First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).

STUDY QUESTION: What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? SUMMARY ANSWER: Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. WHAT IS KNOWN ALREADY: The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. STUDY DESIGN, SIZE, DURATION: This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: ß = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: ß = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). LIMITATIONS, REASONS FOR CAUTION: Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. WIDER IMPLICATIONS OF THE FINDINGS: The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. STUDY FUNDING/COMPETING INTEREST(S): 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. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Simultaneous quantification of tryptophan metabolites by liquid chromatography tandem mass spectrometry during early human pregnancy.

OBJECTIVES: In this study we describe the development and validation of a liquid chromatography mass spectrometry method (LC-MS/MS) to quantify five tryptophan (TRP) metabolites within the kynurenine- and serotonin pathway and apply the method to serum samples of women in the first trimester of pregnancy. A secondary aim was to investigate the correlation between body mass index (BMI) and the five analytes. METHODS: A LC-MS/MS was developed for the analysis of TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA). Serum samples (n=374) were analyzed of pregnant women (median gestational age: 8 ± 2 weeks) participating in a subcohort of the Rotterdam Periconceptional Cohort (Predict study). RESULTS: The LC-MS/MS method provided satisfactory separation of the five analytes (7 min run). For all analytes R2 was >0.995. Within- and between-run accuracies were 72-97% and 79-104%, and the precisions were all <15% except for the between-run precisions of the low QC-samples of 5-HTP and 5-HT (both 16%). Analyte concentrations were determined in serum samples of pregnant women (median (IQR)); TRP (µmol/L): 57.5 (13.4), KYN (µmol/L): 1.4 (0.4), 5-HTP (nmol/L): 4.1 (1.2), 5-HT (nmol/L): 615 (323.1), and 5-HIAA (nmol/L): 39.9 (17.0). BMI was negatively correlated with TRP, 5-HTP, and 5-HIAA (TRP: r=-0.18, p<0.001; 5-HTP: r=-0.13, p=0.02; natural log of 5-HIAA: r=-0.11, p=0.04), and positively with KYN (r=0.11, p=0.04). CONCLUSIONS: The LC-MS/MS method is able to accurately quantify kynurenine- and serotonin pathway metabolites in pregnant women, providing an opportunity to investigate the role of the TRP metabolism in the (patho)physiology of pregnancy.

Lifestyle care for transformation of medical care using an early life course approach.

It is well known that a healthy lifestyle plays a key role in maintaining reproductive and general health, and preventing lifestyle-related diseases throughout the entire life course. Lifelong health is shaped during the preconception period and the first 1000 days of life. The importance of a healthy lifestyle during these periods can be emphasized by introducing the concept of the early life course, which covers from 100 days before conception until 1000 days thereafter. Although awareness of the benefits of a healthy lifestyle has grown, adherence is disappointing and the implementation of lifestyle interventions in medical care is scarce. Hence, we are convinced that now is the right time to turn the tide. The focus should shift from cure to prevention and promotion of health. The new concept of lifestyle care includes lifestyle interventions that support the adoption of a healthy lifestyle to optimize health and prevent lifestyle-related diseases, including subfertility and adverse pregnancy outcomes. In this paper, we advocate for the implementation of lifestyle care in medical care, define the early life course, elaborate on lifestyle care as part of lifestyle medicine, and provide examples towards the successful implementation of blended lifestyle care, which can be more widely implemented and transform medical care.

Periconceptional maternal social, lifestyle and medical risk factors impair embryonic growth: The Rotterdam Periconceptional Cohort.

RESEARCH QUESTION: What is the association between the degree of a state of maternal vulnerability, determined by suboptimal periconceptional social, lifestyle and medical exposures and embryonic growth? DESIGN: In total, 555 pregnancies, comprising 324 naturally conceived pregnancies and 231 pregnancies conceived after IVF and intracytoplasmic sperm injection (ICSI) were included from the Rotterdam Periconceptional Cohort (Predict Study) between November 2010 and August 2018. Data on periconceptional social, lifestyle and medical exposures, i.e. vulnerability markers, were collected through self-administered questionnaires. To estimate embryonic growth, crown-rump length (CRL) and embryonic volume measurements were taken at 7, 9 and 11 weeks of gestation using three-dimensional ultrasound scans and virtual reality techniques. RESULTS: Exposure to two or more vulnerability markers was negatively associated with embryonic growth in naturally conceived pregnancies. The CRL and embryonic volume trajectories of embryos of women exposed to two vulnerability markers were reduced compared with those of women exposed to zero or one vulnerability marker (√CRL: ß = -0.29 mm, 95% CI -0.56 to -0.02; 3√EV: ß = -0.14 cm3, 95% CI -0.27 to -0.01). These associations were not found in pregnancies conceived after IVF or ICSI. CONCLUSIONS: This study showed that a higher degree of the periconceptional state of maternal vulnerability is associated with reduced embryonic growth (CRL and embryonic volume) in naturally conceived pregnancies.