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.

The one-carbon metabolism as an underlying pathway for placental DNA methylation - a systematic review.

Epigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health. Micronutrients including folate, choline, and vitamin B12 provide methyl groups for the one-carbon metabolism and subsequent DNA methylation processes. Placental DNA methylation changes in response to one-carbon moieties hold potential targets to improve obstetrical care. We conducted a systematic review on the associations between one-carbon metabolism and human placental DNA methylation. We included 22 studies. Findings from clinical studies with minimal ErasmusAGE quality score 5/10 (n = 15) and in vitro studies (n = 3) are summarized for different one-carbon moieties. Next, results are discussed per study approach: (1) global DNA methylation (n = 9), (2) genome-wide analyses (n = 4), and (3) gene specific (n = 14). Generally, one-carbon moieties were not associated with global methylation, although conflicting outcomes were reported specifically for choline. Using genome-wide approaches, few differentially methylated sites associated with S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), or dietary patterns. Most studies taking a gene-specific approach indicated site-specific relationships depending on studied moiety and genomic region, specifically in genes involved in growth and development including LEP, NR3C1, CRH, and PlGF; however, overlap between studies was low. Therefore, we recommend to further investigate the impact of an optimized one-carbon metabolism on DNA methylation and lifelong health.

The intake of ultra-processed foods and homocysteine levels in women with(out) overweight and obesity: The Rotterdam Periconceptional Cohort.

PURPOSE: Today's diet consists of a substantial proportion of ultra-processed foods (UPF), especially in women with overweight and obesity in the reproductive period. High UPF intake results in an inadequate and unbalanced diet leading to derangements of several metabolic pathways detrimental to pregnancy and birth outcomes. Therefore, we aim to investigate whether UPF intake in the periconceptional period affects total homocysteine plasma levels (tHcy). METHODS: 1532 participants were included from the prospective Rotterdam Periconceptional Cohort. UPF intake was calculated using Food Frequency Questionnaires including items classified as 4 in the Nova classification, and tHcy was measured by using liquid chromatography-tandem mass spectrometry system, with an interassay coefficient of variation of < 5.5%. Multivariable linear regression modeling was used and adjusted for covariates and significant interaction terms. RESULTS: Women with overweight or obesity showed significantly higher percentage of UPF intake (respectively, 50.3 and 51.3%) and higher tHcy (respectively, 6.6 and 6.3 µmol/L, Kruskal-Wallis test; respectively, p < 0.001 and p = 0.04) compared to women with normal BMI (UPF intake: 46.8%, tHcy: 6.1 µmol/L). A 10% higher intake of UPF was associated with an increase in tHcy (adjusted: ß = 1.31, 95% CI = 0.38-2.23). Analysis stratified for BMI classification showed comparable associations in normal weight participants (adjusted: ß = 1.07, 95% CI = 0.06-2.07); however, no significant association in participants with overweight (adjusted: ß = 0.06, 95% CI = - 0.95-1.07) and obesity (adjusted: ß = 1.70, 95% CI = - 0.52-3.92) was shown. CONCLUSION: This study showed that a higher intake of UPF is associated with increased tHcy. Better knowledge and awareness of the nutritional quality of the diet in the periconceptional period may contribute to 1-CM and subsequently improve pregnancy course and outcome. TRIAL REGISTRATION NUMBER AND DATE: NTR4356, November 2010.

First-trimester 3D power Doppler imaging markers of utero-placental vascular development are associated with placental weight and diameter at birth: The Rotterdam Periconception Cohort.

