Abstract
Introduction: Dietary fat intake during pregnancy and childhood is important for health. However, several health aspects are inconclusive. Methods: We systematically searched Medline, Cochrane Library, and Epistemonikos for systematic reviews (SRs) of randomized controlled trials (RCTs) and/or prospective cohort studies published from January 01, 2015, to December 31, 2019, assessing the association of dietary fat intake (including dietary supplements) during pregnancy and across childhood with pregnancy, perinatal, and child health outcomes. Results: Thirty-one SRs, mainly of RCTs, were included. Omega-3 fatty acids supplementation during pregnancy reduced the risk of early preterm birth, and in some SRs also any preterm birth, increased gestation length and birth weight, but mostly was not associated with other pregnancy/perinatal outcomes. Pre- and postnatal polyunsaturated fatty acids (PUFAs) intake was not consistently associated with growth, neurological, visual and cognitive outcomes, allergic diseases, cardiovascular, and metabolic health in childhood. Reduced saturated fatty acids (SFAs) intake and its replacement with PUFA/monounsaturated fatty acids had favourable effects on blood pressure and blood lipids in children. No apparent effects of total or trans fat on health outcomes across target groups were observed. Conclusion: Omega-3 PUFA supplementation during pregnancy and SFA intake reduction in childhood require further consideration in dietary recommendations targeting these populations.
Introduction
Non-communicable diseases (NCDs), in particular cardiovascular diseases, are the leading cause of mortality worldwide and impose a substantial economic burden [1]. Diet is one of the key contributors to NCDs, importantly, one that is modifiable [2]. A life course approach offers new options for prevention of NCDs [3]. This approach assumes that environmental exposures, including diet, acting throughout the lifespan, affect the health of an individual and of future generations. Thus, the time from before conception through childhood has been recognized as an important period to intervene on determinants of later health, including nutrition [4].
Dietary fat intake has been linked to and extensively studied in the context of NCDs [5]. However, many aspects of its consumption, especially in early life, and in relation to other outcomes such as growth and neurodevelopment, still remain unclear. Fats as a macronutrient group are not homogenous. Its complexity is only partly reflected by conventional classification, and additionally builds on structural and biological differences of fatty acids (FAs) within and across these classes [5]. This heterogeneity translates into a variety of health outcomes associated with its intake, which are additionally dependent on the timing to certain fat type exposure, e.g., in foetal life, the postnatal period, or later childhood. Evidence-based recommendations on dietary fat intake require an extensive synthesis of findings from available studies, by taking into account its complexity. Systematic reviews (SRs) are the established study design to investigate the effects of nutrition interventions and associations between dietary exposures and health outcomes.
The scope of this scoping review was to identify, describe, and summarize the current evidence from SRs for dietary fat or fat quality in pregnant and lactating women and infants, children, and adolescents in relation to immediate and long-term health outcomes. Findings should inform the development of a position paper by the “International Union of Nutritional Sciences (IUNS) Task Force on Dietary Fat Quality.”
Methods
This scoping review is one of the review series undertaken by the IUNS Task force on Dietary Fat Quality group, all summarizing available evidence and guidelines on fat intake and fat quality for different target groups. Here, we adapted previously described research methods by the group that evaluated the evidence for dietary fat or fat quality and risk of chronic diseases in adults [6, 7]. We applied the methodology proposed in the Joanna Briggs Institute’s (JBI) Reviewers’ Manual [8] and adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension for scoping reviews, the PRISMA-ScR Statement [9].
Search Strategy
We searched the following electronic databases Medline (via Ovid), the Cochrane Database of Systematic Reviews and Epistemonikos from 1 January 2015 to 31 December 2019 for relevant articles, with no language restrictions applied. The search strategy for each database is reported in Online Supplementary Material 1 (for all online suppl. material, see https://doi.org/10.1159/000533757). Additionally, hand search of references from included articles was done.
Selection of Studies
Inclusion and exclusion criteria applied in the study selection process are listed in Table 1. Additionally, for SRs of studies involving both children and adults, and those of mixed interventions (e.g., polyunsaturated fatty acid (PUFA) supplementation and fish intake) or mixed study designs, if no respective subgroup analysis was reported, we excluded SRs with more than 1/3 of the studies not meeting our inclusion criteria.
