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Systematic Review
Revised

Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis

[version 2; peer review: 2 approved]
Previously titled: 'Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a meta-analysis'
PUBLISHED 29 Jan 2021
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Background: Circulating into foetal circulation across the placental barrier, abnormal maternal serum lipids predispose neonates to metabolic dysfunction and thereafter affect the steroid metabolism and functions of extra-embryonic foetal tissues.
Methods: A systematic review was conducted by searching PubMed–MEDLINE and the Cochrane library between January 2010 and January 2020. The included studies were English case control studies that described original data on at least one raw lipid measurement during pregnancy in healthy women who delivered large for gestational age (LGA) newborns and in healthy women with non-LGA newborns. The data extracted from 12 studies were pooled, and the weighted mean difference (WMD) in lipid levels was calculated using random effects models. A meta-analysis was performed to identify sources of heterogeneity and to describe the significant value of the collected studies.
Results: Of 649 published articles identified, a total of 12 met the inclusion criteria. Compared with women who had non-LGA newborns, those who had LGA newborns had significantly higher triglyceride (TG) levels (WMD = 0.28, 95% CI −0.02 to 0.54) and lower high density lipoprotein cholestrol (HDL-C) levels (WMD = 0.08, 95% CI −0.13 to −0.03), but not have significantly lower high-density lipoprotein cholesterol (LDL-C) levels. Moreover, the levels of total cholesterol, low-density lipoprotein cholesterol, and very low density lipoprotein cholesterol (VLDL-C) were inconsistent between both groups.
Conclusions: High levels of TG and low levels of HDL-C could cause births of LGA newborns whereas maternal serum of TC, LDL-C and VLDL-C cannot be used as predictor of LGA.

Keywords

GDM, healthy women, LGA, maternal lipids, non-LGA

Revised Amendments from Version 1

The title of this article has been changed to maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis. The authors' role of Muhammad Pradhika Mapindra (https://orcid.org/0000-0002-3082-4479) has been added with writing- review, and editing. Several words that expressed misunderstandings about fetuses have been edited to the more appropriate words, such as infants or newborns. In the subheading of study characteristics and assessment of risk bias, the text has been updated according to reviewers' suggestions. Following this, figure 1 elucidates the process of the literature review is replaced by another figure with more precise information. In the results section, the confusing sentences have been changed relevant to reviewers' comments. Furthermore, in the discussion section, the information from previous studies regarding neonatal outcomes of women with high maternal lipids is added. Also, as the reviewer's suggestion, additional information about an unhealthy lifestyle that can affect the disturbances of maternal lipid levels is included in the discussion section. Moreover, the clinical implications from our study findings have been added to the discussion section. As a consequence of these changes, the abstract and keywords of this article are revised as well.

See the authors' detailed response to the review by Victor Samuel Rajadurai
See the authors' detailed response to the review by Kian Djien Liem

Introduction

The early stages of pregnancy involve endocrine and metabolic changes and is an important period for placenta formation and foetal development. Epidemiological studies have shown that excessive lipid exposure in the maternal intrauterine environment can affect the development of foetal organs and lead to maternal metabolic impairment1. Abnormalities in maternal serum lipids have been highly correlated with birth weight and may be a cause of neonatal metabolic dysfunction2. The prevalence of foetal macrosomia in developed countries ranges from 5% to 20%, and several studies have reported that gestational diabetes mellitus (GDM) and maternal obesity were strongly associated with the risks for low and high birth weights. Disturbances in maternal metabolism affect blood glucose and other maternal macronutrients, such as lipids, and subsequently affect the development of the foetus24. The role of triglycerides (TG) is yet to be completely understood, but a cohort study in Amsterdam reported that maternal TG concentrations during the early stages of pregnancy were linearly related with the prevalence of large for gestational age (LGA) newborns5. Macrosomic foetuses may develop stillbirth and are at risk for neonatal mortality57. Therefore, LGA newborns have increased risk for developing type 2 diabetes, cardiovascular diseases and hypertension in their adult age59.

High maternal serum lipid levels have been shown to increase the likelihood of pregnancy problems, such as GDM, pre-eclampsia and pre-term delivery2. Moreover, increase in the levels of TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) can account for adverse outcomes of normal gestation. Maternal serum lipids are transferred through the placenta, suggesting that they can affect foetal sterol metabolism and the metabolic functions of extra-embryonic foetal tissues6,7,9. These studies implied how essential lipid levels are to foetal development. The impact of high maternal lipid levels on foetal birth weight remains barely recognised in clinical practice, although this is known to be a cause of cardiovascular disease and diabetes2.

