Abstract
Introduction
Embryonic and fetal growth are important determinants for birth outcomes and health later in life. Especially during the periconception period, when critical processes occur and growth rates are the highest, maternal exposures can have profound effects on growth of the embryo (Dickey and Gasser, 1993; Gluckman et al., 2010; Steegers-Theunissen et al., 2013). Indeed, maternal exposures, such as a poor diet quality and smoking, during the periconception period have been found to reduce embryonic growth (van Uitert et al., 2013b; Abdollahi et al., 2021; Pietersma et al., 2022). Previous studies have revealed that smaller embryos are associated with reduced fetal growth, lower birthweight, and cardiovascular risk factors in the future child (Mook-Kanamori et al., 2010; Jaddoe et al., 2014; Ustunyurt et al., 2015; Xu et al., 2022).
The exact biological mechanisms underlying impaired embryonic growth and the subsequent adverse outcomes remain, however, largely unclear. It has been demonstrated that one-carbon metabolism is of key importance in the periconception period because of its role in the biosynthesis of DNA and proteins, and epigenetic modifications (Steegers-Theunissen et al., 2013; Kalhan, 2016). Derangements in one-carbon metabolism as a result of poor maternal exposures have been associated with impaired embryonic and fetal growth, with implications for future health (Steegers-Theunissen, et al., 2013). Another potential biological mechanism that contributes to fetal growth is the tryptophan (TRP) metabolism. TRP metabolism is linked to one-carbon metabolism as it provides methyl donors and shares substrates and cofactors (Steegers-Theunissen et al., 2013). TRP is an essential amino acid, and its free concentration is dependent on protein and energy intake, and other exposures (Wurtman et al., 2003; Badawy, 2017b). Physiologically, 95% of free TRP is metabolized through the kynurenine (KYN) pathway, with 1-5% through the serotonin pathway, and the rest of TRP is reserved for the indole pathway and protein synthesis (Fig. 1) (Bender, 1983; Oxenkrug, 2010). TRP metabolites are involved in processes essential to maintain pregnancy, including immune regulation, anti-oxidative processes, and regulation of vascular tone (Badawy, 2015; Broekhuizen et al., 2021).
Throughout pregnancy, the TRP metabolite concentrations are closely regulated, and alterations of KYN pathway or serotonin pathway metabolites have been associated with pregnancy complications, such as pre-eclampsia and fetal growth restriction (FGR) (Gumusoglu et al., 2021; van Zundert et al., 2022a). In late pregnancy, maternal TRP and KYN concentrations were inversely associated with FGR (van Zundert, et al., 2022a; Yaman et al., 2023). Studies investigating TRP metabolism in the placenta showed that in placentas of FGR pregnancies the KYN pathway was downregulated, while the serotonin pathway was upregulated (Ranzil et al., 2019). Animal studies also suggest that increased maternal serotonin pathway metabolite concentrations have a negative effect on fetal growth, illustrated by reduced fetal weight after administration of 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) (Salas et al., 2007).
To date, however, human studies investigating the role of the TRP metabolism in fetal growth are scarce and focus on late pregnancy or on placental TRP metabolism (van Zundert et al., 2022a). To expand our understanding of the biological mechanisms involved in (patho)physiological embryonic and fetal growth, we studied the association between first trimester maternal TRP metabolites and embryonic growth. The secondary aim of this study was to investigate the associations between first trimester maternal TRP metabolites and fetal growth and birthweight, and the risk of small-for-gestational age (SGA) at birth.
Materials and methods
Study design and setting
This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective tertiary hospital-based cohort study with the aim to explore determinants of periconception parental health in relation to reproductive and pregnancy course and outcomes, and potential underlying mechanisms. The cohort profile has been described in detail previously (Steegers-Theunissen et al., 2016; Rousian et al., 2021). In short, women were eligible if they were older than 18 years, familiar with the Dutch language, and <11 weeks pregnant.
