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Objective: To assess the feasibility of embedding omega-3 fatty acid testing and targeted supplementation (the Omega-3 Test-and-Treat Program) into routine antenatal care to reduce the risk of preterm birth.

Study design: Prospective implementation evaluation study, using the Quality Enhancement Research Initiative (QUERI) framework.

Setting, participants: Women with singleton pregnancies undergoing routine antenatal screening during early pregnancy (before 20 weeks’ gestation) and their health care providers, South Australia, 19 April 2021 – 30 June 2022.

Intervention: Addition of omega-3 fatty acid testing option to SA Pathology test referral forms for the South Australian Maternal Serum Antenatal Screening (SAMSAS) program, with the aim of identifying women with low omega-3 fatty acid levels during early pregnancy and providing evidence-based supplementation guidance for reducing the risk of preterm birth.

Main outcome measures: Program feasibility (uptake and fidelity); representativeness of women tested for omega-3 fatty acid status; and omega-3 fatty acid status, by proportion of total serum fatty acids (low, < 3.7%; moderate, 3.7–4.3%; sufficient, > 4.3%).

Results: A total of 4801 requests for omega-3 fatty acid tests (26.1% of 18 362 SAMSAS referrals) were submitted to SA Pathology during the initial implementation phase of the Omega-3 Test-and-Treat Program. The monthly number of test requests increased from 15 (2.4% of 627 SAMSAS referrals) in April 2021 to 340 (29.4% of 1156 SAMSAS referrals) in June 2022. The socio-demographic and clinical characteristics of women referred for omega-3 fatty acid testing were similar to those for women who were not. Serum samples were insufficient for omega-3 fatty acid testing in 19 cases; of the 4782 tests performed, omega-3 fatty acid levels were low in 702 (14.7%), moderate in 1638 (34.2%), and sufficient in 2442 tests (51.1%). Of 5057 samples received by the Omega-3 Laboratory, 4935 (97.6%) were analysed within 72 hours. Thirty-three of 4801 omega-3 fatty acid test referrals (0.7%) were for women beyond 20 weeks of pregnancy; 58 referrals (1.2%) were for women with non-singleton pregnancies.

Conclusion: The Omega-3 Test-and-Treat Program is a feasible approach to reducing the risk of preterm birth with a targeted nutritional intervention that could be integrated into routine antenatal care in Australia.

Importance: Breastfed infants are at risk of iron deficiency, which is associated with suboptimal development. There is a paucity of evidence on the effects of iron supplementation on child development, and current guidelines are divergent.

Objective: To assess whether daily iron supplementation, 1 mg/kg, between 4 and 9 months in exclusively or predominantly breastfed infants improves psychomotor development at 12 months.

Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled trial conducted between December 2015 and May 2020 with follow-up through May 2023 in an outpatient setting in Poland and Sweden. Participants were healthy singleton infants born at term with birth weight greater than 2500 g who were exclusively or predominantly breastfed (>50%) and did not have anemia (hemoglobin >10.5 g/dL) at age 4 months. Exclusion criteria included major illness, congenital anomaly, food allergy, and difficulty communicating with caregivers.

Interventions: Iron (micronized microencapsulated ferric pyrophosphate), 1 mg/kg, or placebo (maltodextrin) once daily from age 4 to 9 months.

Main Outcomes and Measures: The primary outcome was psychomotor development assessed by motor score of Bayley Scales of Infant and Toddler Development III at 12 months, adjusted for gestational age, sex, and maternal education. Secondary outcomes included cognitive and language scores at 12 months; motor, cognitive, and language scores at 24 and 36 months; iron deficiency (serum ferritin <12 ng/mL), and iron deficiency anemia (iron deficiency and hemoglobin <10.5 g/dL) at 12 months.

Results: Of 221 randomized infants (111 female), 200 (90%) were included in the intention-to-treat analysis (mean [SD] age, 12.4 [0.8] months). Iron supplementation (n = 104) compared to placebo (n = 96) had no effect on psychomotor development (mean difference [MD] for motor score, -1.07 points; 95% CI, -4.69 to 2.55), cognitive score (MD, -1.14; 95% CI, -4.26 to 1.99), or language score (MD, 0.75; 95% CI, -2.31 to 3.82) at 12 months. There were no significant differences at 24 and 36 months. The intervention did not reduce the risk for iron deficiency (relative risk [RR], 0.46; 95% CI, 0.16 to 1.30) or iron deficiency anemia (RR, 0.78; 95% CI, 0.05 to 12.46) at 12 months.