Previous studies have suggested that pregnant women with GDM and normal blood glucose levels had an increased risk for delivering LGA newborns10. The positive association between early maternal hypertriglyceridemia and LGA newborns in low-risk women is well recognised in some studies6. To further investigate the relationship between maternal lipid levels and LGA newborns, we conducted a systematic review of existing cohort studies to determine the potential role of maternal lipid levels as a risk factor for uncomplicated pregnancy related to LGA newborn delivery.

Methods

Eligibility criteria

This study is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA P) guidelines (Figure 1; Reporting guidelines11). Only research papers written in English between January 2010 and January 2020 were included in our search. We retrieved several papers with abstracts that mentioned an association between maternal TG and LGA newborns. For additional citations, references were collected from the included articles. Then, we determined the eligibility of the included studies using a critical appraisal skill programme (CASP) checklist for cohort model to determine the quality of the included studies. Based on the assessment using CASP tools, we finally included 12 articles to assess and review. The variables extracted from the literature are shown in Table 2. Full-text articles were acquired and evaluated for eligibility.

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure1.gif

Figure 1. Flowchart of the Literature Review Process.

Literature search

We conducted our search, which was conducted from April 2020 to June 2020, in the following databases: PubMed (MEDLINE), Library of Michigan University and the Cochrane library. We applied search strings, including combinations of search terms, as keywords placed in the titles or abstracts of the studies (Table 1). The keywords we used for the search strategy were as follows: 1. maternal lipid profile, lipid profile or lipoprotein and 2. LGA or large for gestational age.

Table 1. Electronic search strings.

Data BaseKeywords (Search Strategy)
PubMed(Lipid profile[all fields] OR Triglycerides[MeSH Terms] OR Cholesterol[MeSH] AND LGA[all fields] OR Large
for Gestational Age[all fields]
Michigan Library(Maternal Lipid profile[all fields] OR Triglycerides[MeSH Terms] OR Cholesterol[MeSH] AND Large for
Gestational Age[all fields]
Cochrane
Library
(Lipid profile[all fields] OR Triglycerides[all fields] OR Cholesterol[MeSH] AND LGA[all fields] OR Large for
Gestational Age[all fields]

Study selection

We included studies that assessed the relationship between maternal serum TG levels during early to late pregnancy and LGA newborn delivery by healthy women or women who had no confounding factors, such as obesity, GDM, type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), intake of medications that can alter lipid levels and maternal obesity. Lipid profiles, including TG, TC, HDL-C, LDL-C and VLDL-C, were measured from healthy pregnant women who had the outcome LGA newborn delivery. We did not include unpublished studies, letter to the editor, commentary, supplementary materials and conference paper. We excluded studies that did not show any relevance or similarity with our study purposes. This study evaluated maternal serum TG levels measured during pregnancy but not pre-conception TG levels.

Data extraction and analysis

Maternal serum lipid levels in mmol/L and mg/dL were compared between LGA and non-LGA newborns. The study design, study population, method of data collection, gestational age at sampling and serum lipid levels were evaluated for all the selected studies. We measure lipid levels in mmol/l to make them homogenous so all lipid level measurements being reported in mg/dl were converted to mmol/L12. The reported mean and standard deviation (SD) values in the selected studies were recorded. However, we found several studies that reported their findings in the form of median and interquartile range; we used a digital calculator to change these into estimated mean and SD13.

Data abstraction

All authors recorded and reviewed the collected articles. The main authors determined the study design, time frame and criteria for the included studies. The other authors helped retrieve the articles and process the data with statistical analyses. We decided to include studies that had prospective and retrospective cohort designs.

Statistical methods

First, we measured the maternal lipid levels with the standard unit of mmol/L in all included studies; data on maternal lipid levels in mg/dL were converted to mmol/L. Thereafter, we used the Review Manager version 5.3 (RevMan) software designed by Cochrane for statistical analyses. The mean difference and analysed statistical significances of the reported maternal serum lipid levels were calculated and evaluated in terms of impact on the outcome of LGA delivery. I2 statistics was performed to assess heterogeneity.

