Ontogeny of circulating lipid metabolism in pregnancy and early childhood – a longitudinal population study
Curation statements for this article:-
Curated by eLife
Public Evaluation Summary:
This manuscript is of interest to readers in the field of metabolomics, particularly lipidomics. It measures hundreds of cord and plasma lipid species in mother-child pairs in a longitudinal fashion starting in gestation up to four years after birth. The authors perform regression analyses of cord lipid species with clinical characteristics at birth and 4 years old to support the key claims of the paper.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
There is mounting evidence that in utero and early life exposures may predispose an individual to metabolic disorders in later life; and dysregulation of lipid metabolism is critical in such outcomes. However, there is limited knowledge about lipid metabolism and factors causing lipid dysregulation in early life that could result in adverse health outcomes in later life. We studied the effect of antenatal factors such as gestational age, birth weight, and mode of birth on lipid metabolism at birth; changes in the circulating lipidome in the first 4 years of life and the effect of breastfeeding in the first year of life. From this study, we aim to generate a framework for deeper understanding into factors effecting lipid metabolism in early life, to provide early interventions for those at risk of developing metabolic disorders including cardiovascular diseases.
Methods:
We performed comprehensive lipid profiling of 1074 mother-child dyads in the Barwon Infant Study (BIS), a population-based pre-birth cohort and measured 776 distinct lipid features across 39 lipid classes using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We measured lipids in 1032 maternal serum samples at 28 weeks’ gestation, 893 cord serum samples at birth, 793, 735, and 511 plasma samples at 6, 12 months, and 4 years, respectively. Cord serum was enriched with long chain poly-unsaturated fatty acids (LC-PUFAs), and corresponding cholesteryl esters relative to the maternal serum. We performed regression analyses to investigate the associations of cord serum lipid species with antenatal factors: gestational age, birth weight, mode of birth and duration of labour.
Results:
The lipidome differed between mother and newborn and changed markedly with increasing child’s age. Alkenylphosphatidylethanolamine species containing LC-PUFAs increased with child’s age, whereas the corresponding lysophospholipids and triglycerides decreased. Majority of the cord serum lipids were strongly associated with gestational age and birth weight, with most lipids showing opposing associations. Each mode of birth showed an independent association with cord serum lipids. Breastfeeding had a significant impact on the plasma lipidome in the first year of life, with up to 17-fold increases in a few species of alkyldiaclylglycerols at 6 months of age.
Conclusions:
This study sheds light on lipid metabolism in infancy and early childhood and provide a framework to define the relationship between lipid metabolism and health outcomes in early childhood.
Funding:
This work was supported by the A*STAR-NHMRC joint call funding (1711624031).
Article activity feed
-
-
Public Evaluation Summary:
This manuscript is of interest to readers in the field of metabolomics, particularly lipidomics. It measures hundreds of cord and plasma lipid species in mother-child pairs in a longitudinal fashion starting in gestation up to four years after birth. The authors perform regression analyses of cord lipid species with clinical characteristics at birth and 4 years old to support the key claims of the paper.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
-
Reviewer #1 (Public Review):
In this paper, Burugupalli et al studied the lipid metabolism in pregnancy, and from birth to four years. They performed lipid profiling in 1074 samples from mothers and their offsprings in the BIS, which is a population based pre-birth cohort. The authors measured 776 distinct lipid species across 42 lipid classes using UHPLC. The study included measurement of lipids in 1032 maternal serum at 28 weeks' gestation, 893 cord serum at birth, and 793, 735, and 511 plasma samples at 6, 12 months, and four years, respectively. They showed that lipidome was different between the mother and their newborns, and the change increased with age. These studies also demonstrated that cord serum contained higher levels of long chain poly-unsaturated fatty acids (LCPUFAs), and cholesteryl esters compared to the maternal …
Reviewer #1 (Public Review):
In this paper, Burugupalli et al studied the lipid metabolism in pregnancy, and from birth to four years. They performed lipid profiling in 1074 samples from mothers and their offsprings in the BIS, which is a population based pre-birth cohort. The authors measured 776 distinct lipid species across 42 lipid classes using UHPLC. The study included measurement of lipids in 1032 maternal serum at 28 weeks' gestation, 893 cord serum at birth, and 793, 735, and 511 plasma samples at 6, 12 months, and four years, respectively. They showed that lipidome was different between the mother and their newborns, and the change increased with age. These studies also demonstrated that cord serum contained higher levels of long chain poly-unsaturated fatty acids (LCPUFAs), and cholesteryl esters compared to the maternal samples. Phosphatidylethanolamine containing LC-PUFAs also increased with postnatal age, while lysophospholipids and triglycerides decreased. Regression analyses to investigate the associations of cord serum lipid species with birth factors, including gestational age, birth weight, mode of birth and duration of labor showed that the majority of the cord serum lipids associated with gestational age and birth weight, with most lipids having opposing associations. The authors concluded that there "were marked changes in the plasma lipidome over the first four years of life. This study sheds light on lipid metabolism in infancy and early childhood and provide a framework to define the relationship between lipid metabolism and health outcomes in early childhood."