Conclusion and Relevance: No benefit was found with daily low-dose iron supplementation between 4 and 9 months with respect to psychomotor development, risk of iron deficiency, or iron deficiency anemia among breastfed infants in a setting of low risk of anemia.

Objectives: This study aimed to investigate the effects of a higher intake of electrolytes from parenteral nutrition (PN) on plasma electrolyte concentrations in very low birth weight (VLBW, <1500 g) infants.

Methods: This was a single-center cohort study including all VLBW infants born before (n = 81) and after (n = 53) the implementation of a concentrated PN regimen. Daily nutritional intakes and plasma concentrations of sodium, chloride, potassium, phosphate, and calcium were collected from clinical charts.

Results: During the first postnatal week, electrolyte intakes were higher in infants who received concentrated PN compared with infants who received original PN. Infants who received concentrated PN had a lower incidence of hypokalemia (<3.5 mmol/L; 30% vs 76%, P < 0.001) and severe hypophosphatemia (<1.0 mmol/L; 2.2% vs 17%, P = 0.02). While the relatively high prevalence of severe hypophosphatemia in infants who received original PN can be explained by a phosphorus intake below the recommendation, the potassium intake during the first 3 postnatal days (mean ± SD: 0.7 ± 0.2 mmol/kg/d) was within the recommendation. The prevalence of early hypernatremia was not affected by the different sodium intake in the 2 groups.

Conclusions: In VLBW infants, a sodium-containing PN solution (about 2.7 mmol/100 mL) does not cause hypernatremia during the first days of life. Furthermore, providing at least 1 mmol potassium/kg/d during the first 3 postnatal days might be necessary to prevent early hypokalemia.

Aim: The aim of this study was to investigate the associations between sodium supply, fluid volume, sodium imbalances and severe intraventricular haemorrhage (IVH) in extremely preterm (EPT) infants.

Methods: We used data from the EXtremely PREterm infants in Sweden Study (EXPRESS) cohort consisting of all infants born at 22 to 26 gestational weeks from 2004 to 2007 and conducted a nested case–control study. For every infant with severe IVH (grade 3 or peri-ventricular haemorrhagic infarction), one IVH-free control infant with the birthday closest to the case infant and matched for hospital, sex, gestational age and birth weight was selected (n = 70 case–control pairs).

Results: Total sodium supply and fluid volume were higher in infants with severe IVH compared with controls [daily total sodium supply until postnatal Day 2: mean ± SD (mmol/kg/day): 5.49 ± 2.53 vs. 3.95 ± 1.91, p = 0.009]. These differences were accounted for by sodium and fluid from transfused blood products. High plasma sodium concentrations or large sodium fluctuations were not associated with severe IVH.

Conclusion: Our results suggest a relationship between sodium-rich transfusions of blood products and severe IVH in EPT infants. It is unclear whether this is an effect of sodium load, volume load or some other transfusion-related factor.

Background: Evidence showing the beneficial effects of enhanced parenteral nutrition (PN) to very low-birth-weight (VLBW,<1500 g) infants is accumulating. However, PN composition and its impact on growth outcomes are questioned. This study aimed to investigate the associations between administration of a concentrated PN regime and intakes of energy and macronutrients as well as postnatal growth in VLBW infants. 

Methods: We compared 2 cohorts of VLBW infants born before (n = 74) and after (n =44) a concentrated PN regime was introduced into clinical use. Daily nutrition and fluid intake during the first 28 postnatal days and all available growth measurements during hospitalization were retrospectively collected from clinical charts. 