Study population
In total, 2051 pregnancies were included in the Predict Study between November 2010 and December 2020 (Fig. 2). We excluded pregnancies conceived after oocyte donation (n = 23), since no information was collected of the donors. In addition, pregnancies with an increased a priori risk of reduced embryonic growth were excluded: multiple pregnancies (n = 63), miscarriages (n = 145), congenital anomalies (n = 83), and fetal and neonatal deaths (n = 24). Then, pregnancies with missing first trimester 3D ultrasound imaging (n = 245) or missing first trimester maternal serum samples (n = 35) were excluded.
Since longitudinal crown-rump length (CRL) was one of the features of embryonic growth assessed in this study, and gestational age is the most important determinant of embryonic growth, gestational age was not based on the CRL. The gestational age was calculated using the first day of the last menstrual period (LMP) when women conceived naturally and had a regular menstrual cycle (25-31 days). The gestational age was adjusted for the duration of the menstrual cycle if the menstrual cycle deviated by 3-7 days from 28 days, with a fixed number of days each cycle.
The gestational age was determined using the CRL at 9 weeks of gestation; however, when women conceived naturally but had an irregular menstrual cycle (<21 days or >35 days), the LMP was missing or when the difference between the gestational age based on the LMP and the gestational age based on the CRL at 9 weeks of gestation was ≥7 days. For pregnancies conceived after IVF and ICSI, the gestational age was calculated from the conception date: the oocyte retrieval day minus 14 days for the fresh embryo transfers or minus 19 days for the cryopreserved embryo transfers (Steegers-Theunissen, et al., 2016).
Pregnancies of which the gestational age was based on the CRL were excluded from the analysis with embryonic growth features as outcome (n = 318). As a result, the primary analysis was performed on a study sample consisting of 1115 pregnancies, and the secondary analysis was performed on a study sample of 1433 pregnancies.
Data collection
TRP metabolites
Non-fasting venous blood was drawn during the hospital intake at 8.4 (interquartile range (IQR) = 7.3-9.4) weeks of gestation, and TRP metabolites were determined in the serum using a validated liquid chromatography (tandem) mass spectrometry (LC-MS/MS) method (van Zundert et al., 2022b). The following TRP metabolites were determined: TRP, KYN, 5-HTP, 5-HT, and 5-hydroxyindole acetic acid (5-HIAA). The KYN/TRP and 5-HTP/TRP ratios were determined as they may provide an indication of the KYN pathway and serotonin pathway, respectively (Badawy and Guillemin, 2019).
Embryonic growth features
Embryonic growth features included CRL and embryonic volume (EV), which were measured using 3D ultrasound imaging and virtual reality techniques (Steegers-Theunissen et al., 2016; Rousian et al., 2021). These measurements have been proven reliable and reproducible (Rousian et al., 2010). Transvaginal 3D ultrasounds were performed at ∼7, 9, and 11 weeks of gestation using a Voluson E8 or E10 (GE Healthcare, Austria) ultrasound machine. Accurate and precise 3D CRL and EV measurements were performed offline using 4D view software (GE Healthcare, Austria) and the V-Scope volume rendering application. A hologram of the embryo was created, which allowed for interaction and real depth perception. Manually, the signal of the uterus and umbilical cord was removed based on differences in echogenicity between the structures. The CRL was measured manually three times using a tracing tool, and the EV was measured using a semi-automated method (Steegers-Theunissen et al., 2016; Rousian et al., 2021).
Fetal growth parameters and birth outcomes
EFW: estimated fetal weight; AC: abdominal circumference; FL: femur length; HC: head circumference; BPD: biparietal diameter.
Birthweight was retrieved from delivery reports. For both EFW and birthweight, standard scores (percentiles and z-scores) were calculated based on Dutch reference curves, adjusted for gestational age, and for gestational age and fetal sex, respectively (Gaillard et al., 2011; Hoftiezer et al., 2016). Percentiles were used to identify SGA cases, defined as a birthweight below the 10th percentile (Hoftiezer et al., 2016).
