Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence

Abstract

Background: Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.

Methods: Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24-49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status.

Results: Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters.

Conclusions: Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.

Keywords: Amino acids; Cytokines; Fatty acids; Hormones; Inflammation; Lipoprotein lipids; Metabolic networks; Metabolomics; Postpartum; Pregnancy; Trimesters.

Fig. 1

Cross-sectional and longitudinal associations between pregnancy and lipoprotein-related measures. Left panel, cross-sectional analyses in which pregnant women (n = 322) were compared to non-pregnant women (n = 3938). The associations were adjusted for age and meta-analysed for three Finnish population-based cohorts. Middle panel, longitudinal analyses in which women who were pregnant at follow-up (but not at baseline) (n = 18) were compared to women who were non-pregnant at both time points (n = 519). Right panel, longitudinal analyses in which women who were pregnant at baseline (but not at follow-up) (n = 44) were compared to women who were non-pregnant at both time points (n = 519). Longitudinal associations were adjusted for baseline age. Open diamonds indicate P ≥ 0.0008, closed diamonds indicate P < 0.0008. C cholesterol, CI confidence interval, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, LDL low-density lipoprotein, PL phospholipids, SD standard deviation, TG triglycerides, VLDL very-low-density lipoprotein

Fig. 2

Cross-sectional and longitudinal associations between pregnancy and fatty acids. The study design is as explained in the legend for Fig. 1. The percentage sign (%) refers to the proportion of an individual measure of the total fatty acids. Open diamonds indicate P ≥ 0.0008, closed diamonds indicate P < 0.0008. CI confidence interval, FA fatty acids, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SD standard deviation

Fig. 3

Cross-sectional and longitudinal associations between pregnancy and metabolic, inflammatory and hormonal measures. The study design is as explained in the legend for Fig. 1. Open diamonds indicate P ≥ 0.0008, closed diamonds indicate P < 0.0008. CI confidence interval, SD standard deviation, SHBG sex hormone-binding globulin

Fig. 4

Correlations between cross-sectional and longitudinal metabolic associations of pregnancy. Left panel, linear fit to summarise the correspondence between cross-sectional (pregnant women compared to non-pregnant women) and longitudinal associations for women pregnant at follow-up but not at baseline (in comparison to women non-pregnant at both time points). Right panel, linear fit to summarise the correspondence between cross-sectional and longitudinal associations for women pregnant at baseline but not at follow-up (in comparison to women non-pregnant at both time points). Each point represents a single metabolic measure. Horizontal and vertical grey lines denote 95% CIs for the cross-sectional and longitudinal associations, respectively. The grey shaded areas serve to guide the eye for the slope. A linear fit for the overall correspondence summarises the match between cross-sectional and longitudinal associations, with R ² denoting the goodness of fit. A slope of ±1 and R ² = 1 would strongly support the causal effects of pregnancy on the metabolic measures. C cholesterol, CI confidence interval, DHA docosahexaenoic acid, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, LDL low-density lipoprotein, PL phospholipids, PUFA polyunsaturated fatty acids, SD standard deviation, TG triglycerides, VLDL very-low-density lipoprotein

Fig. 5

Cross-sectional associations between pregnancy trimesters and metabolic measures. Pregnant women in their first (n = 48), second (n = 116) and third trimester (n = 67) were compared to non-pregnant women (n = 2588). Associations were adjusted for age and meta-analysed for NFBC1966 and YFS. Open circles indicate P ≥ 0.0008, closed circles indicate P < 0.0008. C cholesterol, CI confidence interval, FA fatty acids, HDL high-density lipoprotein, IDL intermediate-density lipoprotein, LDL low-density lipoprotein, PL phospholipids, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SD standard deviation, SHBG sex hormone-binding globulin, TG triglycerides, VLDL very-low-density lipoprotein