Results: Infants who received concentrated PN compared with original PN had higher parenteral intakes of energy (56 vs 45 kcal/kg/d, P < 0.001), protein (2.6 vs 2.2 g/kg/d, P = 0.008), and fat (1.5 vs 0.7 g/kg/d, P < 0.001) during the first postnatal week. Changes in standard deviation scores for weight and length from birth to postnatal day 28 were more positive in the concentrated PN group (mean [95% CI]; weight change: –0.77 [–1.02 to –0.52] vs –1.29 [–1.33 to –1.05], P = 0.005; length change: –1.01 [–1.36 to –0.65] vs –1.60 [–1.95 to –1.25], P = 0.025). There were no significant differences in fluid intake and infant morbidity between the groups. 

Conclusion: Our results suggest that concentrated PN is useful and seems to be safe for improving early nutrition and growth in VLBW infants.

Introduction: Nutrients play a crucial role for growth and brain development after preterm birth. Meeting the nutritional needs of preterm infants is challenging. Particularly, the most immature infants have a high risk of malnutrition and poor growth during hospital care. To meet recommended energy and nutrient intakes during early postnatal life, a concentrated parenteral nutrition (PN) regimen was implemented in clinical use in 2012 at the neonatal intensive care unit at Umeå University Hospital (Umeå, Sweden). However, electrolyte homeostasis is labile after preterm birth and infants require an electrolyte supply that corresponds to their energy and protein intakes to avoid electrolyte disturbances. Although sodium imbalances such as hyper- and hyponatremia are common in the most immature preterm infants, there is limited knowledge to what extent these imbalances are affected by fluid volume and sodium supply. Furthermore, it is unclear whether the early high sodium concentrations lead to any adverse effects, including intraventricular hemorrhage, or simply reflect immediate adaptive processes after preterm birth.

Aim: This thesis investigates the impact of nutrition on growth, nutritional biomarkers, and health outcomes in preterm infants born with a birth weight below 1500 g.

Methods: We used data from two study populations. First, we collected data for all very low birth weight infants (< 1500 g) born between 2010 and 2013 and treated at Umeå University Hospital (Umeå, Sweden; n = 134). Second, we used data from the EXtremly PREterm infants in Sweden Study (EXPRESS). We included all infants born before 27 gestational weeks in Sweden between 2004 and 2007 who survived the first 24 h (n = 602). Data collection for both study populations included a) intakes of all parenteral and enteral nutritional products and other fluids during the first 28 postnatal days, b) all anthropometric measurements during hospital stay, c) perinatal data, and d) neonatal morbidity.

Results: The concentrated PN regimen improved early energy and macronutrient intakes in very low birth weight infants. Furthermore, weight and length growth from postnatal week two to a postmenstrual age of 36 weeks improved in very low birth weight infants who received the concentrated PN regimen compared with infants who received the previous original PN regimen (Paper I). Increased parenteral energy and protein intakes provided by the concentrated PN regimen, did not induce a higher occurrence of electrolyte imbalances as electrolytes were supplied according to the current recommendations (Paper II). In the EXPRESS cohort, the majority of extremely preterm infants had hypernatremia during the first and hyponatremia during the second postnatal week. Gestational age and supply of sodium, rather than fluid volume, were the major factors determining the risks of hyper- and hyponatremia (Paper III). High total supply of sodium was significantly correlated with severe intraventricular hemorrhage if mostly mediated by blood product transfusions (Paper IV).

Conclusions: Our results suggest that in very immature preterm infants a concentrated PN regimen improves early nutrient intakes and postnatal growth without causing electrolyte disturbances. Hyper- and hyponatremia are common and the supply of sodium is a major predictor. The impact of sodium on severe intraventricular hemorrhage needs further investigation.

Introduktion: Att möta energi- och näringsbehovet hos barn som föds för tidigt är utmanande, framförallt för de allra minsta barnen som på grund av omogenhet har hög risk för undernäring och dålig tillväxt. Med syfte att möta det rekommenderade energi- och näringsbehovet direkt efter födelsen hos för tidigt födda barn implementerades därför en koncentrerad parenteral näringslösning (PN) på den neonatala intensivvårdsavdelningen vid Umeå universitetssjukhus i februari 2012. Även elektrolytobalans är vanligt hos för tidigt födda barn. För att undvika denna obalans behöver för tidigt födda barn en elektrolytförsörjning som motsvarar energi- och proteinintaget. Både högt och lågt natrium (hyper- och hyponatremi) är vanliga tillstånd hos de mest omogna barnen men det finns begränsad kunskap i vilken utsträckning dessa obalanser påverkas av vätskevolym och natriumintag. Vidare är det oklart om höga natriumkoncentrationer leder till negativa konsekvenser, som exempelvis intraventrikulär blödning, eller om natriumobalanser enbart återspeglar en omedelbar anpassning efter för tidig födelse.