Results

Study characteristics and assessment of risk bias

Our search retrieved 649 articles, 147 of which were independently identified as duplications and thus leaving 502 articles. Subsequently, we decided to select 77 of 502 articles that had titles and abstracts that were related to the measurement of lipoprotein levels in pregnant women and its impact on neonates. Of the 77 articles, 40 articles that had suitable research methods and outcomes were read in full text. We found that 28 of the 40 articles did not indicate mean ± SD or median with upper and lower quartiles for maternal lipid level measurements. Thus, leaving 12 articles that were suitable for inclusion. We cross-checked the remaining articles to ensure that original studies were reported. Detailed information on author’s name, publication year, sample size, study design, the determined lipid level and the definitions of LGA was recorded and tabulated in Microsoft Excel 2010 software (Table 2 and Table 3).

Table 2. Characteristics of the included studies.

StudyStudy
design
Year of
publication
Total
number
of
samples
(n)
LGA
(n)
Non-
LGA
(n)
Gestational
age at
sampling
(weeks)
LGA definitionBiochemical lipid
(s) determined
Vrijkotte9 Prospective
Cohort
20124,008963,912Singleton
pregnancies,
first
trimester
Neonatal birth weight above 90th percentile for
gestational age, regardless of sex groups, from the
Dutch Perinatal Registration.
Non-fasting TC and
TG
Mitra14Prospective
Cohort
2012501040Singleton
pregnancies,
third
trimester
Neonatal birth weight above 90th percentile for
gestational age-corrected birth weight curve.
TC, TG, HDL, LDL,
Parlakgumus15Prospective
Cohort
201341126385Singleton
pregnancies,
second
trimester
Neonatal birth weight above 90th percentile for
gestational age on Lubchenco growth charts.
Fasting TG, VLDL,
HDL
Harville16Prospective
Cohort
201432535290Singleton
pregnancies
Neonatal birth weight in the top 10% for
gestational age in the study population.
Fasting TG
Lin Hou17Prospective
Cohort
20142,7905542,236Singleton
pregnancies,
third
trimester
Neonatal birth weight above 90th percentile for gestational age based on birth weight percentiles by sex and gestational age in Southern China Fasting TC, HDL-C,
LDL-C, TG
Kui Ye18Prospective
Cohort
20151204331873Singleton
pregnancies,
third
trimester
Neonatal birth weight above 90th percentile for
gestational age
Fasting TC, TG, HDL-
C, LDL-C
Wang3Retrospective
Cohort
20175,2188564,362Singleton
pregnancies,
first
trimester
Neonatal birth weight above 90th percentile for
gestational age based on birth weight percentiles
by sex and gestational age in Southern China
Non fasting TC, TG,
HDL-C, LDL-C
Farias6Prospective
Cohort
201718836152Singleton
pregnancies,
Neonatal birth weight above 90th percentile of the
INTERGROWTH-21st curves.
Fasting HDL-C,
LDL-C,
Geraghty7Prospective
Cohort
201732796231singleton
pregnancies
Neonatal birth weight above 90th percentile of the
INTERGROWTH-21st curves.
, TG
Pazhohan19Prospective
Cohort
2017951248703Singleton
pregnancies,
first
trimester
Neonatal birth weight above 90th percentile of the
INTERGROWTH-21st curves.
Fasting TC, HDL-C,
LDL-C, TG
Liang4Prospective
Cohort
20182,8392,405435Singleton
pregnancies
Neonatal birth weight above 90th percentile of the
INTERGROWTH-21st curves.
Fasting TG,
Lee20Prospective
Cohort
201962368555Singleton
pregnancies,
first
trimester
Neonatal birth weight >90th percentile for
gestational age using data derived from Korean
population.
Fasting TC, TG, HDL-
C, LDL-C

Table 3. Mean values of lipid profiles during pregnancy in women with LGA newborns and controls.