INTRODUCTION: Early utero-placental vascular development impacts placental development and function throughout pregnancy. We investigated whether impaired first-trimester utero-placental vascular development is associated with pathologic features of the postpartum placenta. METHODS: In this prospective observational study of 65 ongoing pregnancies, we obtained three-dimensional power Doppler ultrasounds of the placenta at 7, 9 and 11 weeks of gestation. We applied VOCAL software to measure placental volume (PV), virtual reality based segmentation to measure utero-placental vascular volume (uPVV) and applied a skeletonization algorithm to generate the utero-placental vascular skeleton (uPVS). Vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-, crossing- or vessel point). Following delivery, placentas were measured and histologically examined according to the Amsterdam criteria to assess maternal vascular malperfusion (MVM). We used linear mixed models to estimate trajectories of PV, uPVV and uPVS development. Multivariable linear regression analysis with adjustments for confounders was used to evaluate associations between PV, uPVV and uPVS development and features of the postpartum placenta. RESULTS: We observed no associations between first-trimester PV development and measurements of the postpartum placenta. Increased first-trimester utero-placental vascular development, reflected by uPVV (ß = 0.25 [0.01; 0.48]), uPVS end points (ß = 0.25 [0.01; 0.48]), bifurcation points (ß = 0.22 [0.05; 0.37]), crossing points (ß = 0.29 [0.07; 0.52]) and vessel points (ß = 0.09 [0.02; 0.17]) was positively associated with the postpartum placental diameter. uPVV was positively associated with postpartum placental weight. No associations were found with MVM. DISCUSSION: Development of the first-trimester utero-placental vasculature is associated with postpartum placental size, whereas placental tissue development contributes to a lesser extent.

Prenatal counseling of an isolated fetal small head circumference during the second trimester expert ultrasound examination.

OBJECTIVE: To evaluate perinatal and postnatal outcomes of fetuses with an isolated small head circumference (HC) on expert ultrasound examination in the second trimester for further recommendations in prenatal care. STUDY DESIGN: In a retrospective cohort we included singleton-pregnancies with a fetal HC > -3.0 SD and ≤ -1.64 SD determined on expert ultrasound examination between 18 and 24 weeks of gestational age. Three subgroups were determined: "isolated small HC (ISHC)", "small HC plus abdominal circumference (AC) ≤ p10 (SHC+)" and "small HC plus AC ≤ p10 and Doppler abnormalities (SHC + D)". After ultrasound examination, genetic testing was sometimes offered and postnatally genetic tests were performed on indication. RESULTS: We included 252 pregnancies: 109 ISHC, 104 SHC+, and 39 SHC + D. In the ISHC and SHC+ subgroup, 96 % of the fetuses were born alive and did not die neonatal. In the SH + D group this was only 38 %. In the SHC+ subgroup, less fetuses were delivered vaginal (non-instrumental) compared to the ISHC subgroup (61 % vs. 73 %, p < 0.01). In the ISHC and SHC+ subgroup s some fetuses were diagnosed with congenital defects (4 % vs. 10 %, p = 0.08) and with a genetic anomaly (6.4 % vs. 7.7 %, p = 0.13) after 24 weeks or postnatally. In SHC + D subgroups 5 % presented with congenital defects and 2.6 % with a genetic anomaly. CONCLUSION: We conclude that fetuses with a small HC without structural anomalies on second trimester expert ultrasound require follow-up and special medical attention. We recommend differentiating between ISHC, SHC+, and SHC + D for prenatal counseling. Genetic testing and referral to a clinical geneticist should be considered.

Preconception maternal gastric bypass surgery and the impact on fetal growth parameters.

