The estimated global preterm birth rate in 20201 was more than 10% of livebirths or 13.4 million infants. Nutrition in the neonatal period is a key factor to optimise growth, neurodevelopment, and later metabolic disease risk2. There is no consensus on optimal nutrition for preterm infants, leading to substantial practice variation3. We aimed to assess the quality of nutritional guidelines for preterm infants, the consistency of recommendations, and the gaps in these recommendations. This review is reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 checklist. The study protocol was registered with PROSPERO (CRD42022327248). We searched six databases and 44 websites for nutritional guidelines for preterm infants before first hospital discharge, which were endorsed, prepared, or authorised by a regional, national, or international body, written in English, and published between 2012-2023. Two reviewers independently screened articles and extracted relevant data including nutritional recommendations (ranges or descriptions), the quality of recommendations (certainty of evidence and strength of recommendation), and gaps in recommendations, defined as those identified by the guidelines or when recommendations were based on very low certainty evidence. Disagreements were resolved by discussion or a third reviewer. Four reviewers appraised the included guidelines using AGREE II. We identified 7051 records, 27 guidelines were included in the review, 26% of which were of high quality. Most guidelines lacked stakeholder involvement and rigour of development. Twelve guidelines had recommendations for macronutrient intake, 18 for micronutrient intake, 12 for feeding, eight for fortification, and 14 for monitoring of nutritional adequacy. Only two guidelines provided recommendations for all five of these aspects. We found considerable variation in recommendations, many of which lacked details of certainty of evidence and strength of recommendation. Recommendations for feeding types and breastmilk fortification were consistent among high quality guidelines, but recommendations varied for intakes of almost all nutrients and monitoring of nutritional adequacy. Different guidelines gave different certainty of evidence for the same recommendations. Most gaps in recommendations were due to a very low certainty of evidence. Future development of nutritional guidelines for preterm infants should follow the standard guideline development method and ensure rigorous process including stakeholders’ involvement to improve the reporting of strength of recommendation, certainty of evidence, and gaps in recommendation. Evidence is needed to support recommendations about macro and micronutrient intakes, breastmilk fortification, and markers on adequacy of intake of different nutrients.

Breast-feeding is associated with fewer comorbidities in very-low-birth-weight (VLBW) preterm infants. Bronchopulmonary dysplasia (BPD) of VLBW infants is a multifactorial pathology in which nutritional aspects may be of special importance. The aim of this study is to determine, in a cohort of VLBW infants, whether breast milk nutrition is associated with a reduced prevalence and severity of BPD. A retrospective study was conducted to record the intake of mother’s own milk (MOM), pasteurised donor human milk or preterm formula milk in the first 2 weeks of postnatal life of 566 VLBW newborns at our hospital during the period January 2008–December 2021. After applying the relevant exclusion criteria, data for 489 VLBW infants were analysed; 195 developed some degree of BPD. Moderate or severe BPD is associated with less weight gain. Moreover, the preferential ingestion of breast milk in the first and second postnatal weeks had effects associated with lower OR for BPD, which were statistically demonstrable for mild (OR 0·16; 95 % CI 0·03, 0·71) and severe (OR 0·08; 95 % CI 0·009, 0·91) BPD. Breast-feeding during the first weeks of postnatal life is associated with a reduced prevalence of BPD, which is frequently associated with less weight gain as a result of greater respiratory effort with greater energy expenditure.

