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. 2023 Jul 25;15(15):3287. doi: 10.3390/nu15153287

Early Pregnancy Maternal Plasma Phospholipid Saturated Fatty Acids and Fetal Growth: Findings from a Multi-Racial/Ethnic Birth Cohort in US

Ling-Jun Li 1,2,3,4, Ruochen Du 5, Marion Ouidir 6, Ruijin Lu 7, Zhen Chen 8, Natalie L Weir 9, Michael Y Tsai 9, Paul S Albert 10, Cuilin Zhang 1,2,3,4,*
Editor: Hans Demmelmair
PMCID: PMC10420908  PMID: 37571228

Abstract

Saturated fatty acids (SFAs) during pregnancy are associated with disrupted metabolic programming among offspring at birth and later growth. We examined plasma phospholipid SFAs in early pregnancy and fetal growth throughout pregnancy. We enrolled 321 pregnant women from the NICHD Fetal Growth Studies—Singleton Cohort at gestational weeks 8–13. Ultrasonogram schedules were randomly assigned to capture weekly fetal growth. We measured plasma phospholipid SFAs at early pregnancy using blood samples and modeled fetal growth trajectories across tertiles of SFAs with cubic splines using linear mixed models after full adjustment. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each SFA using the Wald test. We found that even-chain and very long even-chain SFAs were inversely associated, whereas odd-chain SFAs were positively associated with fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) had a greater fetal weight and size, starting from week 13 until late pregnancy (at week 39: 3429.89 vs. 3269.08 g for estimated fetal weight; 328.14 vs. 323.00 mm for head circumference). Our findings could inspire future interventions using an alternative high-fat diet rich in odd-chain SFAs for optimal fetal growth.

Keywords: saturated fatty acids, odd-chain fatty acids, even-chain fatty acids, very-long-chain fatty acids, fetal growth, pregnancy, plasma phospholipids

1. Introduction

A body of evidence stemming from human and animal research has shown that maternal nutrition during pregnancy is directly related to the adequate development of the fetus and metabolism [1]. Among all nutritional factors, fatty acids have been widely investigated due to their easy transfer via placental fatty acids binding and transporting proteins to the fetus [2,3]. Emerging evidence has repeatedly reported a positive influence of the maternal antenatal dietary intake of polyunsaturated fatty acids (PUFA) on offspring birth weight and subsequent child growth [4,5,6]. Recent work from our team reported the positive temporal relationship between early pregnancy omega-3 plasma phospholipid PUFAs and fetal growth trajectories throughout pregnancy and their relevance to timing [7].

However, PUFAs are only composed of a small portion of fatty acids, leaving the majority unknown to the etiology of fetal development, such as saturated fatty acids (SFAs). SFAs are hydrogenated, solid at room temperature and highly correlated with dyslipidemia [1,8]. Animal dam models have suggested that SFAs can change the biological mechanisms of the pancreas, liver and adipose tissue in pups, such as the hypertrophy of pancreatic islets [9], proinflammatory status and insulin resistance [10] and greater body weight [11,12]. Four studies on human subjects investigated the effect of SFAs (i.e., dietary, erythrocyte levels and plasma metabolomics) on birth weight, yet the findings were equivocal. Two studies reported an inverse relationship between higher maternal erythrocyte SFAs during mid-late pregnancy and a smaller weight at birth [13,14]. On the contrary, two studies showed that maternal plasma or dietary SFAs are associated with an increased sum of skinfold at birth and a lower risk of smaller-than-gestational-age (SGA) neonates at birth [15,16]. In addition, labeling SFAs as harmful to human metabolism has been disapproved by emerging evidence because it does not differentiate the protective effect of odd-chain SFAs from the overall detrimental effect of even-chain SFAs on cardiometabolic health [17].

The existing significant knowledge gap lies in a few aspects of research on SFAs with fetal development: (1) Current studies only use birth weight as a proxy for in utero growth, which is inaccurate and may not reflect the relevance of timing in fetal growth. (2) Most observational studies assessing SFAs via dietary questionnaires are subject to self-reporting information bias [18,19]. (3) Research on maternal plasma phospholipid SFA compositions (i.e., even-chain, very long even-chain, odd-chain) during early pregnancy is sparse. Therefore, in order to understand the underlying physiology of different high-fat diets and fetal growth, as well as the relevance of timing, we explored associations and their relevance to the timing between maternal plasma phospholipid SFA compositions in early pregnancy and fetal growth trajectories throughout pregnancy, by utilizing data from a US multi-racial/ethnic birth cohort.

2. Materials and Methods

2.1. Study Population and Design

This study was based on data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies—Singletons cohort. The prospective cohort comprised 2802 pregnant women from 12 clinical centers across the United States. Pregnant subjects were recruited if they were 18–40 years of age, were within 8–13 weeks of gestation and did not have major pre-existing chronic diseases, such as diabetes and cancer. We registered the study in the Clinical Trial Registry (NCT00912132) and published the detailed recruitment and study protocol elsewhere [20]. We included 321 women from a nested case–control study for analysis based on the primary cohort. Among them, 107 had GDM, diagnosed according to the Carpenter and Coustan criteria following the recommendations of the American College of Obstetrics and Gynecologists (ACOG), and 214 were non-GDM controls. The ratio of women with GDM and non-GDM controls was 1:2. They were matched according to maternal age (±2 years), self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian/Pacific Islander) and gestational age (GA) at blood collection (±2 weeks).

The institutional review boards at all participating sites approved both the primary and sub-study. All participants provided written informed consent prior to data collection. The participating clinical centers entered study documents and data, including ultrasound measurements and images, into the Clinical Trial Management System, which were then electronically transferred to the Data Coordinating Center.

2.2. Assessments of Plasma Phospholipid Saturated Fatty Acids (SFAs)

Upon enrollment at 8–13 weeks of gestation (visit 0), we collected blood from all participants and stored biospecimens at −80 °C until thawing prior to the assay. Phospholipid fatty acid profiles were extracted using a previously described method [21,22]. Briefly, lipids were extracted with chloroform/methanol, separated using thin-layer chromatography, and the phospholipid batch was derivatized to methyl esters. The final product was injected into a capillary Varian Cp7420 30-m column with a Hewlett Packard 5890 gas chromatograph with flame ionization detection, interphased with HP Chemstation software A.06. All SFA components were calculated in percentages (%) referencing the total weight of the plasma phospholipid FA fraction. The analytic assessments and inter-assay coefficients of variation (CVs) for all SFAs in the same cohort were published elsewhere [23]. We identified eight plasma phospholipid SFAs and 3 SFA-derived indices, including the sum of even-chain SFAs: myristic acid (14:0), palmitic acid (16:0) and stearic acid (18:0); the sum of odd-chain SFAs: pentadecanoic acid (15:0) and heptadecanoic acid (17:0); and the sum of very long even-chain SFAs: arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Table S1 shows the weight of the percentages of all SFAs among all plasma phospholipid FA fractions.

2.3. Fetal Growth Measurement throughout Pregnancy (10–40 Weeks of Gestational Age)

Women received an ultrasonographic examination at enrollment 8–13 weeks into gestation (visit 0) and another one at four following ultrasonography schedules via randomization, as follows: weeks 16, 24, 30, 34 and 38 (group A); weeks 18, 26, 31, 35 and 39 (group B); weeks 20, 28, 32, 36 and 40 (group C); and weeks 22, 29, 33, 37 and 41 (group D), as stated in Table S2 and Figure S1. All study visits allowed ±1 week of the targeted GA to accommodate the subjects’ availability. We captured weekly fetal growth data in a mixed longitudinal randomization scheme without exposing individual women to ultrasound every week [24].