StudyLGA vs. Non-LGATriglyceride
(mmol/L)
Total cholesterol
(mmol/L)
HDL-C
(mmol/L)
LDL-C
(mmol/L)
VLDL
(mmol/L)
Vrijkotte9LGA1.44 ± 0.615.06 ± 0.91--
Non-LGA1.32 ± 0.544.98 ± 0.86--
Mitra14a LGA2.66± 0.881.27 ± 0.221.7 ± 0.242.85 ± 0.251.23± 0.43
Non-LGA2.14± 0.631.61 ± 0.421.77 ± 0.252.95 ± 0.251.02 ± 0.31
Parlakgumus15*aLGA1.61± 0.923.82 ± 0.851.27 ± 0.232.2 ± 0.880.73 ± 0.41
Non-LGA1.59± 1.164.66 ± 1.831.61 ± 0.422.85 ± 1.680.75 ± 0.50
Harville16 LGA1.2 ± 0.7----
Non-LGA1.1 ± 0.5----
Hou17 LGA2.15± 0.526.22 ± 0.491.70±0.242.96 ± 0.44-
Non-LGA1.23± 0.066.33 ± 0.471.77±0.253.09 ± 0.42-
Wang3 LGA1.26 ± 0.684.54 ± 0.801.71 ± 0.482.36 ± 0.68-
Non-LGA1.10 ± 0.694.46 ± 0.801.73 ± 0.452.30 ± 0.66-
Farias6aLGA4.87 ± 1.913.58 ± 2.001.27 ± 0.192.53 ± 0.41-
Non-LGA4.32 ± 2.303.51 ± 0.21.23 ± 0.212.49 ± 0.56-
Geraghty7LGA1.86 ± 0.14 ----
Non-LGA 1.66 ± 0.16----
Pazhohan18aLGA2.27± 1.185.23 ± 0.8---
Non-LGA1.82± 0.485.08 ± 0.77---
Liang4LGA2.15 ± 0.52----
Non-LGA1.23 ± 0.06----
Lee20*aLGA1.38± 0.194.42 ± 0.291.62 ± 0.172.15 ± 0.20-
Non-LGA1.26 ± 0.174.43 ± 0.261.68 ± 0.132.17 ± 0.21-
Kui Ye18LGA3.1 ± 1.26.6 ± 1.32.30 ± 0.53.40 ± 0.80-
Non-LGA2.90 ± 1.26.6 ± 1.42.40 ± 0.53.30 ± 0.80-

*The mean was calculated by inputting the median, lowest range and highest range to the estimating calculator based on SP Hozo13.

aThe data was converted from mg/dL to mmol/L using a standard measuring unit12.

As shown in Table 2, the baseline characteristics of the included studies were explained. There were 12 prospective cohort studies that reported a total of 17,731 cases, 4,430 of which included LGA newborns. Maternal lipid profiles were measured in the first trimester in four articles3,9,19,20; in the second trimester in one article15; in the last trimester in three articles14,17,18 and in any of the gestational weeks in the remaining articles4,6,7,16.

Most of the studies4,6,7,19 used the INTERGROWTH-21st definition of >90th percentile for LGA newborns. Some studies in China3,17 used a referred percentile standard based on a Chinese population, and some14,16,20 used their country’s definition of LGA. A detailed list of the implemented eligibility criteria for each study is shown in Table 2, and the mean values of the determined biochemical lipids are presented in Table 3. There were 12 included studies that investigated the effects of lipid profile in pregnant women who had no complications on LGA newborn delivery. The exposures of maternal lipid profile included TG (N = 12), TC (N = 9), HDL-C (N = 7), LDL-C (N = 7) and VLDL-C (N = 2). Based on the analysis of the RevMan tool, we found that the investigated studies that analysed maternal TG, TC, HDL-C and LDL-C had an I2 of more than 50%; for this reason, we used a random effects model. On the other hand, we used a fixed effect model to assess the studies that investigated maternal VLDL-C, because the I2 was below 50%.

Pregnancy triglyceride samples

There were 11 studies that assessed TG levels during pregnancy; 4,761 case subjects and 14,174 control subjects were included. Maternal serum TG levels in the first trimester were found to be significantly associated with LGA infants, according to three of the included studies3,19,20.

One study reported that maternal serum TG levels in the second trimester were significantly related with the risk for LGA newborns before and after data adjustment9. On the other hand, another study on a similar population15 showed a non-significant correlation between maternal serum TG levels and the risk for LGA newborns. Furthermore, two studies7,17 reported an association between maternal serum TG levels and LGA occurrence. The remaining studies measured TG levels in the first, second and third trimesters and reported significant associations between maternal serum TG levels and the risk for LGA newborns4,7,16.

Figure 2 shows the comparison of the mean differences of the included studies. Random effects model meta-analysis showed that the pooled weighted mean difference was 0.28 mmol/L (95% CI −0.02 to 0.54), and significant heterogeneity was observed (Tau² = 0.19; Chi²= 2460.32, I² = 100%, p = 0.03).