BACKGROUND: Bariatric surgery is increasingly performed in women of reproductive age. As bariatric surgery will result in postoperative rapid catabolic weight loss which potentially leads to fetal malnutrition and directly related impaired intra-uterine growth, it is advised to postpone pregnancy for at least 12-18 months after surgery. OBJECTIVES: To investigate the consequences of preconception gastric bypass surgery (pGB) on fetal growth parameters and maternal pregnancy outcome. SETTING: Maasstad Hospital, The Netherlands, general hospital and Erasmus Medical Center, The Netherlands, university hospital. METHODS: We included 97 pGB pregnancies (Maasstad hospital) and 440 non-bariatric pregnancies (Rotterdam Periconception cohort, Erasmus Medical Center). Longitudinal second and third trimester fetal growth parameters (head circumference, biparietal diameter, femur length, abdominal circumference, estimated fetal weight) were analyzed using linear mixed models, adjusting for covariates and possible confounders. Fetal growth and birthweight in pGB pregnancies were compared to non-bariatric pregnancies and Dutch reference curves. Maternal pregnancy outcome in the pGB group was compared to non-bariatric pregnancies. RESULTS: All fetal growth parameters of pGB pregnancies were significantly decreased at 20 weeks' gestation (P < .001) and throughout the remaining part of pregnancy (P < .05) compared with non-bariatric pregnancies (crude and adjusted models). In our cohort, gestational weight gain was not significantly associated with birthweight corrected for gestational age. Birthweight was significantly lower in pGB pregnancies (estimate -241 grams [95% CI, -342.7 to -140.0]) with a 2-fold increased risk of small-for-gestational-age (SGA) (adjusted odds ratio 2.053 [95% CI, 1.058 to 3.872]). Compared to the non-bariatric pregnancies, we found no significant differences in maternal pregnancy outcome. CONCLUSIONS: PGB is associated with overall reduced fetal growth trajectories and a 2-fold increased risk of SGA, without significant adverse consequences for maternal pregnancy outcome. We recommend close monitoring of fetal growth after pGB.

The prevalence of thyroid dysfunction and hyperprolactinemia in women with PCOS.

Introduction: Ovulatory dysfunction is usually caused by an endocrine disorder, of which polycystic ovary syndrome (PCOS) is the most common cause. PCOS is usually associated with estrogen levels within the normal range and can be characterized by oligo-/anovulation resulting in decreased progesterone levels. It is suggested that decreased progesterone levels may lead to more autoimmune diseases in women with PCOS. In addition, it is often claimed that there is an association between hyperprolactinemia and PCOS. In this large well-phenotyped cohort of women with PCOS, we have studied the prevalence of thyroid dysfunction and hyperprolactinemia compared to controls, and compared this between the four PCOS phenotypes. Methods: This retrospective cross-sectional study contains data of 1429 women with PCOS and 299 women without PCOS. Main outcome measures included thyroid stimulating hormone (TSH), Free Thyroxine (FT4), and anti-thyroid peroxidase antibodies (TPOab) levels in serum, the prevalence of thyroid diseases and hyperprolactinemia. Results: The prevalence of thyroid disease in PCOS women was similar to that of controls (1.9% versus 2.7%; P = 0.39 for hypothyroidism and 0.5% versus 0%; P = 0.99 for hyperthyroidism). TSH levels were also similar (1.55 mIU/L versus 1.48 mIU/L; P = 0.54). FT4 levels were slightly elevated in the PCOS group, although within the normal range (18.1 pmol/L versus 17.7 pmol/L; P < 0.05). The prevalence of positive TPOab was similar in both groups (5.7% versus 8.7%; P = 0.12). The prevalence of hyperprolactinemia was similarly not increased in women with PCOS (1.3%% versus 3%; P = 0.05). In a subanalysis of 235 women with PCOS and 235 age- and BMI-matched controls, we found no differences in thyroid dysfunction or hyperprolactinemia. In according to differences between PCOS phenotypes, only the prevalence of subclinical hypothyroidism was significantly higher in phenotype B (6.3%, n = 6) compared to the other phenotypes. Conclusion: Women with PCOS do not suffer from thyroid dysfunction more often than controls. Also, the prevalence of positive TPOab, being a marker for future risk of thyroid pathology, was similar in both groups. Furthermore, the prevalence of hyperprolactinemia was similar in women with PCOS compared to controls.

Stimulating the Uptake of Preconception Care by Women With a Vulnerable Health Status Through mHealth App-Based Nudging (Pregnant Faster): Cocreation Design and Protocol for a Cohort Study.