At each ultrasonographic examination, trained sonographers performed standard operating procedures using identical equipment (Voluson E8; GE Healthcare, Boston, MA, USA) and assessed a series of fetal growth biometrics, including head circumference (HC, mm), biparietal diameter (BPD, mm), abdominal circumference (AC, mm), femur length (FL, mm) and HC/AC ratio. We then calculated the estimated fetal weight (EFW, g) using a Hadlock formula based on HC, AC and FL [25]. Furthermore, measurement errors in terms of fetal growth biometrics were minimized in our study due to high inter- and intra-grader reliability reported in our study, regardless of maternal obesity status [24].

2.4. Covariates

At study entry, trained research coordinators interviewed participants to collect information on maternal demographics, pregnancy history and lifestyle behaviors, as well as blood pressure measurements, anthropometric indices and infant sex from medical records. We calculated GA at delivery based on the ultrasound-verified last menstrual period (LMP) of mothers and the date of delivery. Among all covariates of interest, we identified maternal pre-pregnancy body mass index (BMI) as a key covariate [26]. Despite having matched maternal age and race/ethnicity between cases and controls, we continued to control for maternal age and race/ethnicity to obtain conservative estimates. We applied a final adjustment model for all statistical analyses, including maternal age, race/ethnicity, nulliparity, pre-pregnancy BMI and infant sex.

2.5. Statistical Analysis

Because our study participants diagnosed with GDM (107 out of 321, 33.3%) were overrepresented compared with the general pregnant population in the US (107 out of 2802, 4%), we re-weighted all assessments following the idea of pseudolikelihood by Samuelsen (1997) [27] to represent the full cohort [24,28]. We used descriptive statistics to summarize crude and weighted characteristics of women and their neonates in the primary and nested case–control cohort (Table S3).

Tertiles of individual SFAs were treated as independent variables, and trajectories of all fetal biometrics were treated as dependent variables and modeled using a cubic spline model estimated using a restricted maximum likelihood approach [29]. Because of the skewed distribution of all fetal growth biometrics, we then log-transformed all assessments to stabilize variances across GA with an approximate normal distribution. The model initially included fixed effects of the linear, quadratic and cubic terms and cubic spline terms of GA (3 knots at the 25th, 50th and 75th percentiles), as well as a random intercept and random effects of the linear, quadratic, and cubic terms and cubic spline terms of weekly GA. The random effect covariance was unstructured, and the random effect of the cubic spline term of weekly GA was removed to facilitate model convergence.

We first applied global testing to investigate the overall difference in fetal growth trajectories across tertiles of SFAs in the full model. Then, we calculated the log–likelihood ratio by adding an interaction term between SFA tertiles and GA followed by Bonferroni correction [30]. Once a significant association was identified from all the steps mentioned above, we calculated the weekly means (back-transform fetal biometrics) and compared weekly differences in fetal growth biometrics across tertiles of each SFA (using the lowest tertile as a reference) in the full model using the Wald test. We further adjusted for family history of diabetes, maternal random glucose level at enrollment, maternal total cholesterol level at enrollment and sum of other SFA subgroups at visit 0 in the sensitivity analyses. We conducted all the analyses using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R Software (version 4.2.1). We reported all estimates with a 95% confidence interval (CI) or p-value. We defined significance as a two-tailed p-value of 0.05.

3. Results

All SFAs and sums of SFA subgroups were significantly associated with fetal weight and size, with at least two or more fetal growth parameters, even after Bonferroni correction (Table 1 and Table S4). Among all SFAs, myristic acid (14:0), pentadecanoic acid (15:0), stearic acid (18:0), lignoceric acid (24:0) and the sum of odd-chain SFAs were consistently and significantly associated with all fetal growth biometrics (p < 0.05).

Table 1.

Summary of significant (Bonferroni corrected p-values < 0.05) impact of increased plasma phospholipid saturated fatty acids during early pregnancy on individual fetal biometric velocity throughout pregnancy (10–40 weeks of gestation).

Saturated Fatty Acids EFW AC FL HC BPD
Myristic acid (14:0) ↓ ↓ ↓ ↓ ↓
Pentadecanoic acid (15:0) ↑ ↑ ↑ ↑ ↑
Palmitic acid (16:0) n.s. ↓ n.s. n.s. n.s.
Heptadecanoic acid (17:0) ↑ ↑ ↑ ↑ ↑
Stearic acid (18:0) ↓ ↓ ↓ ↓ ↓
Arachidic acid (20:0) n.s. n.s. ↓ ↓ ↓
Behenic acid (22:0) ↓ ↓ n.s. ↓ ↓
Lignoceric acid (24:0) ↓ ↓ ↓ ↓ ↓
Sum of even-chain SFAs
(14:0 + 16:0 + 18:0) 		↓ ↓ ↓ ↓ ↓
Sum of odd-chain SFAs
(15:0 + 17:0) 		↑ n.s. ↑ ↑ ↑
Sum of very long even-chain SFAs (20:0 + 22:0 + 24:0) ↓ ↓ n.s. ↓ ↓
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Abbreviations: EFW, estimated fetal weight; AC, abdominal circumference; FL, femur length; HC, head circumference; BPD, biparietal diameter; n.s., non-significant. “↑” indicates a positive association. “↓” indicates an inverse association.

3.1. Even-Chain SFAs and Fetal Growth

Overall, plasma phospholipid even-chain SFA levels were inversely associated with fetal growth throughout pregnancy. Among three even-chain SFAs, myristic acid (14:0) and stearic acid (18:0) were associated with all fetal growth parameters, whereas palmitic acid (16:0) was only associated with AC. Compared with the lowest tertile, the highest tertile of plasma phospholipid myristic acid (14:0) was significantly associated with a decrement in FL and HC, starting in early pregnancy (FL at week 11: 4.11 vs. 4.43 mm, p = 0.05; HC at week 10: 47.05 vs. 55.24 mm, p < 0.00001) and attenuating in early-mid pregnancy (FL at week 15: 12.45 vs. 13.10 mm, p = 0.06; HC at week 17: 137.85 vs. 135.86 mm, p = 0.06) (Table S5A,B and Figure S2). Interestingly, the second tertile of myristic acid (14:0) had a stronger and longer impact on reduced EFW and AC than that of the highest tertile compared with the lowest tertile, starting in early-mid pregnancy (EFW at week 17: 174.76 vs. 181.71 g, p = 0.04; AC at week 13: 66.69 vs. 68.16 mm, p = 0.04) and attenuating in late pregnancy (EFW at week 39: 3331.94 vs. 3490.46 g, p = 0.08; AC at week 39: 348.05 vs. 356.81 mm, p = 0.09) (Table S5A and Figure S2).