Syfte: Denna avhandling undersöker energi- och näringsintag och dess samband med tillväxt, näringsrelaterade biomarkörer och hälsoutfall hos för tidigt födda barn med en födelsevikt under 1500 gram.

Metoder: Två studiepopulationer användes. Alla barn som föddes med en födelsevikt under 1500 gram mellan 2010 och 2013, vårdade på Umeå universitetssjukhus utgjorde den ena studiepopulationen (n = 134). Den andra studiepopulationen utgjordes av data från Extremely PREterm infants in Sweden Study (EXPRESS) där alla barn födda före 27 graviditetsveckor mellan 2004 och 2007 ingick. Från EXPRESS inkluderades barn som överlevde de första 24 timmarna (n = 602). Datainsamlingen för båda studiepopulationerna inkluderade a) intag av alla parenterala och enterala näringsprodukter samt andra vätskor under de första 28 levnadsdagarna, b) alla antropometriska mätningar under sjukhusvistelsen, c) perinatal data och d) neonatal sjuklighet.

Resultat: Koncentrerad PN förbättrade det tidiga energi- och makronutrientintaget hos barn med en födelsevikt under 1500 gram. Vikt- och längdtillväxten förbättrades från andra levnadsveckan till 36 veckor postmenstrual ålder hos barn som fick koncentrerad PN jämfört med barn som fick ursprunglig PN (Delarbete I). Det ökade parenterala energi- och proteinintaget var inte associerat med högre förekomst av elektrolytobalanser eftersom elektrolyter gavs enligt aktuella rekommendationer (Delarbete II). I EXPRESS kohorten hade majoriteten av barnen hypernatremi under den första levnadsveckan och hyponatremi under den andra levnadsveckan. Ålder vid födelse och natriumtillförsel, snarare än vätskevolym, var faktorer som bidrog till hyper- och hyponatremi (Delarbete III). Hög total natriumtillförsel var associerat med svår intraventrikulär blödning men detta samband var främst medierat av natrium från transfusioner av blodprodukter (Delarbete IV).

Slutsatser: En koncentrerad PN förbättrar tidigt energi- och näringsintag samt tillväxt hos för tidigt födda barn utan att orsaka elektrolytobalans. Hyper- och hyponatremi är vanligt och tillförseln av natrium är en viktig faktor. Samband mellan högt natriumintag och svår intraventrikulär blödning behöver ytterligare undersökas.

Background: Hyper- and hyponatremia occur frequently in extremely preterm infants. Our purpose was to investigate plasma sodium (P-Na) concentrations, the incidence of hyper and hyponatremia, and the impact of possible predisposing factors in extremely preterm infants.

Methods: In this observational study, we analyzed data from the EXtremely PREterm (< 27 wk.) infants in Sweden Study (EXPRESS, n = 707). Detailed nutritional, laboratory, and weight data were collected retrospectively from patient records.

Results: Mean ± SD P-Na increased from 135.5 ± 3.0 at birth to 144.3 ± 6.1 mmol/l at a postnatal age of 3 d and decreased thereafter. Fifty percent of infants had hypernatremia (P-Na >145 mmol/l) during the first week of life while 79% displayed hyponatremia (P-Na < 135 mmol/l) during week 2. Initially, the main sodium sources were blood products and saline injections/infusions, gradually shifting to parenteral and enteral nutrition towards the end of the first week. The major determinant of P-Na and the risks of hyper- and hyponatremia was sodium supply. Fluid volume provision was associated with postnatal weight change but not with P-Na.

Conclusion: The supply of sodium, rather than fluid volume, is the major factor determining P-Na concentrations and the risks of hyper- and hyponatremia.