BACKGROUND: Women with a low socioeconomic status often have a vulnerable health status due to an accumulation of health-deteriorating factors such as poor lifestyle behaviors, including inadequate nutrition, mental stressors, and impaired health literacy and agency, which puts them at an unnecessary high risk of adverse pregnancy outcomes. Adequately preparing for pregnancy through preconception care (PCC) uptake and lifestyle improvement can improve these outcomes. We hypothesize that nudging is a successful way of encouraging engagement in PCC. A nudge is a behavioral intervention that changes choice behavior through influencing incentives. The mobile health (mHealth) app-based loyalty program Pregnant Faster aims to reward women in an ethically justified way and nudges to engage in pregnancy preparation by visiting a PCC consultation. OBJECTIVE: Here, we first describe the process of the cocreation of the mHealth app Pregnant Faster that aims to increase engagement in pregnancy preparation by women with a vulnerable health status. Second, we describe the cohort study design to assess the feasibility of Pregnant Faster. METHODS: The content of the app is based on the eHealth lifestyle coaching program Smarter Pregnancy, which has proven to be effective in ameliorating preconceptional lifestyle behaviors (folic acid, vegetables, fruits, smoking, and alcohol) and an interview study pertaining to the preferences of the target group with regard to an mHealth app stimulating PCC uptake. For moral guidance on the design, an ethical framework was developed based on the bioethical principles of Beauchamp and Childress. The app was further developed through iterative cocreation with the target group and health care providers. For 4 weeks, participants will engage with Pregnant Faster, during which opportunities will arise to earn coins such as reading informative blogs and registering for a PCC consultation. Coins can be spent on small fun rewards, such as folic acid, fruits, and mascara. Pregnant Faster's feasibility will be tested in a study including 40 women aged 18 to 45 years, who are preconceptional or <8 weeks pregnant, with a low educational level, and living in a deprived neighborhood. The latter 2 factors will serve as a proxy of a low socioeconomic status. Recruitment will take place through flyers, social media, and health care practices. After finalization, participants will evaluate the app through the "mHealth App Usability Questionnaire" and additional interviews or questionnaires. RESULTS: Results are expected to be published by December 2023. CONCLUSIONS: Pregnant Faster has been designed through iterative cocreation with the target group and health care professionals. With the designed study, we will test Pregnant Faster's feasibility. If overall user satisfaction and PCC uptake is achieved, the app will be further developed and the cohort will be continued with an additional 400 inclusions to establish effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45293.

Human oocyte area is associated with preimplantation embryo usage and early embryo development: the Rotterdam Periconception Cohort.

PURPOSE: To investigate the association between oocyte area and fertilization rate, embryo usage, and preimplantation embryo development in order to establish if oocyte area can be a marker for optimal early embryo development. METHODS: From 2017 to 2020, 378 couples with an indication for IVF (n = 124) or ICSI (n = 254) were included preconceptionally in the Rotterdam Periconception Cohort. Resulting oocytes (n = 2810) were fertilized and submitted to time-lapse embryo culture. Oocyte area was measured at the moment of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf). Fertilization rate, embryo usage and quality, and embryo morphokinetics from 2-cell stage to expanded blastocyst stage (t2-tEB) were used as outcome measures in association with oocyte area. Oocytes were termed "used" if they were fertilized and embryo development resulted in transfer or cryopreservation, and otherwise termed "discarded". Analyses were adjusted for relevant confounders. RESULTS: Oocyte area decreased from t0 to tPNf after IVF and ICSI, and oocytes with larger area shrank faster (ß - 12.6 µm2/h, 95%CI - 14.6; - 10.5, p < 0.001). Oocytes that resulted in a used embryo were larger at all time-points and reached tPNf faster than oocytes that fertilized but were discarded (oocyte area at tPNf in used 9864 ± 595 µm2 versus discarded 9679 ± 673 µm2, p < 0.001, tPNf in used 23.6 ± 3.2 h versus discarded 25.6 ± 5.9 h, p < 0.001). Larger oocytes had higher odds of being used (oocyte area at tPNf ORused 1.669, 95%CI 1.336; 2.085, p < 0.001), were associated with faster embryo development up to the morula stage (e.g., t9 ß - 0.131 min, 95%CI - 0.237; - 0.025, p = 0.016) and higher ICM quality. CONCLUSION: Oocyte area is an informative marker for the preimplantation development of the embryo, as a larger oocyte area is associated with higher quality, faster developing embryos, and higher chance of being used. Identifying determinants associated with oocyte and embryo viability and quality could contribute to improved preconception care and subsequently healthy pregnancies.