Similarly, stearic acid (18:0) showed a comparable magnitude in the second tertile and highest tertiles in terms of EFW, AC, FL, HC and BPD. For example, compared with the lowest tertile, the highest tertile of stearic acid (18:0) was associated with a decrement in HC and BPD, starting from early pregnancy (HC at week 13: 83.4 vs. 85.46 mm, p = 0.0008; BPD at week 12: 18.86 vs. 19.35 mm, p = 0.04) and attenuating in mid-pregnancy (HC at week 18: 147.64 vs. 149.62 mm, p = 0.09; BPD at week 20: 46.37 vs. 47.06 mm, p = 0.10) (Table 2 and Figure S2). Compared with the lowest tertile, the second tertile of stearic acid (18:0) was also associated with a decrement yet with a longer duration in EFW and AC than that of the highest tertile, starting from early pregnancy (EFW at week 30: 1453.76 vs. 1511.69 g, p = 0.03; AC at week 13: 67.74 vs. 70.16 mm, p = 0.0005) and ending in late pregnancy (EFW: 3222.27 vs. 3731.17 g, p = 0.005; AC at week 40: 344.71 vs. 365.62 mm, p = 0.05) (Table 2 and Figure S2).

Table 2.

Back-transformed and pairwise comparison of weekly fetal growth biometrics across stearic acid (18:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort.

GW Estimated Fetal Weight (EFW), g Abdominal Circumference (AC), mm Femur Length (FL), mm
Back-Transformed Geometric Mean
g		 Wald Test for Pairwise Comparison
p-Value		 Back-Transformed Geometric Mean
mm		 Wald Test for Pairwise Comparison
p-Value		 Back-Transformed Geometric Mean mm Wald Test for Pairwise Comparison
p-Value
1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile
10 35.13 36.03 40.58 0.715 0.061 36.05 39.4 41.87 0.059 0.004 2.01 2.42 2.47 0.002 <0.001
11 43.92 44.69 47.72 0.628 0.049 46.55 47.87 49.18 0.258 0.050 3.76 4.26 4.17 <0.001 0.004
12 55.41 56.03 57.51 0.552 0.071 58.04 57.34 57.49 0.328 0.482 6.26 6.78 6.47 <0.0001 0.199
13 70.34 70.77 70.67 0.724 0.749 70.16 67.74 66.81 <0.001 <0.0001 9.41 9.84 9.31 0.017 0.661
14 89.54 89.74 88.09 0.913 0.348 82.55 78.95 77.12 0.0001 <0.0001 12.93 13.20 12.55 0.313 0.199
15 113.93 113.85 110.79 0.970 0.142 94.88 90.82 88.35 <0.001 <0.0001 16.54 16.61 15.99 0.819 0.158
16 144.43 144.03 139.87 0.880 0.082 106.94 103.17 100.36 <0.001 <0.0001 19.97 19.87 19.45 0.801 0.260
17 181.81 181.07 176.34 0.815 0.074 118.65 115.76 112.95 0.016 <0.0001 23.12 22.89 22.8 0.591 0.539
18 226.55 225.46 220.87 0.788 0.121 130.09 128.38 125.84 0.203 <0.001 26.06 25.75 26.00 0.509 0.918
19 278.72 277.29 273.47 0.783 0.249 141.4 140.77 138.69 0.676 0.049 28.99 28.60 29.12 0.472 0.825
20 338.68 336.91 334.13 0.780 0.415 152.59 152.79 151.26 0.901 0.369 31.91 31.46 32.19 0.448 0.677
21 406.89 404.73 403.28 0.771 0.587 163.59 164.35 163.45 0.651 0.927 34.79 34.29 35.16 0.428 0.609
22 483.83 481.12 481.37 0.750 0.751 174.39 175.38 175.19 0.554 0.605 37.59 37.07 38.01 0.415 0.598
23 570.04 566.42 568.87 0.713 0.897 185.00 185.91 186.47 0.595 0.354 40.30 39.75 40.71 0.415 0.630
24 666.15 660.99 666.34 0.660 0.986 195.46 195.98 197.32 0.775 0.267 42.90 42.33 43.25 0.433 0.688
25 772.94 765.21 774.49 0.586 0.905 205.83 205.68 207.83 0.942 0.275 45.36 44.79 45.66 0.462 0.756
26 891.44 879.55 894.24 0.485 0.857 216.21 215.17 218.11 0.634 0.343 47.70 47.13 47.94 0.491 0.814
27 1022.98 1004.62 1026.83 0.354 0.833 226.74 224.64 228.36 0.362 0.448 49.92 49.33 50.13 0.505 0.841
28 1169.33 1141.22 1173.91 0.203 0.826 237.57 234.31 238.79 0.153 0.574 52.02 51.41 52.28 0.496 0.818
29 1332.26 1290.44 1337.56 0.082 0.818 248.84 244.36 249.65 0.040 0.699 54.04 53.39 54.43 0.463 0.730
30 1511.69 1453.76 1518.15 0.032 0.802 260.44 254.82 260.96 0.010 0.797 55.98 55.28 56.61 0.439 0.600
31 1706.19 1633.15 1713.46 0.023 0.808 272.16 265.72 272.52 0.007 0.869 57.86 57.14 58.75 0.453 0.481
32 1913.17 1831.17 1919.6 0.032 0.857 283.76 277.07 284.05 0.014 0.909 59.71 59.01 60.82 0.503 0.408
33 2128.69 2051.11 2130.77 0.077 0.960 294.98 288.87 295.25 0.038 0.922 61.55 60.94 62.75 0.581 0.395
34 2347.34 2297.17 2339.22 0.292 0.858 305.51 301.17 305.78 0.130 0.921 63.42 62.99 64.49 0.704 0.465
35 2563.79 2567.88 2536.39 0.938 0.575 315.13 313.79 315.28 0.639 0.955 65.31 65.21 65.98 0.929 0.663
36 2778.72 2841.97 2724.29 0.315 0.329 324.18 325.9 323.93 0.614 0.936 67.13 67.43 67.22 0.804 0.956
37 2995.99 3086.12 2914.31 0.221 0.210 333.14 336.32 332.4 0.424 0.834 68.72 69.39 68.30 0.626 0.803
38 3221.46 3258.69 3121.99 0.633 0.163 342.6 343.79 341.43 0.761 0.746 69.93 70.81 69.33 0.528 0.732
39 3463.07 3315.86 3367.49 0.126 0.229 353.19 346.99 351.89 0.202 0.741 70.59 71.37 70.42 0.631 0.925
40 3731.17 3222.27 3677.29 0.005 0.685 365.62 344.71 364.73 0.053 0.914 70.56 70.82 71.69 0.933 0.614
GW Head Circumference (HC), mm Biparietal Diameter (BPD), mm HC/AC Ratio
Back-Transformed Geometric Mean
mm 		Wald Test for Pairwise Comparison
p-Value 		Back-Transformed Geometric Mean
mm 		Wald Test for Pairwise Comparison
p-Value 		Back-Transformed Geometric Mean Wald Test for Pairwise Comparison
p-Value
1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile
10 46.38 51.84 49.12 <0.001 0.141 11.36 12.86 12.24 <0.001 0.111 1.27 1.31 1.18 0.338 0.041
11 58.7 62.51 59.75 0.0001 0.402 15.21 16.13 15.42 0.003 0.580 1.26 1.31 1.22 0.066 0.080
12 71.87 73.99 71.25 <0.001 0.394 19.35 19.64 18.86 0.131 0.036 1.25 1.29 1.24 <0.001 0.427
13 85.46 86.10 83.40 0.303 <0.001 23.55 23.29 22.43 0.174 <0.0001 1.24 1.27 1.25 <0.0001 0.119
14 99.05 98.64 96.02 0.613 <0.001 27.61 26.99 26.06 0.014 <0.0001 1.22 1.25 1.24 0.004 0.011
15 112.36 111.42 108.90 0.319 <0.001 31.39 30.64 29.66 0.011 <0.0001 1.21 1.23 1.23 0.034 0.009
16 125.19 124.26 121.87 0.338 0.003 34.84 34.20 33.17 0.037 <0.0001 1.19 1.21 1.21 0.130 0.017
17 137.56 137.04 134.81 0.604 0.014 38.00 37.65 36.57 0.263 <0.0001 1.18 1.18 1.19 0.419 0.069
18 149.62 149.66 147.64 0.975 0.090 41.00 40.98 39.88 0.961 0.002 1.17 1.17 1.17 0.929 0.369
19 161.63 162.06 160.34 0.727 0.311 44.01 44.24 43.14 0.551 0.027 1.16 1.15 1.16 0.634 0.988
20 173.56 174.16 172.87 0.651 0.612 47.06 47.42 46.37 0.385 0.096 1.15 1.14 1.14 0.357 0.463
21 185.33 185.88 185.12 0.689 0.881 50.13 50.50 49.54 0.380 0.170 1.14 1.13 1.13 0.197 0.190
22 196.89 197.18 197.03 0.830 0.921 53.20 53.47 52.65 0.514 0.206 1.14 1.12 1.12 0.118 0.079
23 208.16 208.05 208.54 0.940 0.799 56.24 56.34 55.68 0.819 0.203 1.13 1.12 1.12 0.096 0.042
24 219.11 218.50 219.62 0.693 0.743 59.24 59.11 58.62 0.777 0.184 1.13 1.12 1.11 0.127 0.039
25 229.7 228.59 230.28 0.507 0.733 62.18 61.82 61.48 0.465 0.169 1.12 1.11 1.11 0.236 0.058
26 239.92 238.4 240.53 0.401 0.741 65.02 64.48 64.26 0.304 0.165 1.12 1.11 1.10 0.470 0.108
27 249.78 248.03 250.44 0.360 0.738 67.77 67.13 66.97 0.250 0.173 1.11 1.11 1.10 0.879 0.200
28 259.29 257.63 260.06 0.385 0.701 70.39 69.81 69.64 0.292 0.201 1.10 1.10 1.09 0.548 0.353
29 268.47 267.25 269.49 0.509 0.604 72.87 72.54 72.26 0.525 0.284 1.08 1.09 1.08 0.100 0.589
30 277.28 276.73 278.69 0.770 0.467 75.22 75.27 74.85 0.916 0.504 1.07 1.09 1.07 0.006 0.912
31 285.67 285.91 287.51 0.909 0.369 77.45 77.95 77.36 0.372 0.876 1.05 1.08 1.05 <0.001 0.771
32 293.58 294.56 295.77 0.668 0.334 79.58 80.52 79.74 0.141 0.810 1.04 1.06 1.04 <0.001 0.571
33 300.97 302.48 303.30 0.530 0.342 81.65 82.90 81.94 0.062 0.668 1.02 1.05 1.03 0.002 0.455
34 307.79 309.43 309.89 0.485 0.396 83.66 85.02 83.93 0.035 0.703 1.01 1.03 1.01 0.013 0.370
35 313.98 315.23 315.37 0.597 0.564 85.64 86.81 85.64 0.066 0.997 1.00 1.00 1.00 0.356 0.302
36 319.41 319.81 319.79 0.883 0.885 87.50 88.24 87.08 0.327 0.569 0.98 0.98 0.99 0.561 0.276
37 323.93 323.15 323.39 0.795 0.856 89.10 89.26 88.26 0.850 0.336 0.97 0.96 0.98 0.255 0.233
38 327.41 325.27 326.46 0.472 0.758 90.33 89.87 89.23 0.582 0.219 0.95 0.95 0.96 0.568 0.114
39 329.69 326.16 329.28 0.334 0.898 91.04 90.02 90.03 0.335 0.272 0.93 0.94 0.94 0.119 0.052
40 330.64 325.86 332.16 0.515 0.788 91.13 89.72 90.69 0.541 0.810 0.89 0.95 0.91 0.009 0.214
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HC/AC ratio, head circumference/abdominal circumference ratio.