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure2.gif

Figure 2. Forest Plot of Maternal TG level exposure and LGA outcome.

Total cholesterol

Data on 2,225 patients and 13,218 controls from nine studies3,6,9,14,15,1720 were included to evaluate the relationship between TC and LGA newborns. In contrast to all the studies that reported an insignificant association between TC levels and LGA, Wang reported that abnormal levels of maternal TC in the first trimester were significantly associated with the event of LGA infants3. In fact, some reports were insufficient to prove a significant correlation between TC level and the risk for LGA newborns, whereas other reports found non-significant associations between TC levels and the risk for LGA newborns in the first, second and third trimesters6,17.

Based on the random effects model meta-analysis (Figure 3 and Table 4), the included studies had a pooled weighted mean difference of −0.06 mmol/L (95% CI −0.16 to 0.05) and heterogeneity (Tau2 = 0.02, Chi² = 65.27, I² = 88%) with p value = 0.26.

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure3.gif

Figure 3. Forest Plot of Maternal TC exposure and LGA outcome.

Table 4. Mean differences in TG, TC, HDL-C, LDL-C and outcome among the LGA newborns.

StudyTriglycerideTotal CholesterolHigh-Density Lipoprotein
Cholesterol
Low-Density Lipoprotein
Cholesterol
Very Low-Density
Lipoprotein
Cholesterol
Weight
%
Mean
Difference
IV, Random,
95% CI
Weight
%
Mean Difference
IV, Random, 95%
CI
Weight
%
Mean Difference
IV, Random, 95%
CI
Weight
%
Mean Difference
IV, Random, 95%
CI
Weight
%
Mean
Difference
IV, Random,
95% CI
Farias65.30.55 [-0.17, 1.27]2.20.07 [-0.58, 0.72]14.20.04 [-0.03, -0.11]12.00.04 [-0.12, 0.20]-Not estimable
Geraghty79.10.20 [0.17, 0.23]-Not estimable-Not estimable-Not estimable
Harville168.50.10 [-0.14, 0.34]-Not estimable-Not estimable-Not estimable-Not estimable
Kui Ye188.90.20 [0.05, 0.35]11.40.00 [-0.17, 0.17]14.9-0.10 [-0.16, -0.04]15.70.10 [-0.00, 0.20]-Not estimable
Lee209.10.12 0.07, -0.17]15.0-0.01 [-0.08, 0.06]16.9-0.06 [-0.10, 0.02]18.6--0.02 [-0.07, 0.03]-Not estimable
Liang N49.10.92 [0.90, 0.94]-Not estimable-Not estimable-Not estimable-Not estimable
Lin Hou179.10.19 [0.15, 0.23]15.7-0.11 [-0.16, -0.06]18.3-0.07 [-0.09, -0.05]19.0-0.12 [-0.16, -0.08]-Not estimable
Mitra146.30.46 -0.12, 1.04]10.6-0.34 [-0.53, -0.15]6.6-0.07 [-0.24, -0.10]11.20.00 [-0.17, 0.17]25.40.21 [-0.07.
0.49]
Parlakgumus157.70.02 [-0.35, 0.39]5.3-0.84 [-1.21, -0.47]11.6-0.34 [-0.44, -0.24]4.8-0.65 [-1.00, -0.30]74.6-0.02 [-0.19,
0.15]
Pazohan198.90.45 [0.30, 0.60]13.50.15 [0.04, 0.26]-Not estimable-Not estimable-Not estimable
Vrijkotte98.90.12 [-0.00, 0.24]10.80.08 [-0.10, 0.26]-Not estimable-Not estimable-Not estimable
Wang310.00.16 [0.11, 0.21]15.40.08 [0.02, 0.14]17.5-0.02 [-0.05, 0.01]18.60.06 [0.01, 0.11]-Not estimable
Total (95% CI)100.00.28 [0.02, 0.54]100.0-0.06 [-0.16, 0.05]100.0-0.08 [-0.13, -0.03]100.0-0.03 [-0.11, 0.06]-Not estimable

High density lipoprotein - cholesterol

The analysis of HDL-C and risk for LGA newborns included 1,881 patients and 8,603 controls from seven studies3,6,14,15,17,18,20. HDL-C levels in the third trimester of pregnancy were significantly associated with both LGA and SGA infants14,18. In addition, one study found a significant association in the second trimester6. On the other hand, one study showed HDL-C as the only lipid that was not significantly related with the birth of LGA infants3.