Inclusion and exclusion criteria applied to select studies eligible for this scoping review
Inclusion criteria . | |
---|---|
Study design | • SRs of randomized controlled trials (RCTs) or prospective cohort studies, including nested case-control studies and case-cohort studies |
Population | • Pregnant and lactating women and infants, children and adolescents as study participants |
Intervention/exposure | • Interventions of or exposure to dietary fat (total fat) and/or fat quality, i.e., |
o Saturated fatty acids (SFA) | |
o Monounsaturated fatty acids (MUFA) | |
o Polyunsaturated fatty acids (PUFA) or long-chain polyunsaturated fatty acids (LCPUFA) | |
o Trans-fatty acids (TFA) | |
o Omega-6 (linoleic acid [LA]) | |
o Omega-3 fatty acids (FA) including: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA) | |
o Dietary cholesterol | |
• Intervention or exposure as described above that was delivered either as part of a diet or in a form of dietary supplements | |
Comparison | • Placebo/usual diet or different intake of fat |
Outcomes | • Immediate outcomes, including pregnancy and perinatal outcomes, infant growth, body composition, visual function, neurodevelopment |
• Prevention of chronic diseases, such as overweight and obesity, metabolic and cardiovascular outcomes and allergic diseases | |
Timeframe | • SRs published from January 01, 2015, to December 31, 2019 (timeframe consistent with the review for adults) |
Inclusion criteria . | |
---|---|
Study design | • SRs of randomized controlled trials (RCTs) or prospective cohort studies, including nested case-control studies and case-cohort studies |
Population | • Pregnant and lactating women and infants, children and adolescents as study participants |
Intervention/exposure | • Interventions of or exposure to dietary fat (total fat) and/or fat quality, i.e., |
o Saturated fatty acids (SFA) | |
o Monounsaturated fatty acids (MUFA) | |
o Polyunsaturated fatty acids (PUFA) or long-chain polyunsaturated fatty acids (LCPUFA) | |
o Trans-fatty acids (TFA) | |
o Omega-6 (linoleic acid [LA]) | |
o Omega-3 fatty acids (FA) including: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA) | |
o Dietary cholesterol | |
• Intervention or exposure as described above that was delivered either as part of a diet or in a form of dietary supplements | |
Comparison | • Placebo/usual diet or different intake of fat |
Outcomes | • Immediate outcomes, including pregnancy and perinatal outcomes, infant growth, body composition, visual function, neurodevelopment |
• Prevention of chronic diseases, such as overweight and obesity, metabolic and cardiovascular outcomes and allergic diseases | |
Timeframe | • SRs published from January 01, 2015, to December 31, 2019 (timeframe consistent with the review for adults) |
Exclusion criteria . | |
---|---|
Study design | • SRs of non-randomized intervention trials, case-control or cross-sectional studies were excluded |
Population | • Solely special population groups, such as individuals with overweight and obesity, with chronic diseases (e.g., neurodevelopmental disorders), or other underlying health conditions including preterm birth, small for gestational age |
Intervention/exposure | • Solely oils (as a conventional food and not as dietary supplements), solid fats, or specific fatty foods (e.g., butter, nuts, seeds, fish), or including circulating FA as exposure |
Exclusion criteria . | |
---|---|
Study design | • SRs of non-randomized intervention trials, case-control or cross-sectional studies were excluded |
Population | • Solely special population groups, such as individuals with overweight and obesity, with chronic diseases (e.g., neurodevelopmental disorders), or other underlying health conditions including preterm birth, small for gestational age |
Intervention/exposure | • Solely oils (as a conventional food and not as dietary supplements), solid fats, or specific fatty foods (e.g., butter, nuts, seeds, fish), or including circulating FA as exposure |
Selection Process of Sources of Evidence
Initial screening of the records by title and abstract was performed independently by two reviewers (B.P.G., M.K., and B.M.Z.). Full-text publications were obtained and assessed against our inclusion/exclusion criteria by two independent reviewers (B.M.Z., M.K.). Any discrepancies or ambiguities regarding final record inclusion were resolved through discussion with a third author (B.P.G.).
Data Extraction
For included SRs, two reviewers (B.M.Z. and M.K.) independently extracted the study characteristics, which were then cross-checked by the third reviewer (B.P.G.). We extracted the following data: author, year of publication, aim of SR, design of included studies, number of included studies, number of participants, description of participants/population, description of intervention/exposure, comparison (e.g., highest vs. lowest intake category), outcomes, direction of effect/association, certainty of evidence (according to GRADE [10]), and search date of SR.