Unlike myristic acid (14:0) and stearic acid (18:0), palmitic acid (16:0) was associated with a reduced AC in the fetus during mid-pregnancy. Compared with the lowest tertile, the highest tertile of palmitic acid (16:0) was associated with a reduced AC from week 18 (125.8 vs. 129.4 mm, p = 0.02) to week 23 (182.41 vs. 186.54 mm, p = 0.07) (Table S6).

Regarding the sum of even-chain SFAs, compared with the lowest tertile, the highest tertile was significantly associated with a reduced fetal weight and size, starting from early pregnancy (EFW at week 13: 68.47 vs. 71.53 g, p = 0.03; AC at week 16: 102.35 vs. 105.64 mm, p = 0.03; FL at week 14: 9.12 vs. 9.63 mm, p = 0.009) to mid-pregnancy (EFW at week 19: 268.51 vs. 279.3 g, p = 0.07; AC at week 21: 160.32 vs. 164.22 mm, p = 0.08; FL at week 19: 28.33 vs. 29.15 mm, p = 0.15) (Table S7 and Figure S3).

3.2. Odd-Chain SFAs and Fetal Growth

In contrast to even-chain SFAs, higher levels of individual and subgroup odd-chain SFAs were associated with a larger fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) was associated with a larger EFW, AC, FL, HC and BPD throughout pregnancy, starting from early pregnancy (EFW at week 13: 73.22 vs. 67.03 g, p < 0.00001; AC at week 12: 59.13 vs. 56.77 mm, p = 0.002; FL at week 16.16 vs. 15.49 mm, p = 0.05; HC at week 13: 87.23 vs. 83.29 mm, p < 0.00001; BPD at week 12: 19.97 vs. 19.44 mm, p = 0.02) and attenuating in late pregnancy (EFW at week 36: 2778 vs. 2703.66 g, p = 0.14; AC at week 32: 282.88 vs. 277.97 mm, p = 0.07; FL at week 19: 29.12 vs. 28.06, p = 0.07; HC at week 39: 328.14 vs. 323 mm, p = 0.13; BPD at week 40: 92.66 vs. 88.91 mm, p = 0.07) (Table 3 and Figure 1).

Table 3.

Back-transformed and pairwise comparison of weekly fetal growth biometrics across pentadecanoic acid (15:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort.