Covariates
Data on maternal characteristics were collected via a general questionnaire and a validated food frequency questionnaire (FFQ), which were both filled out before the hospital intake during the first trimester of pregnancy (Feunekes et al., 1993; Fayet et al., 2011). The general questionnaire collected data on date of birth, geographical background, educational level, smoking, and folic acid supplement use. Based on the date of birth and the conception date, the age at conception was calculated. Geographical background was classified as either Western or non-Western, following the categorization proposed by Alders (2001). Educational levels were categorized into three groups based on the International Standard Classification of Education (ISCED): low (ISCED 0-2), intermediate (ISCED 3-4), and high (ISCED 5-8) (United Nations Educational Scientific and Cultural Organization, 2012). Smoking included any smoking during the periconception period. Folic acid supplement use was considered adequate in this study when initiated before conception. Information on maternal protein and energy intake were obtained from the FFQ taking into account the reliability using the Goldberg cut-off, which compared an individual’s reported energy intake to their basal metabolic rate and physical activity (Black, 2000). A comprehensive description of this method can be found in the recent publication of Smit et al. (2022). The completeness of the questionnaire was checked by a trained research nurse upon hospital intake. Additionally, anthropometric measurements were performed using a standard protocol and blood was drawn. BMI was calculated by dividing weight (kg) by the square of height (m). Data on conception mode, parity, and fetal sex were retrieved from medical records. Conception mode referred to the method through which pregnancy was achieved, encompassing naturally conceived pregnancies and IVF/ICSI pregnancies.
Statistical analysis
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Baseline characteristics, including periconception maternal characteristics, fetal and birth outcomes, and TRP metabolite concentrations, were presented as means with SD or as numbers of individuals. However, for 5-HIAA, owing to its right-skewed distribution, the median and IQR were used instead.
5-HIAA was (natural) log-transformed to obtain an approximate normal distribution for the analyses. In addition, a square root transformation for CRL and a cube root transformation for EV were adopted to obtain a constant variance and an approximate normal distribution of residuals provided the included covariates.
Multivariable mixed models were constructed to investigate the associations between maternal TRP metabolites and embryonic growth trajectories. Mixed models are flexible and can handle unbalanced data and meanwhile account for the correlated (repeated) measurements within each pregnancy by including a random intercept (Laird and Ware, 1982). Model 1 (crude model) was only adjusted for a cubic spline function of gestational age at the moment of the ultrasound. To identify potential confounders, a directed acyclic graph based on existing literature and a correlation matrix were constructed. Covariates additionally included in Model 2 (adjusted model) were gestational age at the blood draw, maternal age, geographical background, educational level, smoking, folic acid supplement use, protein intake/energy intake, BMI, conception mode, parity, and fetal sex. Including the covariates as nonlinear terms and including all possible two-way interactions did not improve the fit based on the Akaike information criterion and Bayesian information criterion.
Multivariable linear regression models were used to assess the associations between TRP metabolites and EFW and birthweight. Since the EFW z-scores were already adjusted for gestational age and SGA for gestational age and fetal sex, these covariates were not included in the multivariable model. Model 2 included the covariates gestational age at the blood draw, maternal age, geographical background, educational level, smoking, folic acid supplement use, protein intake/energy intake, BMI, conception mode, parity, and fetal sex (only for EFW). Finally, multivariable logistic regression models, using the same covariates as in the linear regression model for birthweight, were built to investigate the associations between TRP metabolites and SGA.
Results were displayed as effect estimates (β or odds ratio (OR)) with 95% CI. All statistical analyses were performed using R version 4.2.1 and IBM SPSS Statistics for Windows version 28 (IBM Corp, 2021; R Core Team, 2022).