Data Categorization and Presentation
Descriptive summaries of the obtained results on dietary fat and fat quality in relation to various health outcomes by timing of the intervention/exposure (e.g., prenatal or postnatal period) and by different target groups (e.g., lactating mothers or infants) were provided. Additionally, bubble charts were created for visual presentation of the results.
Results
Of 5,282 records identified from the electronic databases and those identified through citation search, 31 SRs [11‒41] were included in this scoping review (Fig. 1). Excluded reports are listed in the Online Supplementary Material 2. Of all included SRs, 20 were exclusively SRs of RCTs [11‒17, 20,22‒25, 28, 30,33‒35, 37, 38, 40], two of observational studies [26, 39], and 9 with different study designs [18, 19, 21, 27, 29, 31, 32, 36, 41]. Overall, in 7 SRs (23%) no quantitative data synthesis was conducted. The number of studies and participants per outcome ranged from 1 to 41 studies and from 42 to 61,737 participants. Seventeen SRs [11, 12, 15, 17, 19, 20, 22, 24, 26, 27, 29, 30, 33‒35, 40, 41] investigated maternal fat intake (in a diet or in a form of supplements) exclusively or mainly during pregnancy. Eight SRs focused on early postnatal interventions and/or exposures either in breastfeeding mothers or infants or both [14, 16, 23, 25, 28, 32, 38, 39]. Three SRs included studies on pre- and postnatal interventions/exposures [18, 21, 37], and three evaluated the role of dietary fat and/or fat quality exclusively in childhood [13, 31, 36]. Six SRs assessed exclusively fat intake in a diet [26, 27, 31, 36, 39, 41], other focused mainly on fats supplementation. The majority of SRs assessed PUFA intake, including 21 SRs on omega-3 PUFA intake [11‒13, 15‒17, 19‒24, 26, 32‒35, 37, 39‒41]. Often the authors applied different criteria to classify eligible interventions (e.g., any PUFA vs. long-chain PUFA [LCPUFA] vs. omega-3 PUFA but possibly in combination with arachidonic acid [AA]) and assessed various combinations of different FA (e.g., docosahexaenoic acid [DHA] alone, or plus eicosapentaenoic acid [EPA], or plus EPA and AA), in various doses and duration. Fat supplements used varied within SRs and between SRs (e.g., fish oil or algal DHA). In the majority of the studies included in the reviews, the PUFA origin was predominantly marine-based. Only a few SRs focused on total fat, saturated FA (SFA), trans FA [26, 27, 31, 32, 36, 41] or dietary cholesterol intake [26] in pregnancy, postnatally or in childhood. Outcomes assessed in the eligible SRs included pregnancy, birth and perinatal (infant and maternal) outcomes, growth parameters and body composition, visual and cognitive outcomes, neurodevelopment, metabolic and cardiovascular outcomes, allergy, atopy, and asthma. Details on characteristics of all included SRs are presented in online supplementary Table 1. Direction of the effect estimates for different health outcomes by study design, timing, and type of intervention/exposure are shown in Table 2a, b.
Bubble plots showing the direction of the effects/associations between dietary fat/fat quality (a) in pregnancy and perinatal and maternal outcomes; (b) in different periods (prenatal, postnatal, childhood) and health outcomes in infants/children, together with GRADE certainty ratings
Bubble plots showing the direction of the effects/associations between dietary fat/fat quality (a) in pregnancy and perinatal and maternal outcomes; (b) in different periods (prenatal, postnatal, childhood) and health outcomes in infants/children, together with GRADE certainty ratings
Total Fat Intake
Maternal Intake (Exclusively or Mainly during Pregnancy)
Three SRs assessed the associations of maternal total fat intake during pregnancy in relation to pregnancy and offspring outcomes based on the prospective cohort studies. The associations of maternal total fat intake with the risk of gestational diabetes mellitus (GDM) [26], gestational weight gain (GWG) [27], and blood pressure in the offspring [41] were inconsistent. Maternal fat intake was inversely associated with the offspring carotid intima-media thickness in childhood in one of these SRs [41]; however, no association was found for this outcome in the young adulthood.
Maternal and/or Infant Intake (Mainly Postnatally)
In a SR examining the influence of maternal and/or infant dietary exposure to total fat on the risk of allergic outcomes or autoimmune diseases, no consistent associations were observed in the identified cohort studies [32].