Background:  Transfusion practices are highly variable between hospitals and previous studies have suggested that blood transfusions may increase the risk of necrotizing enterocolitis (NEC).

Aim: To explore the association between blood transfusions and incidence of NEC in extremely preterm infants.

Methods: We used data from a Swedish population-based study including extremely preterm infants (<27 weeks) born between 2004–2007, (n = 602). All data on blood transfusions and haemoglobin (Hb) concentrations up to 28 days of age was collected for survivors. We performed a nested case-control study where two controls were chosen for each case of NEC (n = 21).

Results: During the first 28 days of life, infants received a median (25th-75th percentile) of 6 (3–9) blood transfusions resulting in 75 (44–120) ml/kg of blood. Predictors for receiving a higher volume of blood transfusions were days on respiratory support (R = 0.345, p < 0.001), hospital (R = 0.339, p < 0.001), low birth weight (R = -0.236, p < 0.001) and total steroid dose (R = 0.209, p < 0.001). Hb was not a significant predictor.

Overall NEC incidence was 5.8%. There was no significant difference between NEC cases and controls in number of blood transfusions (p = 0.420), volume of blood transfused from birth to NEC diagnosis (p = 0.274), or during the 48 h preceding NEC diagnosis (p = 0.459).

Conclusions: Blood transfusions were given liberally in Sweden compared to other studied populations. Morbidity related variables, especially those related to respiratory illness, were significant predictors of blood transfusion. NEC incidence was comparable with other populations but no significant association was found between blood transfusions and NEC among these extremely preterm infants.

Background: Hypernatremia is common in extremely preterm infants but it is unclear to what extent it is affected by sodium (Na) and fluid intakes. It is assumed that infants normally lose 5–10% of birth weight during the first postnatal days.

Aim: To explore associations between early intakes of Na and fluids and biochemical levels of Na as well as weight change during early postnatal life.

Method: We investigated a population-based cohort of Swedish extremely preterm infants (<27 gestational weeks). Detailed data of Na intakes, biochemical levels of Na and anthropometric measurements were retrospectively obtained from hospital records. Data are expressed as mean±SD.

Results: Preliminary analyses of 547 infants (gestational age 25.3 ± 1.1, birth weight 762 ± 170g) showed that highest Na levels occurred at day 3 of life (144.3 ± 6.2mmol/L) and were associated with Na intake during the first 2 days of life (R=+0.25), gestational age (R=-0.23) and birth weight (R=-0.18) (p < 0.001 for all).

Of included infants 32% lost more than 10% of birth weight during the first 3 days. There was a strong correlation between fluid intake within the first two days of life and weight change between birth and day 3 (R=+0.56, p < 0.001). Among those (27%) who lost between 5–10% in weight, fluid intakes were on average 103 mL/kg/d.

Conclusion: Early Na levels were significantly correlated with early Na intake, low gestational age as well as low birth weight. In order to avoid hypernatremia and excessive weight loss, fluid and Na intakes during the first 2 days need to be strictly regulated.

Background: Severe intraventricular haemorrhage (IVH) is a serious neonatal morbidity among extremely preterm infants that has been associated with adverse neurodevelopmental consequences. We aimed to explore the associations between sodium supply, sodium imbalances and severe IVH.

Methods: We used data from the EXtremely PREterm Infants in Sweden Study (EXPRESS) including all extremely preterm infants (< 27 weeks) born during 2004 and 2007 in Sweden (n = 707) and conducted a nested case-control study. For every infant with severe IVH (grades 3 to 4, n = 70) one control infant with a normal cranial ultrasound, a birthday closest to the case infant, and matched for hospital, sex, gestational age, and birth weight was selected.

Results: Sodium supply was higher in infants with severe IVH compared with controls [Daily sodium supply until postnatal day 2: Mean ± SD (mmol/kg/d): 5.49 ± 2.53 vs. 3.95 ± 1.91, P = 0.009]. This association did not remain significant when we excluded the amount of sodium delivered from transfused blood products from total sodium supply. High concentrations of or large fluctuations in plasma sodium were not related to severe IVH.

Conclusion: Although our results suggest a relationship between sodium supply and severe IVH via blood product transfusions, it is unclear whether this represents an effect of solute or volume load.