Ethical approval
Ethical clearance was sought and obtained from the local Medical Ethical Committee of the Erasmus MC, University Medical Center, Rotterdam and the Central Committee on Research The Hague (15 October 2004, MEC-2004-277; Steegers-Theunissen, et al., 2016). All participants gave written informed consent at enrolment.
Results
Baseline characteristics
Table 1 shows the baseline characteristics of the total study population (n = 1115), including information on the periconception maternal characteristics, fetal and birth outcomes, and absolute maternal TRP concentrations. In Supplementary Table S1, the baseline characteristics of the study sample used for the secondary analysis (n = 1433) are presented, which were comparable with those described below. Supplementary Table S2 shows the baseline characteristics of the total excluded population and of those excluded based on missing first trimester 3D ultrasound data or missing first trimester serum samples. Those who were excluded from the analysis tended to have higher BMI and lower educational level, and were more likely to smoke, conceive naturally, be multiparous, and have an inadequate folic acid supplement intake.
Periconception maternal characteristics
The mean maternal age at conception was 32.5 (SD = 4.5) years, and the mean BMI was 25.5 (SD = 4.8) kg/m2 (Table 1). Women mostly had a Western geographical background (n = 918 [86.3%]), were highly educated (n = 626 [58.8%]), and often nulliparous (n = 597 [54.3%]). Slightly less than half of the women conceived after IVF/ICSI treatment (49.1%) and the others conceived naturally (50.9%). During the periconception period, one-third of the women consumed alcohol (n = 308 [29.0%]), 147 (13.8%) women smoked, and a few women (n = 15 [1.4%]) used drugs. Most women initiated folic acid supplement use before conception (n = 896 [84.4%]), which was considered adequate. Women consumed daily 72.6 g protein (SD = 19.6) and 8215.0 kJ (SD = 2223.2) energy, both of which are in accordance with current recommendations in obstetric practice (Most et al., 2019; Murphy et al., 2021).
Fetal and birth outcomes
Mid-pregnancy, at 20.1 (IQR = 19.9-20.6) weeks of gestation, the EFW in our study population was slightly higher than in the general Dutch population (z-score = 0.5 (SD = 1.0)), while the birthweight was slightly lower than in the general Dutch population (z-score = -0.10 (SD = 1.1)). Women delivered at a mean gestational age of 38.8 (SD = 2.0) weeks, and in 11.6% (n = 129), this concerned a SGA-baby.
Embryonic growth
The associations between maternal TRP metabolite concentrations and CRL and EV trajectories are presented in Table 2. Results described below are based on the adjusted model, unless stated otherwise. An inverse association was found between maternal 5-HTP concentrations and both CRL and EV trajectories (√CRL: β = -0.015, 95% CI = -0.028 to -0.001; 3√EV: β = -0.009, 95% CI = -0.016 to -0.003). The median decrease in CRL and EV during the first trimester of pregnancy for +2SD 5-HTP concentrations compared to mean 5-HTP concentrations is illustrated in Fig. 3. In addition, the maternal 5-HTP/TRP ratio was inversely associated with both CRL and EV trajectories (√CRL: β = -0.843, 95% CI = -1.597 to -0.088; 3√EV: β = -0.529, 95% CI = -0.902 to -0.157). No associations were found between other TRP metabolites and CRL or EV trajectories.
Fetal growth and birth outcomes
Tables 3 and 4 show the associations between maternal TRP metabolite concentrations and EFW and SGA, respectively. In Supplementary Table S3, the associations between maternal TRP metabolite concentrations and birthweight are presented. Inverse associations were found between maternal 5-HTP concentrations and both EFW and birthweight, though not statistically significant. Comparable results were found for the maternal 5-HTP/TRP ratio. In addition, a higher maternal 5-HTP/TRP ratio was associated with an increased risk of SGA (OR = 1.006, 95% CI = 1.000-1.013). In contrast, increased maternal KYN concentrations were associated with higher birthweight and a reduced risk of SGA in the unadjusted models (birthweight z-score: β = 0.188, 95% CI = 0.010-0.365, SGA: OR = 1.006, 95% CI = 1.000-1.013). The analysis revealed no other associations between TRP metabolites and fetal growth or birth outcomes.
