Periconceptional Non-medical Maternal Determinants Influence the Tryptophan Metabolism: The Rotterdam Periconceptional Cohort (Predict Study)

Abstract

Background: The vital role of the maternal tryptophan (TRP) metabolism in maternal health and pregnancy is well established. However, non-medical maternal determinants influencing the TRP metabolism have been poorly investigated. We hypothesise that periconceptional maternal non-medical determinants alter the TRP metabolism, affecting both kynurenine (KP) and serotonin pathway (SP) metabolite concentrations. Therefore, we investigated the influence of non-medical maternal determinants on the TRP metabolism during the periconception period.

Methods: About 1916 pregnancies were included from the Rotterdam Periconceptional Cohort between November 2010 and December 2020. Data on periconceptional non-medical maternal determinants were collected through questionnaires. Serum samples were collected at 8.5 (SD = 1.6) weeks of gestation and TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), 5-HT (5-hydroxytryptamine) and 5-hydroxyindole acetic acid (5-HIAA) were determined using validated liquid chromatography (tandem) mass spectrometry. Mixed models were used to determine associations between periconceptional non-medical maternal determinants and these metabolites.

Results: In total 11 periconceptional non-medical maternal determinants were identified. Protein intake was positively associated with TRP (β = .12, 95% CI = 0.07-0.17), while age, energy intake and body mass index (BMI) (β = -.24, 95% CI = -0.37 to -0.10) were negatively associated with TRP. Age, BMI and total homocysteine were associated with higher KYN, whereas non-western geographical origin was associated with lower KYN (β = -.09, 95% CI = -0.16 to -0.03). Protein intake and total homocysteine (β = .07, 95% CI = 0.03-0.11) had a positive association with 5-HTP, while a negative association was found for energy intake. A non-western geographical origin and drug use were associated with higher 5-HT, and BMI with lower 5-HT (β = -6.32, 95% CI = -10.26 to -2.38). Age was positively associated with 5-HIAA (β = .92, 95% CI = 0.29-1.56), and BMI negatively.

Conclusions: Periconceptional non-medical maternal determinants, including age, geographical origin, drug use, energy and protein intake, BMI and total homocysteine, influence KP and SP metabolite concentrations.

Keywords: Tryptophan; kynurenine; non-medical determinants; periconception period; serotonin.

Figure 1.

Kynurenine and serotonin pathway of the tryptophan metabolism. The analytes determined in this study are coloured grey. Tryptophan is converted to N-formylkynurenine by the hepatic tryptophan 2,3-dioxygenase (TDO) or the extra-hepatic indole amine 2,3-dioxygenase (IDO). This is the rate-limiting step in the kynurenine pathway. N-formylkynurenine is hydrolysed to kynurenine by arylformamidase. Kynurenine is further metabolised into the downstream kynurenine pathway metabolites kynurenic acid, anthranilic acid, 3-hydroxy-anthranilic acid, quinolinic acid, picolinic acid, and nicotinamide adenine dinucleotide (NAD+). Tryptophan is converted to 5-hydroxytryptophan, which is the rate limiting step of the serotonin pathway. Then, 5-hydroxytryptophan is converted to 5-hydroxytryptamine by aromatic amino acid decarboxylase. Finally, 5-hydroxytryptamine is converted to 5-hydroxyindoleacetic acid via 2 enzymatic steps involving the enzymes monoamine oxidase and aldehyde dehydrogenase.

Figure 2.

Scatter plot matrix of first-trimester tryptophan metabolite serum concentrations.

Figure 3.

Forrest plots demonstrating the effect estimates including 95% confidence intervals of the multivariable mixed models for each determinant.

Figure 4.

Summary of periconceptional non-medical maternal determinants of the tryptophan metabolism. ↑, positive association; ↓, negative association, •, no association. The associations that were significant in the multivariable model are coloured black. If the direction of the associations was the same in the bivariable as in the multivariable model but not statistically significant the arrows are coloured grey. Abbreviations: 5-HTP, 5-hydroxytryptophan; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindole acetic acid; KYN, kynurenine; TRP, tryptophan.