Childhood Intake
One SR [36] of RCTs and prospective cohort studies evaluated the association of total fat intake in children aged 2–18 years of age with weight, height, body mass index and blood lipids and reported no consistent associations.
Saturated FAs
Maternal Intake (Exclusively or Mainly during Pregnancy)
Childhood Intake
The authors of one SR reported reduction of total and LDL-C and lower DBP, when SFA was reduced or replaced by monounsaturated fatty acid (MUFA) or PUFA in childhood [31]. For all other outcomes, no effects were observed.
Trans FAs
Maternal Intake (Exclusively during Pregnancy)
Childhood Intake
No studies were identified [31].
Monounsaturated FAs
Maternal Intake (Exclusively or Mainly during Pregnancy)
Any PUFA, Any LCPUFA, and Omega-3 FAs
Maternal intake (Exclusively or Mainly during Pregnancy)
In most SRs (83%), maternal supplementation with omega-3 FA (i.e., DHA and/or EPA, or fish oil) was associated with higher birth weight in the offspring [11, 20, 21, 24, 33]. The effect on birth length was either positive [11] or statistically not significant [33]. Two SRs reported an inverse association with the risk of low birth weight [11, 35], while two other SRs found this association was statistically not significant [21, 24]. Maternal omega-3 PUFA supplementation during pregnancy was associated with lower risk of early preterm birth (<34 weeks of gestation) [11, 20, 35]. This beneficial effect was also observed for the preterm delivery (<37 weeks of gestation) in two SRs [20, 35], including a Cochrane review (with the most recent search date compared to other included SRs) and its recent update [43], while other SRs did not report significant effects on preterm delivery <37 weeks of gestation [11, 17, 21, 24]. Finally, three out of four SRs of RCTs reported prenatal omega-3 supplementation to induce a small increase of the length of gestation [20, 21, 35]. No consistent beneficial effects of PUFA/omega-3 FA supplementation/dietary intake were reported for several pregnancy, birth or perinatal outcomes, such as GWG [26, 27], gestational hypertensive disorders [21, 24, 35], the risk of small for gestational age [20, 21, 24, 35], intrauterine growth retardation (IUGR) [11, 21, 24, 35] or maternal peri-/postnatal depression [21, 24, 29, 35]. Four SRs assessed the effect of maternal prenatal omega-3 FA supplementation/intake in the prevention of GDM and found it ether ineffective [22, 35], unfavourable [26] or unable to determine due to lack of studies [24]. In most SRs, maternal omega-3 supplementation during pregnancy was not significantly associated with perinatal death [17, 20, 24, 35]. In several SRs, maternal and/or neonatal adverse events related to omega-3 supplementation were assessed. Overall this intervention was considered as safe [11, 20, 21, 35]. Maternal omega-3 FA intake/supplementation during pregnancy was not consistently associated with offspring visual function [21, 24, 37], cognitive [21, 24, 30, 35, 37], or neurodevelopmental outcomes [21, 24, 35, 37], as well with the risk of autism or attention deficit hyperactivity disorder in offspring [21], growth measures [21, 33, 40], body mass index [33, 35, 40], and body composition in infancy or childhood [33, 40]. Finally, the evidence was inconclusive for the association of maternal omega-3 PUFA intake and offspring blood pressure [41] or the risk of diabetes in childhood [35].
The effects of maternal omega-3 FA supplementation during pregnancy on allergies, atopic dermatitis, and asthma/wheeze in offspring were assessed in five SRs and revealed inconsistent results [12, 15, 19, 21, 34]. These results differed depending on the outcome measures applied and offspring age at assessment.