Figure 4 and Table 4 show the results of the meta-analysis of the included studies. The pooled weighted mean difference was 0.08 (95% CI −0.13 to −0.03), and heterogeneity was found (Tau2 = 0.00, Chi² = 46.53, I² = 87%), with p = 0.003.

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure3.gif

Figure 4. Forest Plot of Maternal HDL-C exposure and LGA outcome.

Low density lipoprotein - cholesterol

Six of the included studies3,6,14,15,17,18,20, which recruited 1,881 patients and 8,603 controls, majority reported no significant correlations between LDL-C concentration and LGA newborns as a neonatal outcome. On the other hand, four studies3,6,15,20 showed that LDL-C concentration was associated with LGA newborns. This association was found during the second and third trimesters of pregnancy6. Furthermore, the study by Wang supported this association by showing that LDL-C concentrations played a significant role in the risk for LGA newborns and that three lipids (TG, TC and LDL-C) were significant contributing factors3.

Figure 5 and Table 4 show that the pooled weight mean difference was −0.03 (95% CI −0.11 to 0.06) and that heterogeneity was found (Tau2 = 0.01, Chi² = 50.91, I² = 88%), with p = 0.56.

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure5.gif

Figure 5. Forest Plot of Maternal LDL-C exposure and LGA outcome.

Very low density lipoprotein - cholesterol

Studies and available information on the impact of VLDL on LGA remain unclear. Nevertheless, two studies that included a total of 36 patients and 425 controls reported that there was no correlation between VLDL and LGA newborns14,15. Based on our meta-analysis, the level of maternal serum VLDL was not significantly associated with births of LGA newborns (p = 0.60) (Figure 6).

d3e0b86d-c7d6-4a99-94b3-ee2bb3caa10e_figure6.gif

Figure 6. Forest Plot of Maternal VLDL exposure and LGA outcome.

Discussion

Data from 12 published articles were evaluated in this systematic review to determine the relationship between lipid values measured during pregnancy and the risk for LGA newborns. Our review presented some valuable findings. We discovered that TC levels were inconsistent in both groups of women who delivered LGA and non-LGA newborns. This finding suggested that TC level as a determinant of LGA newborn delivery is clinically not useful. In support of this result, almost all studies reported that TC levels were similar across the groups. In addition, Parlakgumus15 reported that TC levels in the second trimester took a decisive role on the risk for LGA newborns, compared with the results of many studies.

Many of the studies reported increase in TG levels in women who delivered LGA newborns. Our meta-analysis concluded that maternal TG levels were significantly elevated in women who would deliver LGA neonates. Moreover, maternal HDL-C levels were lower in women with LGA newborns than in those with non-LGA newborns. Therefore, a low level of maternal HDL-C concentration was significantly associated with the risk for LGA newborns. Levels of maternal LDL-C had no significant weight on women who had LGA newborns. Therefore, LDL-C and VLDL-C levels were not significant causative factors of LGA outcomes in pregnant women who had no comorbidities.

Exclusion of all confounding factors, such as T1DM, T2DM, GDM, maternal obesity and excessive gestational weight gain (GWG), which can affect the increased risk for LGA newborns in women who had abnormal lipid profiles, was important. A large prospective study on more than 700 women showed significant correlations of T1DM and HbA1c ≥ 42 mmol/L (6%) during 26 and 34 weeks age of gestation with increased risks of LGA newborns21. Similarly, a retrospective cohort study by Lisa et al. showed considerably higher rates of LGA newborns in women with T1DM (39%) than in women with T2DM (17%); their multivariate analysis on non-Caucasian women demonstrated an increased risk for LGA newborns in women who had T1DM (OR = 4.07; 95% CI 1.46 to 11.35) and T2DM (OR = 2.47; 95% CI 1.15 to 5.32)22.