Compared to preterm appropriate for gestational age (AGA) fetuses, fetuses with fetal growth restriction (FGR) have earlier visualisation of coronary artery blood flow (CABF) but impaired cardiac function. This dichotomy remains uncharacterised during postnatal life. This study compared CABF and cardiac function in preterm FGR infants, against AGA infants during the postnatal period. FGR was defined as birthweight < 10th centile for gestation and sex with absent/reversed antenatal umbilical artery Doppler. Diastolic CABF was measured in the left anterior descending coronary artery. Twenty-eight FGR infants were compared with 26 AGA infants (gestation and birthweight, 29.7 ± 1.3 vs 29.9 ± 1 weeks, P = 0.6 and 918 ± 174 vs 1398 ± 263g, P < 0.001, respectively). Echocardiography was performed in the second week of life. FGR infants had higher CABF (velocity time integral, 2.4 ± 0.9 vs 1.6 ± 0.8 cm, P = 0.002). Diastolic function was impaired (↑ trans-mitral E/A ratio in FGR infants; 0.84 ± 0.05 vs 0.79 ± 0.03, P = 0.0002) while the systolic function was also affected (mean velocity of circumferential fibre shortening [mVCFc], 1.9 ± 0.3 vs 2.7 ± 0.5 circ/s, P < 0.001). Indexing CABF to cardiac function noted significant differences between the groups (CABF: E/A [FGR vs AGA], 2.9 ± 1.1 vs 2.1 ± 1, P = 0.01 and CABF: mVCFc [FGR vs AGA], 1.3 ± 0.5 vs 0.6 ± 0.3, P < 0.001). Diastolic blood pressure (BP) was significantly higher, and CABF to diastolic BP ratio trended higher in FGR infants (30 ± 2 vs 25 ± 3 mmHg, P < 0.001 and 0.08 ± 0.03 vs 0.06 ± 0.03, P = 0.059, respectively). Greater CABF in FGR infants did not translate into better cardiac function. This dichotomy may be a persistent response to fetal hypoxaemia (fetal programming) and/or reflection of altered cardiac architecture.

Adolescent pregnancy is associated with adverse birth outcomes. However, the determinants of these outcomes are understudied. The present study sought to identify the predictors of adverse birth outcomes among pregnant adolescents in Ghana. In this prospective health centre-based study, 416 pregnant adolescents, aged 13–19 years old, were followed, and 270 birth outcomes were evaluated. We collected data on socio-demographic variables, eating behaviour, household hunger scale (HHS), lived poverty index (LPI) and compliance to antenatal interventions. The prevalence of low birth weight (LBW) and preterm births (PTB) were 15⋅2 and 12⋅5 %, respectively. Pregnant adolescents with no formal education (AOR 9⋅0; P = 0⋅004; 95 % CI 2⋅1, 39⋅8), those who experienced illness (AOR 3⋅0; P = 0⋅011; 95 % CI 1⋅3, 7⋅0), those who experienced hunger (OR 2⋅9; P = 0⋅010; 95 % CI 1⋅3, 6⋅5) and those with high LPI (OR 2⋅5; P = 0⋅014; 95 % CI 1⋅2, 5⋅3) presented increased odds of delivering preterm babies compared with those who have had secondary education, did not experience any illness, were not hungry or having low LPI, respectively. Pregnant adolescents who used insecticide-treated net (ITN) (AOR 0⋅4; P = 0⋅013; 95 % CI 0⋅2, 0⋅9) presented reduced odds LBW children; while those who experienced illness (AOR 2⋅7; P = 0⋅020; 95 % CI 1⋅2, 6⋅0), poorer pregnant adolescents (OR 2⋅5; P = 0⋅014; 95 % CI 1⋅1, 4⋅8) and those who experienced hunger (AOR 3⋅0; P = 0⋅028; 95 % CI 1⋅1, 8⋅1) presented increased odds of LBW children compared with those who used ITN, were not ill, were not poor or did not experience hunger. Adverse birth outcomes were associated with ANC compliance and socioeconomic factors of the pregnant adolescents. Hence, strengthening antenatal uptake and compliance by pregnant adolescents, promoting their livelihood and socioeconomic status, and interventions to prevent teenage pregnancies are strongly recommended.

There has been an increase in the use of extracorporeal membrane oxygenation for severe neonatal cardiac failure. However, the frequency of complications is high, particularly in preterm and low-birth-weight neonates. Herein, we present combination treatment with transcatheter balloon atrioseptostomy and bilateral pulmonary artery banding in a collapsed preterm neonate. This strategy can be an alternative to circulatory support using extracorporeal membrane oxygenation.