Maternal and/or Infant Intake (Mainly Postnatally)
In four SRs [14, 21, 23, 38], no consistent effects of various combination of PUFA/omega-3 FA, delivered as supplements or food (e.g., fish oil or fortified infant formula/foods) to breastfeeding mothers or infants on infant growth and/or body composition were reported. Similarly, four SRs reported either not statistically significant or inconsistent [14, 21, 23, 28] findings for PUFA/omega-3 FA infant formula or maternal postnatal supplementation in relation to visual acuity, which often depended on outcome measure applied, age at assessment, and type of intervention (FA composition). In line with this, another SR of RCTs reported no statistically significant effects for maternal postnatal omega-3 FA supplementation on visual acuity. However, beneficial effect was observed in this SR when supplementation was delivered to infants [37]. No effects of omega-3 PUFA supplementation in breastfeeding women and of supplementing or fortifying infant formula with these FA on cognitive outcomes in childhood were observed in 3 SRs [21, 23, 37]. Inconsistent effects of postnatal (maternal and infant) LCPUFA/omega-3 FA supplementation were reported in relation to neurological development [14, 21, 23, 28, 37]. Overall, no apparent evidence for statistical significant effects of this intervention (supplementation or intake from diet) was reported in relation to offspring obesity and/or cardiovascular health in two SRs [18, 23]. Early life omega-3 FA intake was not associated with the risk of type 1 diabetes [39]; however, limited evidence for beneficial effects on insulin sensitivity measures was reported in one SR [18]. A SR of RCTs showed that omega-3 FA supplementation during pregnancy and lactation or in infancy was associated with reduced allergic sensitization to egg, but not to other allergens, in offspring at 1 year of age [32]. Inconsistent or not significant effects of postnatal (maternal and/or infant) PUFA/omega-3 FA supplementation were reported in relation to atopic dermatitis [21, 25], allergies [21, 25], and asthma [16, 21, 25].
Childhood Intake
Omega-3 FA supplementation in school-age children had no effects on various cognitive outcomes [13].
Any Omega-6 FAs
Maternal intake (Exclusively or Mainly during Pregnancy)
Maternal and Infant Intake (Mainly Postnatally)
No association between early life (during pregnancy and in infants) omega-6 FA supplementation and the risk of type 1 diabetes in children was reported [39].
Dietary Cholesterol
Maternal intake (Exclusively during Pregnancy)
Higher maternal dietary cholesterol intake was associated with a higher risk of GDM in one SR [26].
Certainty of Evidence Ratings
The GRADE approach (or its modification) to rate the certainty of evidence was used in 11 (35%) of included SRs (including 5 Cochrane reviews) [14, 21, 25, 28, 31, 32, 34‒36, 38, 39]. GRADE certainty ratings are presented in Table 2a, b. The association of maternal omega-3 LCPUFA intake/supplementation in pregnancy with reduced risk of preterm birth (including early preterm birth) and low birth weight was rated as high in one SR [35]. Additionally, high certainty of evidence was assigned to the association of reduced SFA intake in childhood (or its replacement with MUFA/PUFA) with lower blood pressure and blood lipids levels [31]. For other outcomes, the certainty was rated as moderate, low, or very low.
Discussion
This scoping review provides a comprehensive summary of evidence from SRs on a broad range of health outcomes associated with fat intake and its quality during pregnancy and across childhood. Omega-3 PUFA (DHA and/or EPA) supplementation during pregnancy led to a reduced risk of early preterm birth and in several SRs also or any preterm birth. In childhood, SFA reduction and its replacement with PUFA or MUFA had beneficial effects on blood pressure and lipids. These findings were based on a high certainty of evidence. For other clinically relevant outcomes, including pregnancy and birth outcomes, infant growth and neurodevelopment, cardiovascular and allergic outcomes, either null effect or inconsistent results in relation to dietary fat intake and its quality were reported, and no firm conclusions can be drawn.
One potential explanation for inconsistent findings was the heterogeneity between the individual studies in the eligible SRs, which include differences in the study populations, variety of assessed interventions in terms of FA composition, dose used, mode of delivery, duration and timing of the intervention, various outcomes measures used, and children age at outcome assessment. Similarly, discrepancies observed between some SRs likely derive from the applied inclusion/exclusion criteria in relation to these study characteristics. These make the overall evidence summary challenging.
As the number of studies on the health effects of certain FA during pregnancy and childhood rapidly increases, also the number of SRs increases. Since completion of the search for our scoping review, some new SRs that focus on maternal omega-3 PUFA supplementation have been published. Beneficial effect of such interventions on the risk of preterm birth was confirmed in further SRs [44, 45]. Importantly, in 2022, Best et al. [43] shared results of an update of the 2018 Cochrane Review [35] including additional RCTs with a total of 36 trials (23,726 women) that evaluated the risk of preterm birth and 12 trials (16,782 women) that evaluated the risk of early preterm birth. High certainty evidence showed a 12% reduction of preterm birth (risk ratio 0.88, 95% confidence interval: 0.81–0.95) and a 35% reduction of early preterm birth (risk ratio 0.65, 95% confidence interval: 0.46–0.92). Moreover, in line with our findings, evidence on maternal omega-3 PUFA supplementation on child cognitive performance/neurodevelopment remained inconclusive [46, 47]. Finally, maternal omega-3 PUFA supplementation during pregnancy had no overall beneficial effect on the risk of eczema and asthma/wheeze in offspring [48, 49]; however, some specific effects in subgroups were suggested.