The paper is well written and the experimental approach is sound. The paper contains a large amount of data and addresses an important and an understudied area of science. However, there are a couple of areas that need to be improved. First, the authors need to better define the significance of their findings. They try to link the levels of certain lipids with gestational age, birth weight, mode of birth and duration of labor. However, there are several lipids that have been shown to have toxicity in certain cells. For example, ceramides have been shown to cause cardiotoxicity in adults. The authors need to assess the levels of these potential toxic lipids in the serum and whether they are linked to any changes in the overall or system physiology. Additionally, it is hard to read and understand some of the graphs that are provided in the paper. Finally, the authors need to study whether environmental factors during early infancy (such as exposure to second hand smoke or body weight, etc) also correlate with a change in serum lipids.
The paper will likely have a high impact on the field, as it identifies changes in plasma lipids at the early stages after birth and its link with factors related to pregnancy. -
Reviewer #2 (Public Review):
In this manuscript, Burugupalli et al. perform longitudinal lipid profiling on a key demographic that fills a gap in the field: mother-child pairs. The strengths of the paper include comprehensive lipid profiling of over 700 lipid species and an impressive longitudinal cohort of over 1000 mother-child dyads.
The authors validate their measurements using ultra high-performance liquid chromatography, with quality control samples measured every 20 samples. They perform principal component analysis to show how the circulating lipidome is different among mothers, newborns, and infants. Additionally, they perform longitudinal analyses using adjusted linear regression models to show associations between circulating lipids with birth weight and BMI at 4 years old.
The work is likely to be impactful in the field of …
Reviewer #2 (Public Review):
In this manuscript, Burugupalli et al. perform longitudinal lipid profiling on a key demographic that fills a gap in the field: mother-child pairs. The strengths of the paper include comprehensive lipid profiling of over 700 lipid species and an impressive longitudinal cohort of over 1000 mother-child dyads.
The authors validate their measurements using ultra high-performance liquid chromatography, with quality control samples measured every 20 samples. They perform principal component analysis to show how the circulating lipidome is different among mothers, newborns, and infants. Additionally, they perform longitudinal analyses using adjusted linear regression models to show associations between circulating lipids with birth weight and BMI at 4 years old.
The work is likely to be impactful in the field of lipid biology. More broadly, information will be useful for exploratory hypothesis-generating ideas in the field of lipidology, particularly in pediatric subjects.
-
Reviewer #3 (Public Review):
Strengths:
The present manuscript is impressive in scope. I appreciate the deep effort put in by the team to identify clinical associations between a wide range of maternal and child parameters, and the measured lipid species. In particular, as the authors explicitly stated that they wanted to correlate lipid signatures to known child parameters that portend the metabolic syndrome, their analyses rightly focused on those variables, such as birth weight and BMI. The scientific descriptions are meticulous and detailed, a testament to the strength of the team's analytical chemistry capabilities, that render this work an immensely useful lipidomic atlas for the research community. It is also to the authors' credit that they cross-validated some of their findings in a distinct, ethnically more diverse cohort, …Reviewer #3 (Public Review):
Strengths:
The present manuscript is impressive in scope. I appreciate the deep effort put in by the team to identify clinical associations between a wide range of maternal and child parameters, and the measured lipid species. In particular, as the authors explicitly stated that they wanted to correlate lipid signatures to known child parameters that portend the metabolic syndrome, their analyses rightly focused on those variables, such as birth weight and BMI. The scientific descriptions are meticulous and detailed, a testament to the strength of the team's analytical chemistry capabilities, that render this work an immensely useful lipidomic atlas for the research community. It is also to the authors' credit that they cross-validated some of their findings in a distinct, ethnically more diverse cohort, namely GUSTO, which enhances the robustness of their results.Weaknesses:
Although the goal of the authors was to find out whether specific lipid signatures correlate with factors predisposing to poor health outcomes in later life, several other interesting and impactful clinical questions could also have been answered with the present dataset.For example, in the section on birth mode and labor duration, the authors assert that there are specific cord serum lipid signatures that associate with birth mode and labor duration. The authors should determine whether any maternal lipid signature during pregnancy can predict labor duration. Further, details on the use of epidurals and labor inducers, if any, do not seem to be given. This is particularly important since some of these chemicals are lipophilic in nature and may interact or shape maternal and cord lipidomes.
Complications during labor are not uncommon. From the manuscript, it seemed that mothers who had experienced labor complications were not excluded from the analysis. If so, it would seem appropriate for the authors to discuss how various complications e.g., breech births, meconium aspiration, might associate with gestational lipid signatures, with immediate implications for triage and emergency planning.
The child's lipidome can be influenced by nutrition. In the first year of life, it is therefore heavily shaped by the milk (breast and/or formula) consumed. However, the authors have not discussed milk as a source of lipids that can influence the ontogeny of the child's lipidome.
In sum, while the design and execution of the investigation have been generally done well, the analyses presented in the manuscript have limited clinical impact. To attain the team's long-term goal of understanding how early life events impact health outcomes in later life, more decades of research is still needed. The interim data gathered and presented in this work can be better employed in understanding events proximal to labor, delivery and the first year of life to generate timely and impactful clinical insights.
-