GW Estimated Fetal Weight (EFW), g Abdominal Circumference (AC), mm Femur Length (FL), mm
Back-Transformed Geometric Mean
g		 Wald Test for Pairwise Comparison
p-Value		 Back-Transformed Geometric Mean mm Wald Test for Pairwise Comparison
p-Value		 Back-Transformed Geometric Mean Wald Test for Pairwise Comparison
p-Value
1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile
10 41.85 32.27 35.96 0.001 0.109 43.76 36.67 38.62 <0.001 0.021 2.68 2.14 2.57 <0.001 0.525
11 47.07 42.06 45.36 0.008 0.461 49.66 46.25 48.40 0.005 0.370 4.37 3.9 4.33 0.002 0.782
12 55.24 54.46 57.54 0.520 0.083 56.77 56.82 59.13 0.948 0.002 6.59 6.38 6.67 0.169 0.602
13 67.03 70.05 73.22 0.021 <0.0001 65.17 68.13 70.59 <0.0001 <0.0001 9.27 9.47 9.53 0.321 0.176
14 83.38 89.46 93.22 0.001 <0.0001 74.88 79.96 82.52 <0.0001 <0.0001 12.29 12.95 12.76 0.024 0.086
15 105.35 113.42 118.45 0.001 <0.0001 85.83 92.07 94.68 <0.0001 <0.0001 15.49 16.52 16.16 0.006 0.058
16 134.02 142.69 149.83 0.003 <0.0001 97.84 104.28 106.87 <0.0001 <0.0001 18.71 19.94 19.55 0.005 0.045
17 170.13 178.10 188.18 0.025 <0.0001 110.55 116.46 118.94 <0.0001 <0.0001 21.88 23.08 22.83 0.014 0.043
18 213.64 220.47 234.09 0.125 <0.0001 123.42 128.58 130.81 <0.0001 <0.0001 24.98 25.99 25.99 0.066 0.054
19 263.96 270.61 287.73 0.235 <0.0001 135.99 140.67 142.49 0.001 <0.0001 28.06 28.83 29.12 0.212 0.072
20 321.22 329.34 349.24 0.233 <0.0001 148.1 152.67 153.95 0.004 <0.001 31.09 31.67 32.21 0.391 0.085
21 385.65 397.50 419.03 0.143 <0.0001 159.65 164.49 165.14 0.003 0.001 34.02 34.49 35.22 0.529 0.091
22 457.56 475.86 497.51 0.054 <0.0001 170.60 176.09 176.03 0.001 0.002 36.84 37.25 38.11 0.600 0.093
23 537.39 565.13 585.13 0.013 <0.0001 181.00 187.43 186.61 0.0001 0.001 39.51 39.93 40.86 0.608 0.095
24 625.81 665.91 682.42 0.003 <0.0001 190.94 198.52 196.94 <0.0001 0.001 42.04 42.53 43.45 0.575 0.101
25 723.81 778.66 790.04 <0.001 <0.0001 200.59 209.38 207.09 <0.0001 0.001 44.43 45.03 45.89 0.525 0.116
26 832.86 903.68 908.87 <0.001 <0.0001 210.16 220.08 217.15 <0.0001 0.002 46.72 47.44 48.18 0.477 0.140
27 955.00 1041.11 1040.08 <0.001 <0.0001 219.93 230.70 227.27 <0.0001 0.002 48.94 49.77 50.35 0.445 0.177
28 1093.05 1190.85 1185.24 <0.001 <0.0001 230.24 241.37 237.64 <0.0001 0.002 51.14 52.02 52.44 0.437 0.234
29 1249.44 1352.64 1346.23 <0.001 <0.0001 241.38 252.19 248.44 <0.0001 0.002 53.38 54.22 54.48 0.472 0.328
30 1424.33 1526.24 1523.6 0.001 <0.0001 253.23 263.13 259.70 <0.0001 0.003 55.65 56.36 56.5 0.553 0.471
31 1616.67 1711.36 1716.02 0.010 <0.0001 265.53 274.09 271.24 <0.001 0.016 57.92 58.46 58.47 0.667 0.656
32 1824.08 1907.67 1921.04 0.054 0.003 277.97 284.97 282.88 0.008 0.072 60.13 60.52 60.39 0.778 0.845
33 2042.57 2114.8 2134.87 0.149 0.014 290.17 295.64 294.36 0.060 0.162 62.25 62.54 62.26 0.847 0.997
34 2266.30 2332.40 2352.27 0.231 0.030 301.70 305.99 305.42 0.138 0.214 64.23 64.52 64.07 0.847 0.909
35 2488.31 2559.63 2567.07 0.234 0.055 312.14 315.92 315.78 0.170 0.208 66.01 66.48 65.81 0.760 0.888
36 2703.66 2791.87 2778.00 0.197 0.137247 321.54 325.70 325.45 0.185 0.238 67.58 68.4 67.48 0.619 0.947
37 2908.15 3021.68 2988.34 0.152 0.194177 330.17 335.75 334.58 0.139 0.259 68.93 70.23 69.09 0.466 0.925
38 3097.81 3239.88 3203.25 0.102 0.104549 338.36 346.56 343.40 0.036 0.201 70.05 71.94 70.64 0.306 0.733
39 3269.08 3435.79 3429.89 0.076 0.039051 346.46 358.67 352.13 0.003 0.211 70.94 73.48 72.15 0.194 0.522
40 3418.87 3597.76 3677.57 0.171 0.129976 354.87 372.73 361.06 0.026 0.524 71.61 74.8 73.62 0.272 0.483
GW Head Circumference (HC), mm Biparietal Diameter (BPD), mm HC/AC Ratio
Back-Transformed Geometric Mean
mm 		Wald Test for Pairwise Comparison
p-Value 		Back-Transformed Geometric Mean mm Wald Test for Pairwise Comparison
p-Value 		Back-Transformed Geometric Mean Wald Test for Pairwise Comparison
p-Value
1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile 1st Tertile 2nd Tertile 3rd Tertile 2nd vs. 1st Tertile 3rd vs. 1st Tertile
10 58.71 43.93 52.76 <0.0001 0.013 14.20 10.88 13.10 <0.0001 0.096 1.33 1.18 1.39 <0.001 0.348
11 65.57 56.76 63.50 <0.0001 0.155 16.69 14.64 16.42 <0.0001 0.522 1.32 1.22 1.32 <0.0001 0.870
12 73.76 70.50 75.05 0.0001 0.096 19.44 18.73 19.97 0.001 0.021 1.30 1.24 1.27 <0.0001 0.053
13 83.29 84.60 87.23 0.136 <0.0001 22.43 22.90 23.64 0.034 <0.0001 1.28 1.25 1.24 <0.001 <0.0001
14 94.17 98.53 99.83 <0.0001 <0.0001 25.65 26.95 27.34 <0.0001 <0.0001 1.26 1.24 1.21 0.0607 <0.0001
15 106.28 111.94 112.69 <0.0001 <0.0001 29.04 30.74 30.99 <0.0001 <0.0001 1.24 1.22 1.19 0.114 <0.0001
16 119.39 124.62 125.63 0.0001 <0.0001 32.55 34.19 34.53 <0.0001 <0.0001 1.22 1.20 1.17 0.032 <0.0001
17 133.11 136.61 138.53 0.016 <0.0001 36.12 37.33 37.94 0.002 <0.0001 1.20 1.18 1.16 0.001 <0.0001
18 146.86 148.17 151.31 0.412 <0.001 39.65 40.27 41.24 0.146 <0.0001 1.19 1.15 1.16 <0.0001 <0.001
19 160.18 159.72 163.93 0.789 0.007 43.08 43.20 44.50 0.799 0.001 1.18 1.14 1.15 <0.0001 0.005
20 172.91 171.41 176.35 0.423 0.021 46.38 46.19 47.72 0.704 0.003 1.17 1.12 1.15 <0.0001 0.026
21 184.95 183.16 188.47 0.367 0.021 49.52 49.21 50.90 0.553 0.003 1.16 1.11 1.14 <0.0001 0.069
22 196.25 194.9 200.23 0.514 0.010 52.51 52.25 54.02 0.642 0.001 1.15 1.10 1.14 <0.0001 0.141
23 206.85 206.54 211.59 0.887 0.003 55.34 55.30 57.06 0.940 <0.001 1.14 1.10 1.13 <0.0001 0.252
24 216.83 218.01 222.51 0.614 <0.001 58.04 58.33 60.03 0.650 0.0001 1.14 1.10 1.13 <0.0001 0.406
25 226.31 229.22 233.01 0.250 <0.001 60.64 61.33 62.91 0.322 <0.0001 1.13 1.09 1.13 <0.0001 0.582
26 235.48 240.11 243.12 0.089 0.0001 63.19 64.28 65.70 0.149 <0.0001 1.12 1.09 1.12 <0.0001 0.751
27 244.58 250.59 252.88 0.036 <0.0001 65.73 67.16 68.43 0.076 <0.0001 1.11 1.08 1.11 0.0001 0.905
28 253.86 260.60 262.37 0.022 <0.0001 68.34 69.94 71.08 0.052 <0.0001 1.10 1.08 1.10 <0.001 0.937
29 263.44 270.09 271.68 0.026 <0.0001 71.04 72.62 73.69 0.057 <0.0001 1.09 1.07 1.09 0.001 0.770
30 273.10 279.01 280.74 0.056 <0.0001 73.77 75.18 76.23 0.100 <0.0001 1.08 1.06 1.08 0.002 0.634
31 282.54 287.36 289.40 0.143 <0.001 76.45 77.60 78.66 0.214 <0.001 1.06 1.05 1.07 0.016 0.577
32 291.43 295.10 297.48 0.298 0.008 78.99 79.87 80.97 0.384 0.004 1.05 1.04 1.05 0.088 0.589
33 299.38 302.26 304.79 0.441 0.027 81.28 81.98 83.11 0.572 0.015 1.03 1.02 1.04 0.270 0.633
34 306.02 308.83 311.15 0.462 0.031 83.23 83.93 85.04 0.523 0.013 1.02 1.01 1.02 0.621 0.706
35 311.07 314.80 316.38 0.336 0.020 84.74 85.70 86.73 0.387 0.004 1.00 1.00 1.00 0.764 0.850
36 314.81 319.88 320.52 0.216 0.027 85.89 87.27 88.20 0.246 0.004 0.99 0.99 0.98 0.384 0.950
37 317.72 323.72 323.74 0.174 0.045 86.76 88.62 89.47 0.159 0.003 0.97 0.98 0.97 0.374 0.786
38 320.28 325.94 326.21 0.216 0.049 87.48 89.70 90.61 0.103 0.001 0.95 0.96 0.95 0.700 0.618
39 323.00 326.17 328.14 0.500 0.127 88.15 90.50 91.65 0.099 0.001 0.94 0.93 0.93 0.321 0.560
40 326.42 324.09 329.75 0.702 0.628 88.91 90.99 92.66 0.314 0.074 0.92 0.89 0.91 0.064 0.750
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HC/AC ratio, head circumference/abdominal circumference ratio.