Using the embryo-uterus statistical model to predict pregnancy chances by using cleavage stage morphokinetics and female age: two centre-specific prediction models and mutual validation.

BACKGROUND: The predictive capability of time-lapse monitoring (TLM) selection algorithms is influenced by patient characteristics, type and quality of data included in the analysis and the used statistical methods. Previous studies excluded DET cycles of which only one embryo implanted, introducing bias into the data. Therefore, we wanted to develop a TLM prediction model that is able to predict pregnancy chances after both single- and double embryo transfer (SET and DET). METHODS: This is a retrospective study of couples (n = 1770) undergoing an in vitro fertilization cycle at the Erasmus MC, University Medical Centre Rotterdam (clinic A) or the Reinier de Graaf Hospital (clinic B). This resulted in 2058 transferred embryos with time-lapse and pregnancy outcome information. For each dataset a prediction model was established by using the Embryo-Uterus statistical model with the number of gestational sacs as the outcome variable. This process was followed by cross-validation. RESULTS: Prediction model A (based on data of clinic A) included female age, t3-t2 and t5-t4, and model B (clinic B) included female age, t2, t3-t2 and t5-t4. Internal validation showed overfitting of model A (calibration slope 0.765 and area under the curve (AUC) 0.60), and minor overfitting of model B (slope 0.915 and AUC 0.65). External validation showed that model A was capable of predicting pregnancy in the dataset of clinic B with an AUC of 0.65 (95% CI: 0.61-0.69; slope 1.223, 95% CI: 0.903-1.561). Model B was less accurate in predicting pregnancy in the dataset of clinic A (AUC 0.60, 95% CI: 0.56-0.65; slope 0.671, 95% CI: 0.422-0.939). CONCLUSION: Our study demonstrates a novel approach to the development of a TLM prediction model by applying the EU statistical model. With further development and validation in clinical practice, our prediction model approach can aid in embryo selection and decision making for SET or DET.

Circulating maternal prorenin and oocyte and preimplantation embryo development: the Rotterdam Periconception Cohort.