Discussion
Summary of findings
Table 5 summarizes the associations found in this study between first trimester maternal TRP metabolites and embryonic growth, fetal growth, and birth outcomes. It shows that increased first trimester maternal 5-HTP concentrations are associated with a smaller embryo, expressed by reduced CRL and EV trajectories. In addition, our findings suggest that higher first trimester maternal 5-HTP concentrations are also associated with lower EFW and birthweight, and with an increased risk of SGA, while higher maternal KYN concentrations are associated with a higher birthweight, and a reduced risk of SGA.
Comparison with existing literature and interpretation
Studies investigating maternal TRP metabolites in relation to fetal growth or birth outcomes are scarce (van Zundert et al., 2022a). In fact, this is the first human study that found an inverse association between first trimester maternal 5-HTP concentrations and embryonic and fetal growth. The effect estimates of the association between first trimester maternal 5-HTP and embryonic growth (√CRL: β = -0.015, 95% CI = -0.028 to -0.001; 3√EV: β = -0.009, 95% CI = -0.016 to -0.003) were smaller than those of the association between periconception smoking and embryonic growth (√CRL: β = -0.055, 95% CI = -0.159 to -0.006; 3√EV: β = -0.042, 95% CI = -0.089 to 0.006), but larger than those of the association between periconception alcohol use and embryonic growth (√CRL: β = -0.003, 95% CI = -0.005 to -0.003; 3√EV: β = -0.005, 95% CI = -0.040 to 0.030) (van Uitert et al., 2013a; van Dijk et al., 2018).
There are several possible explanations for this finding. Insights from animal studies suggest that maternal 5-HTP can directly inhibit fetal growth by passing into the fetal circulation. These animal studies showed that 5-HTP can induce developmental arrest, inhibit growth, and increase cell death (Gordeeva and Gordeev, 2021; Gordeeva and Safandeev, 2021). In humans, there is increasing evidence that initially nutrition of the embryo is histiotrophic, with secretion of nutrients by uterine glands into the intervillous space, which are taken up by the trophoblast (Burton et al., 2001). The nutrients diffuse into the coelomic fluid from which they may be absorbed by the (secondary) yolk sac, and then reach the embryo. There is a transition toward hemotrophic nutrition when the maternal placental circulation is established (Burton et al., 2001). Additional research is needed to determine whether maternal 5-HTP indeed reaches the embryo through histiotrophic nutrition.
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Another explanation for the inverse association between maternal 5-HTP concentrations and fetal growth may be the involvement of 5-HTP in placental development. Support for this biological mechanism can be found in an animal study that reported reduced fetal and placental weights after treating pregnant rats with 5-HTP (Salas et al., 2007). This study postulated that treatment with 5-HTP increases placental vascular resistance. Consequently, reduced utero-placental blood flow can potentially affect fetal growth negatively.
Disruption of the one-carbon metabolism could also underlie the inverse association between first trimester maternal 5-HTP and embryonic and fetal growth. TRP metabolism provides one-carbon units for the folate cycle and shares cofactors with one-carbon metabolism, which is crucial for epigenetic programming of cells and tissues (Steegers-Theunissen et al., 2013; Shibata et al., 2015). A deficiency of a shared cofactor, for example vitamin B6, can lead to increased 5-HTP and homocysteine concentrations (Shabbir et al., 2013; Steegers-Theunissen et al., 2013). Increased homocysteine is a marker of derangements in one-carbon metabolism, which has been associated with impaired embryonic and placental development (Parisi et al., 2017; Hoek et al., 2021; Rubini et al., 2021, 2022).