Figure 1.

Figure 1

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Back-transformed geometric means of estimated fetal weight and abdominal circumference by gestational weeks to tertiles of pentadecanoic acid (15:0) within the NICHD Fetal Growth Studies—Singletons cohort, 10–40 weeks of gestational age. The 1st (lowest) tertile curve is in blue, the 2nd (middle) tertile curve is in red, and the 3rd (highest) tertile is in green. The gray shaded area and the blown-up graph on the right indicate a significant increment in estimated fetal weight from 13 to 35 week of gestation (A), and a significant increment in abdominal circumference from 12 to 31 weeks of gestation (B) in both the 2nd and 3rd tertiles, compared with the 1st tertile.

Even though there were similar effect sizes, heptadecanoic acid (17:0) exerted a relatively smaller impact on fetal growth than that of pentadecanoic acid (15:0). For instance, compared with the lowest tertile, the highest tertile of heptadecanoic acid (17:0) was associated with EFW, AC, FL, HC and BPD since early-mid pregnancy, yet it attenuated in mid-late pregnancy (EFW at week 23: 580.65 vs. 555.66 g, p = 0.10; AC at week 23: 188.71 vs. 184.96 mm, p = 0.12; FL at week 24: 43.31 vs. 42.02 mm, p = 0.09; HC at week 30: 281.54 vs. 276.73 mm, p = 0.06; BPD at week 33: 83.69 vs. 82.08 mm, p = 0.07) (Table S8 and Figure 2).

Figure 2.

Figure 2

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Back-transformed geometric means of femur length, head circumference and biparietal diameter by gestational weeks to tertiles of heptadecanoic acid (17:0) within the NICHD Fetal Growth Studies—Singletons cohort, 10–40 weeks gestational age. The 1st (lowest) tertile curve is in blue, the 2nd (middle) tertile curve is in red, and the 3rd (highest) tertile is in green. The gray shaded area and the blown-up graph on the right indicate a significant increment in estimated femur length from 19 to 23 week of gestation (A), a significant increment in head circumference from 20 to 29 weeks of gestation (B), and a significant increment in biparietal diameter from 20 to 32 weeks of gestation (C) in both the 2nd and 3rd tertiles, compared with the 1st tertile.

By combing pentadecanoic acid (15:0) and heptadecanoic acid (17:0), the sum of odd-chain SFAs was found to be significant with a larger EFW, FL, HC and BPD, but not with AC. Compared with the lowest tertile, the highest tertile of the sum of SFAs was associated with a greater fetal weight and size, only being significant starting from mid-pregnancy (EFW at week 17: 185.81 vs. 178.43 g, p = 0.03; FL at week 17: 23.14 vs. 22.03 mm, p = 0.02; HC at week 21: 187.27 vs. 184.11 mm, p = 0.03; BPD at week 18: 37.49 vs. 36.9 mm, p = 0.02) until the end of pregnancy (Table S9).

3.3. Very Long Even-Chain SFAs and Fetal Growth

Overall, higher levels of arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0) were associated with a reduced fetal weight and/or size. Compared with the lowest tertile, the highest tertile of lignoceric acid (24:0) was significantly associated with a reduced AC and BPD since early-mid pregnancy (AC at week 29: 257.99 vs. 265.45 mm, p = 0.01; BPD at week 18: 40.07 vs. 40.89 mm, p = 0.04), and such associations attenuated at the end of pregnancy (AC at week 40: 357.71 vs. 374.16 mm, p = 0.07; BPD at week 40: 87.08 vs. 93.7 mm, p = 0.001) (Table S10 and Figure S4A). Interestingly, the impacts of arachidic acid (20:0) and behenic acid (22:0) on reduced fetal weight and size were much weaker and shorter in duration (Tables S11 and S12).

In terms of the sum of very long even-chain SFAs, the impact on reduced fetal weight and size was more significant and longer in duration in the second tertile than that in the highest tertile, compared with the lowest tertile. For example, women in the second tertile of the sum of very long even-chain SFAs exerted an early-pregnancy decrement in fetal growth parameters (EFW at week 13: 68.5 vs. 71.38 g, p = 0.007; AC at week 10: 42.46 vs. 38.31 mm, p = 0.03; HC at week 13: 83.94 vs. 85.82 mm, p = 0.005; BPD at week 12: 19.22 vs. 19.68 mm, p = 0.03) in reference to the lowest tertile. All significant associations lasted until late pregnancy (EFW at week 30: 1463.47 vs. 1529.36 g, p = 0.08; AC at week 33: 290.07 vs. 295.33 mm, p = 0.06; HC at week 36: 315.98 vs. 320.83 mm, p = 0.08; BPD at week 34: 83.39 vs. 84.85 mm, m = 0.07) (Table S13 and Figure S4B).