Emerging evidence demonstrates a link between preterm birth (PTB) and later life cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to compare conventional CVD risk factors between those born preterm and at term. PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. The review protocol is registered in PROSPERO (CRD42018095005). CVD risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index, lipid profile, blood glucose, and fasting insulin among those born preterm (<37 weeks’ gestation) were compared with those born at term (≥37 weeks’ gestation). Subgroup analyses based on gender, age, gestational at birth (<32 weeks’ gestation and <28 weeks’ gestation), and PTB associated with small for gestational age or average for gestational age were also performed. Fifty-six studies provided data on 308,987 individuals. Being born preterm was associated with 3.26 mmHg (95% confidence interval [CI] 2.08 to 4.44) higher mean SBP and 1.32 mmHg (95% CI: 0.61 to 2.04) higher mean DBP compared to being born at term. Subgroup analyses demonstrated that SBP was higher among (a) preterm compared to term groups from early adolescence until adulthood; (b) females born preterm but not among males born preterm compared to term controls; and (c) those born at <32 weeks or <28 weeks compared to term. Our meta-analyses demonstrate higher SBP and DBP among those born preterm compared to term. The difference in SBP is evident from early adolescence until adulthood.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22–3.06; aOR2 = 2.05, 95% CI: 1.33–3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30–3.11; aOR2 = 2.51, 95% CI: 1.69–3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03–2.45; aOR2 = 1.99, 95% CI: 1.05–3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

Percutaneous closure of patent ductus arteriosus is well established in infants weighing >5 kg, but data regarding outcome of preterm especially very low birth weight infants is minimal. Although surgical ligation of patent ductus arteriosus is the preferred and well-accepted modality of treatment after failure of drug therapy in preterm infants, it has also got its own demerits in such a small and fragile subset. Device closure in infants weighing <1.5 kg is rarely attempted because of high chances of complications, especially acute arterial injury due to the arterial sheath. We received a 1.4-kg ventilator-dependent infant for closure of large patent ductus arteriosus. Percutaneous closure of patent ductus arteriosus was done successfully and the infant was discharged on room air with a weight of 1.8 kg. We present here an innovative technique in which successful patent ductus arteriosus device closure was done in a 1.4-kg infant without using arterial sheath.

Dilation and abnormal tortuosity of retinal vessels are the hallmarks of severe retinopathy of prematurity (ROP) in premature infants. The stages of ROP are defined by vessel appearance at the interface between the vascular and avascular retinal areas. Deregulated signaling pathways involving hypoxia-inducible factors such as vascular endothelial growth factor (VEGF) are involved in the pathogenesis of ROP. VEGF-antagonists are increasingly being used as ‘off-label medication’ to treat this condition, with some success. We present Baby SM (female), who was born prematurely at 24 weeks gestation in a tertiary neonatal intensive care unit, and with a birth weight of 640 g. On screening at 35 weeks postmenstrual age (PMA), she was noted to have ROP, which became severe by 37 weeks PMA. She received one dose of intravitreal VEGF antagonist (Bevacizumab), resulting in a decrease in vessel tortuosity and dilation. However, repeat imaging at 4 weeks showed a re-emergence of vessel tortuosity. We believe the observed changes demonstrate an inherent retinal microvascular plasticity in premature neonates. With improved survival of extremely premature neonates and the availability of retinal imaging technology, we are now able to observe this plasticity.

Visual processing problems may be one underlying factor for cognitive impairments related to autism spectrum disorders (ASDs). We examined associations between ASD-traits (Autism-Spectrum Quotient) and visual processing performance (Rey–Osterrieth Complex Figure Test; Block Design task of the Wechsler Adult Intelligence Scale-III) in young adults (mean age=25.0, s.d.=2.1 years) born preterm at very low birth weight (VLBW; <1500 g) (n=101) or at term (n=104). A higher level of ASD-traits was associated with slower global visual processing speed among the preterm VLBW, but not among the term-born group (P<0.04 for interaction). Our findings suggest that the associations between ASD-traits and visual processing may be restricted to individuals born preterm, and related specifically to global, not local visual processing. Our findings point to cumulative social and neurocognitive problems in those born preterm at VLBW.