No associations between 5-HT and embryonic and fetal growth were found in the present study. This can be explained by the methodological difficulty to accurately measure serum 5-HT owing to leakage of 5-HT from thrombocytes during the clotting process. Nevertheless, the concentrations found in our study are comparable with those reported in earlier studies (Ernberg et al., 2000; Comai et al., 2010; Lindström et al., 2018; Zhao et al., 2022). Future research should consider assessing platelet count and 5-HT in other blood fractions as well, such as in platelet-rich plasma (Korse et al., 2017).
Another interesting finding was the association between higher maternal KYN concentrations during the first trimester of pregnancy and a reduced risk of SGA. These associations were only statistically significant in the unadjusted model, and therefore need to be interpreted with caution. Although reference values for maternal KYN concentrations during the first trimester of pregnancy are currently lacking, the concentrations observed in our study align with those recently reported (Sha et al., 2022). Even though maternal KYN concentrations remain relatively stable throughout pregnancy, we accounted for timing of the blood draw in the first trimester of pregnancy by adjusting for gestational age at the moment of the blood draw, which occurred at hospital intake between 7 and 9 weeks of gestation (Schröcksnadel et al., 1996; van Zundert, et al., 2022a). However, as expected, the timing of the blood draw did not affect the results substantially.
In line with our findings, a recent study reported lower maternal KYN concentrations in the third trimester in pregnancies complicated by FGR (Yaman et al., 2023). Explanations for the positive association between first trimester maternal KYN concentrations and SGA involve the several essential functions of the KYN pathway during pregnancy, including its role in neovascularization, vasodilatation of placental arteries, and immune regulation (Wang et al., 2010; Mondal et al., 2016; Badawy, 2017a; Broekhuizen, et al., 2021; Worton et al., 2021). These processes are all important for embryonic and fetal growth, and placental development and functioning. No clear positive associations were found with fetal growth. Since the assessment of fetal growth was based on EFW calculated from the mid-pregnancy anomaly scan, measurements errors cannot be ruled out, which may have weakened the observed effects (Milner and Arezina, 2018).
First trimester maternal KYN concentrations were also not positively associated with embryonic growth in this study. Excess KYN concentrations can induce oxidative stress and dysregulate apoptosis, which may affect embryonic growth negatively (Forrest et al., 2004; Wang et al., 2014). Possibly, the potential harmful effects of increased KYN concentrations may outweigh the relaxing effects on placental arteries, since the embryo is dependent on histiotrophic nutrition rather than on hemotrophic nutrition via the placenta during early pregnancy (Burton, et al., 2001).
Strengths and limitations
To the best of our knowledge, this is the first human study that investigated associations between maternal TRP metabolites in the first trimester of pregnancy and embryonic growth. The primary strengths of our study lie in its periconceptional prospective design, enabling comprehensive data collection on various periconception maternal characteristics through validated general and food questionnaires (Feunekes et al., 1993; Fayet et al., 2011). This allowed building extensive multivariable models to adjust for potential confounders including dietary factors, such as protein and energy intake, although the presence of residual confounding from unobserved and unknown factors, such as comorbidities and medication use (e.g. selective serotonin reuptake inhibitors and interferon alpha), cannot be ruled out (Correia and Vale, 2022). In addition, standardized longitudinal embryonic growth measurements were conducted using 3D ultrasound scans and virtual reality systems, which have been proven highly accurate and reliable (Rousian, et al., 2010, 2021). Furthermore, the TRP concentrations were determined using a recently published LC-MS/MS method, which has been validated in women in early pregnancy, allowing for sensitive and accurate measurements (van Zundert et al., 2022b). Possible selection bias exists if associations differ between excluded and included participants; however, there is no reason to assume, for example, that lower first trimester maternal 5-HTP concentrations result in reduced embryonic growth in the excluded population compared to the study population, especially since participants were unaware of the study’s associations, and the outcome did not impact their pregnancy course or health.