The sensitivity analysis of additional adjustments on family history of diabetes, maternal plasma random glucose levels, total cholesterol levels and the sum of other subgroups of SFAs at visit 0 in the global test did not attenuate any significant associations in the relationships identified above (Tables S14–S17).

4. Discussion

Our prospective longitudinal data suggest opposite associations of subgroups of SFAs with fetal growth throughout pregnancy. Specifically, higher maternal plasma phospholipid odd-chain SFAs in early pregnancy were positively associated with fetal growth. In contrast, higher maternal plasma phospholipid even-chain and very long even-chain SFAs were inversely associated with fetal growth in early pregnancy. The relevance of timing in fetal growth increments or decrements with different subgroups of SFAs significantly started in early-mid pregnancy (10–15 weeks of gestation) and attenuated in mid-late pregnancy (23–40 weeks of gestation).

Traditional evidence indicates that SFAs are strongly associated with impaired insulin sensitivity, glucose intolerance and lipotoxicity, which could be biased by failing to separate the metabolic beneficial components, such as odd-chain SFAs, from conventional cardiometabolic risk components, such as even-chain SFAs [17]. However, instead of avoiding all high-fat diets, emerging research investigated the fat composition and differentiated the good high-fat pattern from the bad [31]. For example, maternal n-3 polyunsaturated fatty acids (PUFAs) levels were proven to be beneficial not only for cardiometabolic health in the general population [32] but also for fetal growth throughout pregnancy [33]. However, current evidence only focuses on growth biometrics after delivery, and the assessment of maternal SFAs is diverse in techniques and gestational age. Therefore, studies regarding plasma phospholipid maternal SFA compositions and fetal growth are sparse in the research scope.

Even-chain SFAs are FAs that are totally hydrogenated, with a linear chain without double bonds between carbon atoms. They are in a stable state at room temperature and include lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0) and stearic acid (18:0) [1]. All even-chain SFAs can be derived from both exogenous intake (e.g., Western diets rich in butter, palm oil and red meat) and endogeneous synthesis (e.g., the de novo lipogenesis [DNL] pathway) [34,35], from which palmitic acid (16:0) and stearic acid (18:0) were mainly synthesized. Such even-chain FAs seemed to mediate multiple biological mechanisms, including increasing oxidative stress [17], inducing insulin resistance via the proteasomal degradation of key insulin-signaling molecules [36] and activating proinflammatory signaling via Toll-like receptor 4 [37]. Our study found that the total sum of maternal even-chain SFAs during early pregnancy was associated with reduced fetal growth from early to mid-late pregnancy. Among them, myristic acid (14:0) and stearic acid (18:0) imposed a much stronger impact on fetal weight and size than that of palmitic acid (16:0). We speculated two possible underlying pathophysiological mechanisms to our observation. First, increased levels of different even-chain SFAs might be attributable to elevated levels of oxidative stress and inflammation in vivo [17,38], and such changes could viciously disrupt the placental circulation and supply of nutrients and oxygen that are vital for fetal growth. Second, it is suggested that placental tissue has lipoprotein receptors and expresses enzymes with lipase and phospholipase activities [39,40,41]. Such activities were involved in the mechanism of maternal FA transfer across the placenta to sustain the fetal lipid requirements. In other words, the elevation of even-chain SFAs might compete with other beneficial yet much larger molecules of FAs (e.g., n-3 PUFAs) through the placenta, indirectly contributing to inadequate fetal growth [13,14].

The origin of odd-chain SFAs has long been attributed to the diet, especially dairy product intake [42]. However, emerging evidence suggests that circulating pentadecanoic acid (15:0) and heptadecanoic acid (17:0) are independently derived. For instance, pentadecanoic acid (15:0) correlated directly with dietary intake, and heptadecanoic acid (17:0) is a product of biosynthesis regulated by dietary intake [43,44]. Several epidemiological studies have shown that both pentadecanoic acid (15:0) and heptadecanoic acid (17:0) have protective effects on glucose homeostasis via the inhibition of hepatic oxidation [45]. Therefore, odd-chain SFAs are inversely associated with metabolic diseases [46,47,48], including reducing the risk of type 2 diabetes (T2D) [17]. Our findings indicate a beneficial impact of elevated maternal plasma phospholipid odd-chain SFAs during early pregnancy and fetal growth throughout pregnancy, indirectly aligned with the optimal effect of odd-chain SFAs suggested a priori. For example, Santaren et al. suggested that circulating pentadecanoic acid (15:0) is inversely associated with plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) [49]. In another study by Zheng et al., research findings also indicated inverse associations between higher levels of odd-chain SFAs and lower levels of major lipids (i.e., total cholesterol, triglycerides, apolipoprotein A-1 and apolipoprotein B) and hepatic markers [50]. We postulate that odd-chain SFAs reduced the inflammation levels both in the maternal environment and placental perfusion, contributing to sufficient fetal nutrients and blood supply.

Regarding very long even-chain SFAs, they have not been extensively studied except for their known roles in hereditary peroxisomal disorders and special food formulations [51]. Common knowledge on very long even-chain SFAs suggests that they are derived from a limited food source, such as peanuts, macadamia nuts and canola oil [52], and from endogenous metabolism from stearic acid (18:0) [53]. Studies have shown that very long even-chain SFAs are the major components of insulin resistance and reduced β-cell mass and function [52,54,55]. Our cohort shows that the sum of very long even-chain SFAs, especially lignoceric acid (24:0), is associated with a reduced fetal weight and size, which might be related to inflammation and disrupted glycemic metabolism. However, emerging evidence suggests that circulating very long even-chain SFAs are protective against cardiovascular outcomes, such as incident heart failure, atrial fibrillation, coronary heart disease, sudden cardiac arrest and even better aging [51]. Further research on such SFA clusters regarding their biological functions and impacts on fetal growth and child health is warranted.

4.1. Clinical Implications

Our study investigated the relationship between maternal plasma phospholipid SFAs in early pregnancy and fetal growth trajectories throughout pregnancy and further identified the relevance of timing for significant associations, in a relatively healthier pregnant population in the US with a lower prevalence of GDM (~4%). Such results remain significant even after adjustment for family history of diabetes, maternal early pregnancy glucose, total cholesterol levels and other subgroups of SFAs. Therefore, findings from the present study are robust even for a generally healthy population with fewer pregnancy complications. Further, this study is able to differentiate the physiological roles of even-chain, odd-chain and very long even-chain SFAs underlying fetal growth throughout pregnancy. Most of our observations on fetal growth were significant from early to mid-pregnancy, a stage of which provided useful information for the development of pre-eclampsia and pre-term birth [56] and even for the assessment of weight at birth [57]. Key findings regarding the beneficial impact of pentadecanoic acid (15:0) and heptadecanoic acid (17:0) in fetal growth can inspire future directions in oral supplementation. Thus, our data might offer evidence to support the targeting of plasma phospholipid odd-chain SFAs in early pregnancy to benefit fetal growth in the general population with pregnancy.