STUDY QUESTION: Could circulating maternal prorenin serve as a proxy for oocyte and preimplantation embryo development, assessed by time-lapse parameters and clinical treatment outcomes? SUMMARY ANSWER: High circulating maternal prorenin concentrations after ovarian stimulation associate with a larger oocyte area, faster cleavage divisions from the five-cell stage onwards and increased chance of successful implantation. WHAT IS KNOWN ALREADY: After ovarian stimulation, circulating prorenin (renin's precursor), is largely ovary-derived. Prorenin may contribute to ovarian angiotensin synthesis, which is relevant in reproduction given its role in follicular development and oocyte maturation. STUDY DESIGN, SIZE, DURATION: Prospective observational cohort study including couples requiring fertility treatment from May 2017 as a subcohort of the ongoing Rotterdam Periconception Cohort conducted in a tertiary referral hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between May 2017 and July 2020, 309 couples with an indication for IVF treatment or ICSI were included. Resulting embryos (n = 1024) were submitted to time-lapse embryo culture. Time of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf) as well as the exact timing of reaching the two- to eight-cell stage (t2-t8), the start of blastulation (tSB), reaching the full (tB), and expanded blastocyst (tEB) were retrospectively recorded. Oocyte area was measured at t0, tPNa, and tPNf. Prorenin was determined at the day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for patient- and treatment-related factors, linear mixed modeling showed that higher prorenin concentrations associate with a larger oocyte area at tPNa (ß 64.45 µm2, 95% CI 3.26; 125.64, P = 0.04), and faster progression from five-cell stage onwards (e.g. ß8-cell -1.37 h, 95% CI -2.48; -0.26, P = 0.02). Prorenin associated positively with pre-transfer outcomes (e.g. ßfertilized oocytes 2.09, 95% CI 1.43; 2.75, P < 0.001) and implantation (odds ratio+ß-hCG-test: 1.79, 95% CI 1.06; 3.08, P = 0.03), but not with live birth. LIMITATIONS, REASONS FOR CAUTION: This prospective observational study provides associations and therefore residual confounding cannot be excluded and causality has to be shown in intervention studies. WIDER IMPLICATIONS OF THE FINDINGS: Theca cell-derived factors, such as prorenin, may help to clarify the underlying endocrine mechanism of oocyte maturation and embryo development, with a special focus on the (patho)physiological reproductive role of prorenin and the identification of factors influencing its secretion and activity, which is of great added value for improving embryo selection and predicting implantation and pregnancy outcomes. This will bring us to investigate which determinants of oocyte quality and embryo development should take center stage in developing preconception care strategies. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Erasmus MC Medical Research Advisor Committee's 'Health Care Efficiency Research' program (OZBS72.16080). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Computational methods for the analysis of early-pregnancy brain ultrasonography: a systematic review.

BACKGROUND: Early screening of the brain is becoming routine clinical practice. Currently, this screening is performed by manual measurements and visual analysis, which is time-consuming and prone to errors. Computational methods may support this screening. Hence, the aim of this systematic review is to gain insight into future research directions needed to bring automated early-pregnancy ultrasound analysis of the human brain to clinical practice. METHODS: We searched PubMed (Medline ALL Ovid), EMBASE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar, from inception until June 2022. This study is registered in PROSPERO at CRD42020189888. Studies about computational methods for the analysis of human brain ultrasonography acquired before the 20th week of pregnancy were included. The key reported attributes were: level of automation, learning-based or not, the usage of clinical routine data depicting normal and abnormal brain development, public sharing of program source code and data, and analysis of the confounding factors. FINDINGS: Our search identified 2575 studies, of which 55 were included. 76% used an automatic method, 62% a learning-based method, 45% used clinical routine data and in addition, for 13% the data depicted abnormal development. None of the studies shared publicly the program source code and only two studies shared the data. Finally, 35% did not analyse the influence of confounding factors. INTERPRETATION: Our review showed an interest in automatic, learning-based methods. To bring these methods to clinical practice we recommend that studies: use routine clinical data depicting both normal and abnormal development, make their dataset and program source code publicly available, and be attentive to the influence of confounding factors. Introduction of automated computational methods for early-pregnancy brain ultrasonography will save valuable time during screening, and ultimately lead to better detection, treatment and prevention of neuro-developmental disorders. FUNDING: The Erasmus MC Medical Research Advisor Committee (grant number: FB 379283).

Periconceptional biomarkers for maternal obesity: a systematic review.