Total TRP was measured instead of free TRP, as free TRP can be influenced by various factors that were not optimal in this study, such as the absence of fasting blood samples (Badawy, 2010). However, this limits the interpretation of maternal TRP concentrations, as only free TRP is available for protein synthesis and metabolic processes. Another potential limitation is the recruitment of women from a tertiary hospital, which may limit external validity. We expect that the direction of the associations will remain consistent in the general population, and there is a possibility that they might even be stronger. Considering the explorative character of this study, we accepted a higher type I error rate, and have not corrected for multiple testing using statistical procedures.
Implications and future research
Our findings provide valuable insights into the role of the maternal TRP metabolism during the first trimester of pregnancy in the physiology of embryonic and fetal growth. Given the pivotal role of embryonic and fetal growth in determining birth outcomes, and long-term health, including potential transgenerational effects, understanding the associated metabolic processes is crucial to achieve the ultimate goal of optimizing embryonic and fetal growth and reducing the occurrence of adverse birth outcomes (Steegers-Theunissen et al., 2013). Our findings suggest that alterations in maternal TRP metabolism, particularly leading to increased 5-HTP concentrations, may contribute to impaired embryonic and fetal growth. This novel finding contributes to our comprehension of the pathophysiology of impaired embryonic and fetal growth, and provides potential preventative and therapeutic targets that warrant further investigation to assess their value in periconception care. A well-balanced diet containing an appropriate intake of macro- and micronutrients is recommended, and vigilance is required when making future dietary recommendations for TRP intake. Future research is needed to identify modifiable factors that influence maternal TRP metabolism, which can be addressed in periconception care to optimize maternal TRP metabolism, and subsequently enhance embryonic and fetal growth. Despite the promising results, additional research within large prospective cohorts and intervention studies is required to validate our findings and to further elucidate the mechanisms through which alterations of maternal TRP metabolites affect embryonic and fetal growth. To develop a full picture of the maternal TRP metabolism, free TRP also needs to be determined in future studies. To measure free TRP accurately, fasting blood samples collected and stored under strictly controlled conditions are required (Badawy, 2010). This remains a challenging task for future studies.
Conclusion
In conclusion, alterations of the maternal TRP metabolism during the first trimester of pregnancy, specifically increased 5-HTP concentrations, are associated with a smaller embryo, and potentially with a smaller fetus and a higher risk of SGA. In contrast, increased maternal KYN concentrations during the first trimester of pregnancy may be associated with a larger fetus and a lower risk of SGA. The findings of this study indicate that maternal TRP metabolism during the first trimester of pregnancy potentially plays a role in the (patho)physiology of embryonic and fetal growth.
Data availability
The data underlying this article will be shared upon reasonable request to the corresponding author.
Acknowledgements
We would like to thank all women of the Rotterdam Periconceptional Cohort (Predict Study) for their participation, without whom the study could not have been performed. In addition, we gratefully acknowledge the help provided by the researchers of the Predict Study team for recruiting participants and collecting data, and by Ann Vanrolleghem for coordination of the Predict Study.
Authors’ roles
Under supervision of M.M., S.K.M.v.Z. and N.C.M.v.E. drafted the manuscript, and L.v.R., S.P.W., P.H.G., R.H.N.v.S., and R.P.M.S.-T. revised it critically. With help of S.P.W. and L.v.R., S.K.M.v.Z. and N.v.E. performed the data analysis. L.v.R., M.M., R.H.N.v.S., and R.P.M.S.-T. helped with interpretation of the data. R.P.M.S.-T. is principal investigator of the Rotterdam Periconceptional Cohort (Predict Study) and initiated the study aims. M.M. developed and designed the LC-MS/MS method used to determine the TRP metabolites in this study, and P.H.G. prepared all serum samples and analyzed the LC-MS/MS data together with M.M. All authors have read and approved the final version to be published.
Funding
This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Conflict of interest
None disclosed.
References
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