An observational study of neuropsychological outcomes at preschool age of tiered lowered oxygen (O2) saturation targets in extremely preterm neonates. We studied 111 three-year-olds born <28 weeks’ gestational age. Fifty-nine participants born in 2009–2010 during a time-limited quality improvement initiative each received three-tiered stratification of oxygen rates (83–93% until age 32 weeks, 85–95% until age 35 weeks, and 95% after age 35 weeks), the TieredO2 group. Comparisons were made with 52 participants born in 2007–2008 when pre-initiative saturation targets were non-tiered at 89–100%, the Non-tieredO2 group. Neuropsychological domains included general intellectual, executive, attention, language, visuoperceptual, visual-motor, and fine and gross motor functioning. Descriptive and inferential analyses were conducted. Group comparisons were not statistically significant. Descriptively, the TieredO2 group had better general intellectual, executive function, visual-motor, and motor performance and the Non-tieredO2 group had better language performance. Cohen’s d and confidence intervals around d were in similar direction and magnitude across measures. A large effect size was found for recall of digits-forward in participants born at 23 and 24 weeks’ gestation, d=0.99 and 1.46, respectively. Better TieredO2 outcomes in all domains except language suggests that the tiered oxygen saturation target method is not harmful and merits further investigation through further studies. Benefit in auditory attention appeared greatest in those born at 23 and 24 weeks. Participants in the tiered oxygen saturation group also had fewer ventilation days and a lower incidence of bronchopulmonary dysplasia, perhaps explanatory for these neuropsychological outcomes at age 3. (JINS, 2015, 21, 322–331)

To date, several studies have investigated the intergenerational effect of preterm and small-for-gestational-age (SGA) births. However, most studies excluded both twin mothers and twin offspring from the analyses. Thus, the objective of this study was to investigate the intergenerational effect of preterm birth and SGA births among twins and singletons. A prospective population-based register study of mother–firstborn offspring pairs recorded in the Swedish Medical Birth Register was performed. The study included 4,073 twins and 264,794 singletons born from 1973–1983 and their firstborns born from 1986–2009. Preterm birth was defined as birth at <37 weeks of gestation, and SGA as birth weight <2 standard deviations of the Swedish standard. Logistic regressions were performed to estimate the intergenerational effect of each birth characteristic. Adjustments were made for maternal grandmothers’ and mothers’ socio-demographic factors, in addition to maternal birth characteristics. Among mothers born as singletons, being born preterm was associated with an increased risk of delivering a preterm child (adjusted odds ratio (OR) 1.39, 95% Confidence Interval (CI) = 1.29–1.50), while being born SGA increased the likelihood of having an SGA child (adjusted OR 3.04, 95% CI = 2.80–3.30) as well as a preterm child (adjusted OR 1.30, 95% CI = 1.20–1.40). In twin mothers, the corresponding ORs tended to be lower, and the only statistically significant association was between an SGA mother and an SGA child (adjusted OR 2.15, 95% CI = 1.40–3.31). A statistically significant interaction between twinning and mother's size for gestational age was identified in a multivariate linear regression analysis, indicating that singleton mothers born SGA were associated with a lower birth weight compared with mothers not born SGA. Preterm birth and SGA appear to be transferred from one generation to the next, although not always reaching statistical significance. These effects seem to be less evident in mothers born as twins compared with those born as singletons.