Periconceptional maternal obesity is linked to adverse maternal and neonatal outcomes. Identifying periconceptional biomarkers of pathways affected by maternal obesity can unravel pathophysiologic mechanisms and identify individuals at risk of adverse clinical outcomes. The literature was systematically reviewed to identify periconceptional biomarkers of the endocrine, inflammatory and one-carbon metabolic pathways influenced by maternal obesity. A search was conducted in Embase, Ovid Medline All, Web of Science Core Collection and Cochrane Central Register of Controlled Trials databases, complemented by manual search in PubMed until December 31st, 2020. Eligible studies were those that measured biomarker(s) in relation to maternal obesity, overweight/obesity or body mass index (BMI) during the periconceptional period (14 weeks preconception until 14 weeks post conception). The ErasmusAGE score was used to assess the quality of included studies. Fifty-one articles were included that evaluated over 40 biomarkers. Endocrine biomarkers associated with maternal obesity included leptin, insulin, thyroid stimulating hormone, adiponectin, progesterone, free T4 and human chorionic gonadotropin. C-reactive protein was associated with obesity as part of the inflammatory pathway, while the associated one-carbon metabolism biomarkers were folate and vitamin B12. BMI was positively associated with leptin, C-reactive protein and insulin resistance, and negatively associated with Free T4, progesterone and human chorionic gonadotropin. Concerning the remaining studied biomarkers, strong conclusions could not be established due to limited or contradictory data. Future research should focus on determining the predictive value of the optimal set of biomarkers for their use in clinical settings. The most promising biomarkers include leptin, adiponectin, human chorionic gonadotropin, insulin, progesterone and CRP.

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.

Maternal Sleep Problems in the Periconceptional Period and the Impact on Health of Mother and Offspring: A Systematic Review.

Knowledge of the impact of sleep problems in the periconceptional period is scarce. Since this period is the most sensitive time window for embryonic and placental development, we aim to study the impact of maternal sleep problems in the periconceptional period on both mother and offspring. We systematically searched various databases up until September 2021 for studies reporting on maternal sleep in the periconceptional period and any outcome in mother and offspring. We included observational studies describing maternal sleep problems in the periconceptional period and associations with either maternal and/or offspring outcomes. The search produced 8596 articles, of which we selected 27 studies. Some associations were found between sleep problems and lower fertility, more hypertensive disorders, more mood disorders in mothers, higher risk of preterm birth and low birth weight, and more sleep and behavior problems in offspring, with associations with maternal mood disorders being most consistent. This systematic review shows that maternal sleep problems in the periconceptional period are associated with a higher risk of various adverse outcomes in both mother and offspring, although not consistently. It shows that good sleep during pregnancy is crucial, starting as early as before conception, especially for maternal mood. Therefore, it is important for clinicians to pay attention to sleep problems in the periconceptional period and provide adequate treatment for potential sleep problems, even before pregnancy.

Assessment of first-trimester utero-placental vascular morphology by 3D power Doppler ultrasound image analysis using a skeletonization algorithm: the Rotterdam Periconception Cohort.