4.2. Strengths and Limitations

Our study has a few notable strengths. The prospective and longitudinal data collection included plasma phospholipid SFAs, abundant forms of circulating SFAs representing both exogenous and endogenous sources of SFAs, and longitudinal fetal growth ultrasound measures. We reported the temporal relationship between plasma phospholipid SFAs in early pregnancy and fetal growth throughout gestation and also identified the relevance of timing for significant associations. In addition, such a comprehensive panel of plasma phospholipid SFAs may further help elucidate the different roles of SFAs underlying the physiology of fetal development.

However, our study was not without limitations. Even though this is one of the largest prospective pregnancy cohorts investigating fetal growth throughout pregnancy, the relatively small sample size of 321 subjects may limit the statistical power of identifying the relevance of timing using pairwise comparisons at each gestation week. Second, we cannot eliminate residual confounding due to the study’s observational nature, even though we controlled for known major confounders in our modeling. Third, dietary patterns or other lifestyle factors in mid-to-late pregnancy might modify the associations found in our study. However, such factors collected via dietary questionnaires are prone to measurement errors due to the subjectivity of self-reporting, and adjusting such factors could incur collider bias because they could be the potential mediators for subsequent fetal growth. Fourth, our observations were found to be significant mostly during early to mid-pregnancy instead of late pregnancy. It could be affected by the reduced power of fetal growth biometrics comparisons between tertiles because subjects gave birth at term. Last, there could be interactive effects among SFAs or between SFAs and other types of FAs, even though we accounted for the confounding effects among subgroups of SFAs for individual SFAs investigated in this study. Further studies with a larger sample size should investigate the underlying interaction among all FAs and are also warranted to verify our findings.

5. Conclusions

In summary, our study differentiates the inverse associations of even-chain and very long even-chain SFAs, in contrast to the positive associations of odd-chain SFAs in early pregnancy with fetal growth throughout pregnancy. Considering the modifiable nature of plasma phospholipid odd-chain SFAs due to their exogenous origins, such as pentadecanoic acid (15:0), our data might provide a potential target toward odd-chain SFAs (e.g., via oral supplements) to benefit fetal growth during pregnancy.

Acknowledgments

We thank all the mothers for participating in this study.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/nu15153287/s1; Supplementary Table S1. Median and IQR of SFAs; Supplementary Table S2. Numbers in different ultrasound schedule groups among 321 subjects; Supplementary Table S3. Maternal characteristics according to weighting; Supplementary Table S4A. Association between individual SFAs and fetal growth biometrics (EFW, AC and FL) throughout 10–40 weeks of gestation; Supplementary Table S4B. Association between individual SFAs and fetal growth biometrics (HC, BPD and HC/AC ratio) throughout 10–40 weeks of gestation; Supplementary Table S5A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across myristic acid (14:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S5B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across myristic acid (14:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S6. Back-transformed and pairwise ratio of weekly fetal growth biometrics across palmitic acid (16:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S7A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of even-chain SFA tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S7B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of even-chain saturated fatty acid tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S8A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across Heptadecanoic acid (17:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S8B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across Heptadecanoic acid (17:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S9A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of odd-chain saturated fatty acids tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S9B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of odd-chain saturated fatty acid tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S10A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across lignoceric acid (24:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S10B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across lignoceric acid (24:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S11. Back-transformed and pairwise comparison of weekly fetal growth biometrics across arachidic acid (20:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S12A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across Behenic acid (22:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S12B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across Behenic acid (22:0) tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S13A. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of very-long-even-chain saturated fatty acids tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S13B. Back-transformed and pairwise comparison of weekly fetal growth biometrics across sum of very long even-chain saturated fatty acid tertiles in the NICHD Fetal Growth Studies—Singletons cohort; Supplementary Table S14. Association between individual SFAs and fetal growth throughout 10–40 weeks of gestation using cubic spline model with gestational weeks after adjusting for maternal family history of diabetes; Supplementary Table S15. Association between individual SFAs and fetal growth throughout 10–40 weeks of gestation using cubic spline model with gestational weeks after adjusting for maternal random glucose level at visit 0; Supplementary Table S16. Association between individual SFAs and fetal growth throughout 10–40 weeks of gestation using cubic spline model with gestational weeks after adjusting for maternal total cholesterol level at visit 0; Table S17: Association between individual SFA and fetal growth throughout between 10–40 weeks gestation using cubic spline model with gestational weeks after adjusting for subgroup SFAs at visit 0. Supplementary Figure S1. Study flow chart; Supplementary Figure S2. Back-transformed geometric means of estimated fetal growth, abdominal circumference, head circumference and biparietal diameter by gestational weeks for tertiles of myristic acid (14:0) and stearic acid (18:0), respectively, within the NICHD Fetal Growth Studies-Singletons cohort, 10–40 weeks of gestational age. The 1st (lowest) tertile curve is in blue, the 2nd (middle) tertile curve is in red, and the 3rd (highest) tertile is in green; Supplementary Figure S3. Back-transformed geometric means of femur length and gestational weeks for tertiles of the sum of even-chain SFAs within the NICHD Fetal Growth Studies—Singletons cohort, 10–40 weeks of gestational age. The 1st (lowest) tertile curve is in blue, the 2nd (middle) tertile curve is in red, and the 3rd (highest) tertile is in green. The gray shaded area and the blown-up graph on the right indicate a significant decrement in femur length from 14 to 18 weeks of gestation in both the 2nd and 3rd tertiles, compared with the 1st tertile; Supplementary Figure S4. Back-transformed geometric means of abdominal circumference and head circumference by gestational weeks for tertiles of lignoceric acid (24:0) and very long even-chain SFAs, respectively, within the NICHD Fetal Growth Studies—Singletons cohort, 10–40 weeks of gestational age. The 1st (lowest) tertile curve is in blue, the 2nd (middle) tertile curve is in red, and the 3rd (highest) tertile is in green. The gray shaded area and the blown-up graph on the right indicate a significant decrement in abdominal circumference from 29 to 39 week of gestation (Figure S4A) in both the 2nd and 3rd tertiles of lignoceric acid (24:0), compared with the 1st tertile. The gray shaded area and the blown-up graph on the right indicate a significant decrement in head circumference from 18 to 33 week of gestation (Figure S4B) in both the 2nd and 3rd tertiles of very long even-chain SFAs, compared with the 1st tertile.

Click here for additional data file. (2.3MB, zip)

Author Contributions

L.-J.L. conceptualized the study hypothesis, participated in data analyses and wrote and edited the manuscript. R.D. performed data analyses and assessed and verified the data. M.O., R.L., Z. C. and C.Z. contributed to the methodology and edited the manuscript. N.L.W. performed fatty acid examination, contributed to the methodology and edited the manuscript. M.Y.T. performed fatty acid examination, contributed to the methodology and edited the manuscript. P.S.A. and Z.C. contributed to the methodology and edited the manuscript. C.Z. designed the study, obtained funding, supervised the analysis, reviewed and edited the manuscript and assessed and verified the data. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The institutional review boards at all participating sites approved both the primary study and sub-study. All participants provided written informed consent prior to data collection. The participating clinical centers entered study documents and data, including ultrasound measurements and images, into the Clinical Trial Management System, which were then electronically transferred to the Data Coordinating Center.

Informed Consent Statement

Written informed consent was obtained from all subjects involved in this study.

Data Availability Statement

Data described in the manuscript, code book and analytic code will be available upon request pending application and approval of a data-sharing agreement.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C and HHSN275201000001Z.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

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Supplementary Materials

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Data Availability Statement

Data described in the manuscript, code book and analytic code will be available upon request pending application and approval of a data-sharing agreement.

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