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

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 (ß = .12, 95% CI = 0.07-0.17), while age, energy intake and body mass index (BMI) (ß = -.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 (ß = -.09, 95% CI = -0.16 to -0.03). Protein intake and total homocysteine (ß = .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 (ß = -6.32, 95% CI = -10.26 to -2.38). Age was positively associated with 5-HIAA (ß = .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.

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.

Prototyping of a Digital Life Course Care Platform for Preconception and Pregnancy Care: Pilot Feasibility and Acceptability Study.

BACKGROUND: A healthy lifestyle plays a key role in the prevention of lifestyle-related diseases, including subfertility and pregnancy complications. Although the benefits of a healthy lifestyle are well-known, long-term adherence is limited. Moreover, memory for lifestyle-related information as well as medical information provided by the medical professional is often poor and insufficient. In order to innovate and improve health care for both the patients and health care professionals, we developed a prototype of a digital life course care platform (Smarter Health app), providing personalized lifestyle care trajectories integrated in medical care journeys. OBJECTIVE: This pilot study aimed to evaluate the feasibility, defined as the actual app use, and the acceptability, which included patient satisfaction and appreciation, of the Smarter Health app. METHODS: Between March 17, 2021, and September 30, 2021, pregnant women familiar with the Dutch language seeking tertiary preconception and pregnancy care were offered the app as part of standard medical care at the outpatient clinic Healthy Pregnancy of the Department of Obstetrics and Gynecology of the Erasmus University Medical Center. Three months after activation of the app, patients received a digital questionnaire consisting of aspects of feasibility and acceptability. RESULTS: During this pilot study, 440 patients visited the outpatient clinic Healthy Pregnancy. Of the 440 patients, 293 (66.6%) activated the app. Of the 293 patients who activated the app, 125 (42.7%) filled out the questionnaire. Of these 125 patients, 48 (38.4%) used the app. Most app users used it occasionally and logged in 8 times during their medical care trajectory. Overall, app users were satisfied with the app (median 5-point Likert scale=2.4, IQR 2.0-3.3). CONCLUSIONS: Our findings showed that the Smarter Health app, which integrates lifestyle care in medical care, is a feasible health care innovation, and that patients were satisfied with the app. Follow-up and evaluation of pregnancy outcomes should be performed to further substantiate wider clinical implementation.

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.

The Role of the Kynurenine Pathway in the (Patho) physiology of Maternal Pregnancy and Fetal Outcomes: A Systematic Review.

Introduction: Tryptophan is the precursor of kynurenine pathway (KP) metabolites which regulate immune tolerance, energy metabolism, and vascular tone. Since these processes are important during pregnancy, changes in KP metabolite concentrations may play a role in the pathophysiology of pregnancy complications. We hypothesize that KP metabolites can serve as novel biomarkers and preventive therapeutic targets. This review aimed to provide more insight into associations between KP metabolite concentrations in maternal and fetal blood, and in the placenta, and adverse maternal pregnancy and fetal outcomes. Methods: A systematic search was performed on 18 February 2022 comprising all KP metabolites, and keywords related to maternal pregnancy and fetal outcomes. English-written human studies measuring KP metabolite(s) in maternal or fetal blood or in the placenta in relation to pregnancy complications, were included. Methodological quality was assessed using the ErasmusAGE quality score (QS) (range: 0-10). A meta-analysis of the mean maternal tryptophan and kynurenine concentrations in uncomplicated pregnancies was conducted. Results: Of the 6262 unique records, 37 were included (median QS = 5). Tryptophan was investigated in most studies, followed by kynurenine, predominantly in maternal blood (n = 28/37), and in the second and third trimester of pregnancy (n = 29/37). Compared to uncomplicated pregnancies, decreased tryptophan in maternal blood was associated with an increased prevalence of depression, gestational diabetes mellitus, fetal growth restriction, spontaneous abortion, and preterm birth. Elevated tryptophan was only observed in women with pregnancy-induced hypertension compared to normotensive pregnant women. In women with preeclampsia, only kynurenic acid was altered; elevated in the first trimester of pregnancy, and positively associated with proteinuria in the third trimester of pregnancy. Conclusions: KP metabolite concentrations were altered in a variety of maternal pregnancy and fetal complications. This review implies that physiological pregnancy requires a tight balance of KP metabolites, and that disturbances in either direction are associated with adverse maternal pregnancy and fetal outcomes.

Periconceptional Maternal Protein Intake from Animal and Plant Sources and the Impact on Early and Late Prenatal Growth and Birthweight: The Rotterdam Periconceptional Cohort.

Plant-based diets continue to rise in popularity, including among women of reproductive age, while consequences for pregnancy outcomes have hardly been studied. During pregnancy, maternal diet is the only source of proteins for the developing fetus. Hence, we investigated the effects of periconceptional maternal animal and plant protein intake on prenatal growth and birthweight. 501 pregnancies were included from the prospective Rotterdam Periconceptional Cohort. Embryonic growth was depicted by crown-rump length (CRL) and embryonic volume (EV) at 7, 9 and 11 weeks using 3D ultrasound scans. Estimated fetal weight (EFW) at 20 weeks and birthweight were retrieved from medical records and standardized. Multivariable mixed models were used for CRL and EV trajectories, and linear regression for EFW and birthweight. A 10 g/day higher maternal animal protein intake was positively associated with increased embryonic growth (CRL: ß = 0.023 √mm, p = 0.052; EV: ß = 0.015 ∛cm, p = 0.012). A positive association, albeit non-significant, was found between maternal animal protein intake and EFW, and birthweight. No clear associations emerged between maternal plant protein intake and prenatal growth and birthweight, with effect estimates close to zero. In conclusion, maternal animal protein intake during the periconception period was positively associated with early and late prenatal growth and birthweight, while no associations were found between maternal plant protein intake and prenatal growth and birthweight.

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.

Management of panhypopituitarism during pregnancy: A case report.

Clinicians face many challenges regarding conception and pregnancy management for women with panhypopituitarism. Fertility in women with panhypopituitarism is often reduced, and they are at risk of obstetric complications. The authors describe the case of a woman with congenital panhypopituitarism who had a successful pregnancy after ovulation induction and optimization of hormonal replacement therapy. This case report emphasizes the importance of careful adjustment of hormonal replacement therapy in managing pregnant women with panhypopituitarism.