9.6–17.6). Maternal blood pressure was measured in early pregnancy, mid pregnancy, and late pregnancy, and placental hemodynamic parameters in mid pregnancy and late pregnancy were measured by ultrasound. Information on gestational hypertensive disorders was collected from medical records. We examined the associations of maternal early pregnancy iron status with maternal systolic and diastolic blood pressure, placental hemodynamic parameters, and the risks of gestational hypertensive disorders using linear and logistic regression models.
Higher maternal early pregnancy serum ferritin concentrations were associated with higher systolic and diastolic blood pressure throughout pregnancy in the basic models (P values < 0.05). After adjustment for maternal inflammation, sociodemographic and lifestyle factors, higher maternal early pregnancy serum ferritin concentrations were only associated with a higher early pregnancy diastolic blood pressure 0.27 (95% CI, 0.03–0.51) mmHg per SD score increase in serum ferritin and with a higher mid pregnancy umbilical artery pulsatility index (P < 0.05). No associations with the risk of gestational hypertensive disorders were present.
No consistent associations were present of maternal iron status in early pregnancy with gestational hemodynamic adaptations or the risks of gestational hypertensive disorders. Further studies are needed to examine the potential role of iron metabolism in the development of gestational hypertensive disorders within higher-risk populations.
Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative ...short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients.
In this single-center, retrospective study, neonates (gestational age < 32 weeks and/or birth weight < 1500 g) with NEC Bell's stage II or III were included. Information on pain (based on COMFORTneo and NRS scores) and analgesic therapy was collected and analyzed for the acute disease period.
Of 79 patients included, 74 (94%) received intravenous analgesic therapy: most commonly morphine, fentanyl, and acetaminophen. The median COMFORTneo score was 11 (IQR 10-11), however, 49 patients had at least one COMFORTneo score ≥ 14 indicating pain. Nineteen patients had persistent high pain scores ≥ 14 with a median duration of 7.2 h (IQR 2.8-14.0).
This study showed that despite analgesic therapy, most NEC patients showed signs of pain, and in some, pain persisted for several hours. It suggests that current analgesic therapy frequently failed to prevent pain and existing pain was often insufficiently treated. This supports the urgent need for individualized pain management guidelines for NEC patients.
This study is unique in reporting on pain management in neonates suffering from necrotizing enterocolitis (NEC) during the full acute disease period. Despite analgesic therapy, the majority of NEC patients experience pain, and in some patients, pain persists for several hours. These findings highlight the need for improvement of neonatal pain management in NEC patients, including better pain monitoring and guidelines for individualized analgesic therapy. Improved pain management guidelines may help to prevent short-term and long-term consequences of neonatal exposure to pain, as well as excessive exposure to opioids.
IMPORTANCE: Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother’s milk when compared with formula. When ...own mother’s milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE: To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother’s milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS: The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed. INTERVENTIONS: Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother’s milk was not (sufficiently) available. MAIN OUTCOMES AND MEASURES: The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life. RESULTS: A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother’s milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 44.7% formula vs 77 42.1% donor milk; mean difference, 2.6%; 95% CI, −12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37). CONCLUSIONS AND RELEVANCE: In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother’s milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary. TRIAL REGISTRATION: trialregister.nl Identifier: NTR3225
Whether maternal iron status during pregnancy is associated with cardiometabolic health in the offspring is poorly known.
We aimed to assess the associations of maternal iron status during early ...pregnancy with body fat measures and cardiometabolic risk factors in children aged 10 y.
In a population-based cohort study among 3718 mother–child pairs, we measured ferritin, transferrin, and transferrin saturation during early pregnancy. We obtained child BMI, fat mass index, and android/gynoid fat mass ratio by DXA, subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging and assessed systolic and diastolic blood pressure, serum lipids, glucose, insulin, and CRP at 10 y.
A one-standard deviation score (SDS) higher maternal ferritin was associated with lower fat mass index difference −0.05 (95% CI: −0.08, −0.02) SDS and subcutaneous fat index difference −0.06 (95% CI: −0.10, −0.02) SDS in children. One-SDS higher maternal transferrin was associated with higher fat mass index difference 0.04 (95% CI: 0.01, 0.07) SDS, android/gynoid fat mass ratio difference 0.05 (95% CI: 0.02, 0.08) SDS, and subcutaneous fat index difference 0.06 (95% CI: 0.02, 0.10) SDS in children. Iron status during pregnancy was not consistently associated with organ fat and cardiometabolic risk factors at 10 y.
Maternal lower ferritin and higher transferrin in early pregnancy are associated with body fat accumulation and distribution but are not associated with cardiometabolic risk factors in childhood. Underlying mechanisms and long-term consequences warrant further study.
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