Previous studies have reported inconsistent associations between maternal serum ferritin concentrations and the risk of spontaneous preterm birth (sPTB). The aim of the present study was to examine the association between Fe biomarkers, including serum ferritin concentrations, and the risk of total ( < 37 weeks), early ( < 34 weeks) and moderate-to-late (34–36 weeks) sPTB. The study cohort included 2254 women with singleton pregnancies attending first-trimester screening in New South Wales, Australia. sPTB included births following spontaneous labour or preterm premature rupture of the membranes. Serum collected at a mean gestational age of 12·0 (sd 0·9) weeks was analysed for Fe biomarkers, including serum ferritin and soluble transferrin receptor (sTfR), and the inflammatory biomarker C-reactive protein. Multivariate logistic regression analysis evaluated the association between low and high Fe levels and sPTB. Women with elevated serum ferritin concentrations were more likely to be older, nulliparous or have gestational diabetes. The multivariate analysis found increased odds of sPTB for women with elevated ferritin levels defined as >75th percentile ( ≥ 43 μg/l) (OR 1·49, 95 % CI 1·06, 2·10) and >90th percentile ( ≥ 68 μg/l) (OR 1·92, 95 % CI 1·25, 2·96). Increased odds of early and moderate-to-late sPTB were associated with ferritin levels >90th percentile (OR 2·50, 95 % CI 1·32, 4·73) and >75th percentile (OR 1·56, 95 % CI 1·03, 2·37), respectively. No association was found between the risk of sPTB and elevated sTfR levels or Fe deficiency. In conclusion, elevated maternal serum ferritin levels in early pregnancy are associated with an increased risk of sPTB from 34 weeks of gestation. The usefulness of early pregnancy ferritin levels in identifying women at risk of sPTB warrants further investigation.

Although closure of ductus arteriosus requires multiple intriguing cell signalling pathways, current treatment options merely act through cyclooxygenase inhibition. Expectedly, medical management of ductus arteriosus is quite far away from optimum and there is an ongoing debate on its efficiency and safety. The ideal therapeutic agent for patent ductus arteriosus should target vascular remodelling and support the arrested molecular steps that should completely eventuate during anatomical closure.

Platelet-rich plasma injection, which has been used as a treatment alternative for many musculoskeletal conditions, can be a promising solution in this context by compensating the relative platelet dysfunction in preterms and providing a convenient microenvironment for proper cellular communication for ductal closure.

First, by inducing hyaluronan synthase, platelet-rich plasma can induce mount formation in the intima, which is the significant defective milestone in preterms. Second, by providing platelet-derived growth factor, it can further stimulate platelet agregation and occlusion of the lumen. Finally, it can provide an increment in local vascular endothelial growth factor and transforming growth factor-β levels, which cannot be achieved because of insufficient intramural hypoxia. Migration of the vascular smooth muscles would further be triggered by transforming growth factor-β and vascular endothelial growth factor, aiding a major contribution to ductal closure.

Above and beyond all other considerations, opportunity of local application would render maximum effectiveness and minimum side effects.

Placental 5α-reductase (5αR) is influenced by in utero compromises and has a role in regulating neuroactive steroid concentrations in the fetus. The objective of this study was to determine if changes in placental 5αR were associated with neonatal outcome after birth. Guinea pigs were delivered by cesarean section at term (GA69, n=22) or preterm (GA62, n=36) and the placenta collected. Preterm neonates were maintained for 24 h unless their condition deteriorated before this time. Enzyme mRNA expression of 5αR type-1 and 5αR type-2 were determined using real-time PCR. All preterm neonates had significantly higher 5αR2 expression in their placenta compared with placentae from term neonates (P<0.0001). Expression was also markedly higher in the placentae from neonates that did not survive until 24 h, compared with surviving preterm neonates (P=0.04). These findings suggest differences of in utero neurosteroidogenic capacity between surviving and non-surviving preterm guinea pig neonates. The increased 5αR2 mRNA expression in the placenta of non-survivors suggests an induction of the neurosteroid pathway due to prior exposure to an in utero compromise, with such exposure possibly a predisposing factor that contributed to their poor ex utero outcome.