A reported study on 175 women with T1DM in the United States discovered similar rates of LGA newborn delivery in women who had HbA1C of >6.5% and <6.5%, suggesting the likelihood of T1DM as a contributing factor23. A cohort study on multi-ethnic groups revealed that GDM and relatively high pregnancy BMI were linked with an increased risk for LGA newborn delivery. The prevalence of LGA newborns among women with GDM was highest in African, American and Hispanic women and lowest in Asian, Filipino and White women24. In another study on GDM, women who had elevated fasting plasma glucose levels were at a relatively high risk for having LGA newborns25. An analysis of 23,000 women in the Hyperglycaemia and Adverse Pregnancy Outcomes study discovered that the macrosomia prevalence in non-obese women was 6.7% in 1,244 patients without GDM and 10.2% in 2,791 patients with GDM. The investigators found that the frequency of macrosomia was 50% higher in women with GDM than in women without GDM in both the non-obese and obese groups26. Moreover, abnormal pre-pregnancy BMI significantly increased the risk for LGA neonates. A previous longitudinal study reported that compared the groups of women with T1DM and T2DM and healthy women found a positive association between maternal serum TG and LGA infants regardless of glycemic levels condition27. Fasting maternal hypertriglyceridemia could be used as a significant predictor of LGA infants that is independent of maternal BMI, weight gain, and blood glucose levels28.

Our review could not exclude women with excessive GWG, because this was not reported in the majority of the included studies. Therefore, we assumed that excessive GWG may have affected our results. Some studies showed that excessive GWG in pregnant women who had no complications increased the risk for delivering LGA newborn; compared with women who had uncomplicated pregnancies, those who exceeded the GWG recommendation had three and six times higher risk for macrosomia births29. The expected association of pre-pregnancy BMI and GWG with maternal and foetal outcomes showed that GWG of >16 kg led to an increased risk for delivering LGA neonates30. A study by Lu et al. reported that high second trimester GWG was significantly related with a relatively high risk for LGA newborns31. The probability of giving birth to an LGA newborn increased by 6.9% per kilogram of maternal weight gain, and the odds ratio was 1.249 for GWG beyond the recommended amount32. Similarly, another study found that the odds ratio for delivering LGA newborns was higher for non-diabetic Caucasian women with BMIs <25 or >25 than in women with GDM and normal BMIs33.

Lower TG and Higher HDL-C levels are linked to the physical inactivity, a tendency to less responsive to regular exercise. A program of exercise training is reported effective to alter the concentrations of lipoprotein, which therefore prompt the lipoprotein levels to be in the expected range34,35. As one of the most simple blood measurements, lipid levels especially LGA and HDL-C could be used as a routine blood test during the pregnancy for fetal programming. Normalization of lipid levels should be one of the main targets during pregnancy. Physical activity and dietary adjustment such as habitual fish consumption would be an effective approach to reduce maternal TG levels and increase HDL-C levels36,37

Moreover, maternal lipid profiles are not only informative to predict neonatal outcomes, but also tends to be important information that is integral to pregnant women’s metabolic status, including act as a potential predictor for GDM in pregnant women. High concentrations of TG, TC, and LDL were found in women diagnosed with GDM throughout the second trimester38. Another prospective cohort had also demonstrated that women who were exhibiting GDM in the second trimester, had shown higher levels of TG, TC, and LDL, and lower levels of HDL during the first trimester, even with normal glycemia and glycated hemoglobin39. These findings emphasized that the role of lipid metabolism is crucial to contribute to the pathogenesis of such metabolic disorders.

Strengths and limitations

This review was the first to directly address the association between maternal lipid profiles and the risk for LGA newborns, without any confounding factors. However, it had several weaknesses. First, this review depended on the design and quality of the included studies, regardless of the baseline lipid level, which was crucial to the results of our meta-analysis. Second, our meta-analysis did not distinguish pregnant women based on trimester of pregnancy but described the effects of physiologic changes in lipid metabolism on pregnant women and the risk for LGA newborns throughout the entire pregnancy; it did not consider the confounding factors that may occur in different trimesters. We assumed that our review results might not be sufficient to meet our expectations. Therefore, all of these reasons became researcher biases, which may have resulted in our findings.

Future studies

Most of the existing observational studies cannot be used to predict the definitive value of the independent contribution of lipid levels to maternal and neonatal outcomes because of the unmeasured confounding factors and methodological limitations. We recommend that future studies analyse women separately based on their non-modifiable characteristics, such as maternal age, race and inherited disorders. Furthermore, we noticed that these observational studies did not exclude women who had excessive GWG, which can contribute to the risk for LGA newborns. Future observational studies must include details on maternal lifestyles and environment to minimise population bias.