In our scoping review, most of the SRs focused on the assessment of the effects of omega-3 PUFA supplementation during pregnancy, confirming its beneficial effects in the reduction of premature birth risk. More research is needed to clarify what is the optimal supplementation dose, specific timing and duration of the supplementation, and which target groups can benefit the most from the supplementation, given the regional differences in PUFA intake from diet and women’s individual risk for certain pregnancy and birth complications. Further, cost-effectiveness analysis of such intervention, suggesting substantial costs savings [50, 51], should assist informed decision making. While maternal omega-3 PUFA supplementation is actively investigated in research, it is often not addressed in the current guidelines targeting pregnant and lactating women that mainly recommend achieving adequate PUFA status through fish consumption [52]. Future studies explaining evidence inconsistency in relation to different health outcomes of interest, can further support translation of the research findings into recommendations and their application on the population level. The evidence regarding fat consumption beyond infancy appears more homogenous, which is reflected in current guidelines that consistently recommend the reduction of SFA intake and its replacement with PUFA/MUFA in childhood [53].
This scoping review has several strengths. In terms of methodology, we followed the recommendations for the review conduct as proposed by JBI Reviewers’ Manual [8], such as thorough and comprehensive search strategy or independent data extraction by two reviewers. We are aware that the evidence from different SRs, addressing similar research question, is to some extent overlapping. As even minor differences in the applied search strategy or selection criteria may substantially affect SR findings, we still aimed to summarize the evidence from all identified SRs. We performed a narrative synthesis of the SRs results, which may be considered a limitation of our study. However, our aim, as of any scoping review, and in contrast to a SR, was to provide a broad overview of the existing evidence in a field of interest. Further, quantitative synthesis of data from included SRs would lead to misleading estimates due to overlapping evidence supporting different SRs [54]. Finally, our scoping review cannot overcome either the limitations of the individual studies included in the SRs, or the limitations of the SRs themselves. However, if available in the SRs, we provided data on the outcome-specific certainty of evidence. The scope of our review was broad, covering multiple population groups (from pregnant and lactating women through infants, to children and adolescents), various interventions/exposures (i.e., different type of FA, delivered in a diet, but also in a form of supplements), and wide range of relevant health outcomes. We also included SRs of different study designs, namely of RCTs and of prospective cohort studies [55]. While we excluded SRs that focused exclusively on specific fatty foods (e.g., fish consumption), we acknowledge that these provide important complementary evidence in a field of our interest.
Conclusions
Existing high certainty evidence provides support for the effectiveness of omega-3 PUFA supplementation during pregnancy in reducing the risk of preterm birth and for the beneficial effects of SFA intake reduction in childhood in relation to cardiovascular outcomes. These findings require consideration in future dietary guidelines targeting these populations. More research on dietary fat intake and fat quality, in particular with respect to PUFA supplementation in early life, is warranted to better define the optimal intervention, its dose, means and timing of delivery, and targets groups likely to benefit the most.
Statement of Ethics
This study utilized exclusively published literature. Thus, an ethics statement is not applicable.
Conflict of Interest Statement
B.K. has received reimbursement for speaking at conferences supported by companies marketing nutritional or healthcare related products. All other authors declare no conflicts of interest.
Funding Sources
The work reported here was supported by the charitable Child Health Foundation (Stiftung Kindergesundheit, Munich, Germany, www.kindergesundheit.de) with partial contribution of a grant provided by IUNS to Stiftung Kindergesundheit. The work of BPG is supported by a grant from the Alexander von Humboldt Foundation, Bonn, Germany. BK is the Else Kröner Seniorprofessor of Paediatrics at LMU – University of Munich, financially supported by the charitable Else Kröner-Fresenius-Foundation, LMU Medical Faculty, and LMU University Hospitals.
Author Contributions
B.P.G., L.S., and B.K. conceptualized the review. B.P.G., B.Z.M., and M.K. screened, selected and analysed the data. B.P.G. prepared the draft manuscript. All authors interpreted the data, reviewed and revised the manuscript, and agreed on the final version.
Data Availability Statement
Publically available, published data were used in this study. Further enquiries can be directed to the corresponding author.