Conclusions

In conclusion, this review demonstrated notable findings from studies on the associations between maternal lipid levels and risk for LGA newborns. Our meta-analysis emphasised that high levels of TG and low levels of HDL-C may affect foetal development and cause births of LGA newborns. On the other hand, maternal serum of TC, LDL-C and VLDL-C cannot be used as predictor of LGA without the other risk factors, such as excessive GWG and insulin resistance. However, we need a better understanding of the relative contributions of other confounding factors, such as gestational age at sampling, maternal age and excessive GWG. We acknowledge that we used exclusion criteria, such as T1DM, T2DM, obesity and hypertension. Excessive GWG was not an exclusion criterion because of the limited amount of studies that excluded such population of women, although we were aware that it may contribute to LGA newborn delivery in healthy women.

Data availability

Underlying data

Figshare: Underlying Data - Maternal Lipid Levels on Pregnant Women without Complication in Developing Risk of Large for Gestational Age Newborn: Meta-Analysis study, https://doi.org/10.6084/m9.figshare.13011941.v240.

Reporting guidelines

Figshare: PRISMA checklist for ‘Maternal Lipid Levels on Pregnant Women without Complication in Developing Risk of Large for Gestational Age Newborn: Meta-Analysis study’, https://doi.org/10.6084/m9.figshare.13011803.v211.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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Mahindra MP, Sampurna MTA, Mapindra MP and Sutowo Putri AM. Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis [version 2; peer review: 2 approved]. F1000Research 2021, 9:1213 (https://doi.org/10.12688/f1000research.26072.2)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 12 Feb 2021
Kian Djien Liem, Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands 
Approved
VIEWS 7
The authors have made adequate changes in the manuscript as suggested. The mistakes have been corrected. ... Continue reading
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Liem KD. Reviewer Report For: Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis [version 2; peer review: 2 approved]. F1000Research 2021, 9:1213 (https://doi.org/10.5256/f1000research.35486.r78460)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 21 Dec 2020
Victor Samuel Rajadurai, Department of Neonatology, KK Women's and Children's Hospital, Singapore, Singapore 
Approved
VIEWS 16
The authors have done a systematic review of the influence of lipid levels in pregnant women and their effect on the developing fetus particularly, large for gestational age (LGA). The review has clearly addressed the rationale for the review, objectives, ... Continue reading
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Rajadurai VS. Reviewer Report For: Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis [version 2; peer review: 2 approved]. F1000Research 2021, 9:1213 (https://doi.org/10.5256/f1000research.28773.r72781)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    1. Thank you for your suggestion.
    We would like to add this information on discussion section.
    “Lower TG and Higher HDL-C levels are linked to the physical inactivity, a tendency ... Continue reading
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for your correcting our article.We would like to answer the questions.

    Results Section
    1. We would like to apologize because of several mistakes about the article screening ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    1. Thank you for your suggestion.
    We would like to add this information on discussion section.
    “Lower TG and Higher HDL-C levels are linked to the physical inactivity, a tendency ... Continue reading
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for your correcting our article.We would like to answer the questions.

    Results Section
    1. We would like to apologize because of several mistakes about the article screening ... Continue reading
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37
Cite
Reviewer Report 03 Nov 2020
Kian Djien Liem, Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands 
Approved with Reservations
VIEWS 37
General comments
This is a well-written manuscript. The authors have tried to explore the relationships between maternal lipid levels and the risk of having a large for gestational age (LGA) offspring using a systematic review. The results are of ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Liem KD. Reviewer Report For: Maternal lipid levels in pregnant women without complications in developing risk of large for gestational age newborns: a study of meta-analysis [version 2; peer review: 2 approved]. F1000Research 2021, 9:1213 (https://doi.org/10.5256/f1000research.28773.r72787)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for your correcting this mistake.
    We would like to answer the questions.

    As one of the most simple blood measurement, lipid levels especially LGA and HDL-C could ... Continue reading
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for correcting these mistakes in Figure 1

    1. Results section, Page 4, the data mentioned under Study characteristics and assessment of risk bias don’t match with the ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for your correcting this mistake.
    We would like to answer the questions.

    As one of the most simple blood measurement, lipid levels especially LGA and HDL-C could ... Continue reading
  • Author Response 29 Jan 2021
    Mahendra Tri Arif Sampurna, Department of Pediatrics, Faculty of Medicine, Airlangga University, Surabaya, 60115, Indonesia
    29 Jan 2021
    Author Response
    Thank you for correcting these mistakes in Figure 1

    1. Results section, Page 4, the data mentioned under Study characteristics and assessment of risk bias don’t match with the ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 08 Oct 2020
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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