STUDY QUESTION: Can three-dimensional (3D) Power Doppler (PD) ultrasound and a skeletonization algorithm be used to assess first-trimester development of the utero-placental vascular morphology? SUMMARY ANSWER: The application of 3D PD ultrasonography and a skeletonization algorithm facilitates morphologic assessment of utero-placental vascular development in the first trimester and reveals less advanced vascular morphologic development in pregnancies with placenta-related complications than in pregnancies without placenta-related complications. WHAT IS KNOWN ALREADY: Suboptimal development of the utero-placental vasculature is one of the main contributors to the periconceptional origin of placenta-related complications. The nature and attribution of aberrant vascular structure and branching patterns remain unclear, as validated markers monitoring first-trimester utero-placental vascular morphologic development are lacking. STUDY DESIGN, SIZE, DURATION: In this prospective observational cohort, 214 ongoing pregnancies were included before 10 weeks gestational age (GA) at a tertiary hospital between January 2017 and July 2018, as a subcohort of the ongoing Rotterdam Periconception Cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: By combining 3D PD ultrasonography and virtual reality, utero-placental vascular volume (uPVV) measurements were obtained at 7, 9 and 11 weeks GA. A skeletonization algorithm was applied to the uPVV measurements to generate the utero-placental vascular skeleton (uPVS), a network-like structure containing morphologic characteristics of the vasculature. Quantification of vascular morphology was performed by assigning a morphologic characteristic to each voxel in the uPVS (end-, vessel-, bifurcation- or crossing-point) and calculating total vascular network length. A Mann-Whitney U test was performed to investigate differences in morphologic development of the first-trimester utero-placental vasculature between pregnancies with and without placenta-related complications. Linear mixed models were used to estimate trajectories of the morphologic characteristics in the first trimester. MAIN RESULTS AND THE ROLE OF CHANCE: All morphologic characteristics of the utero-placental vasculature increased significantly in the first trimester (P < 0.005). In pregnancies with placenta-related complications (n = 54), utero-placental vascular branching was significantly less advanced at 9 weeks GA (vessel points P = 0.040, bifurcation points P = 0.050, crossing points P = 0.020, total network length P = 0.023). Morphologic growth trajectories remained similar after adjustment for parity, conception mode, foetal sex and occurrence of placenta-related complications. LIMITATIONS, REASONS FOR CAUTION: The tertiary setting of this prospective observational study provides high internal, but possibly limited external, validity. Extrapolation of the study's findings should therefore be addressed with caution. WIDER IMPLICATIONS OF THE FINDINGS: The uPVS enables assessment of morphologic development of the first-trimester utero-placental vasculature. Further investigation of this innovative methodology needs to determine its added value for the assessment of (patho-) physiological utero-placental vascular development. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).

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.

The impact of IVF culture medium on post-implantation embryonic growth and development with emphasis on sex specificity: the Rotterdam Periconceptional Cohort.

RESEARCH QUESTION: Are there (sex-specific) differences in first-trimester embryonic growth and morphological development between two culture media used for IVF and intracytoplasmic sperm injection (ICSI) treatment? DESIGN: A total of 835 singleton pregnancies from a prospective hospital-based cohort study were included, of which 153 conceived after IVF/ICSI treatment with Vitrolife G-1™ PLUS culture medium, 252 after culture in SAGE 1-Step™ and 430 were naturally conceived. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9 and 11 weeks of gestation for offline biometric (crown rump length, CRL), volumetric (embryonic volume) and morphological (Carnegie stage) measurements. RESULTS: Embryos cultured in SAGE 1-Step grew faster than those cultured in Vitrolife G-1 PLUS (betaEV 0.030 3√ml [95% CI 0.008-0.052], P = 0.007). After stratification for fetal sex, male embryos cultured in SAGE 1-Step demonstrated faster growth than those cultured in Vitrolife G-1 PLUS (betaEV 0.048 3√ml [95% CI 0.015-0.081], P = 0.005). When compared with naturally conceived embryos, those cultured in SAGE 1-Step grew faster (betaEV 0.040 3√ml [95% CI 0.012-0.069], P = 0.005). This association was most pronounced in male embryos (betaEV 0.078 3√ml [95% CI 0.035-0.120], P < 0.001). CONCLUSIONS: This study shows that SAGE 1-Step culture medium accelerates embryonic growth trajectories compared with Vitrolife G-1 PLUS and naturally conceived pregnancies, especially in male embryos. Further research should focus on the impact of culture media on postnatal development and the susceptibility to non-communicable diseases.

Preferences of women with a vulnerable health status towards nudging for adequate pregnancy preparation as investment in health of future generations: a qualitative study.

BACKGROUND: Women with a vulnerable health status, as determined by a low socioeconomic status and poor lifestyle behaviours, are at risk for adverse pregnancy outcomes. Offering tailored preconception lifestyle care can significantly help to improve pregnancy outcomes. We hypothesize that so-called 'nudges' can be a successful way of increasing the uptake of preconception lifestyle care. A nudge is a behavioural intervention that supports healthy choices by making them easier to choose. Nudging, however, raises many moral questions. Effectiveness and respect for autonomy are, among other criteria, required for a nudge to be morally permissible. In general, the target group knows best what they find permissible and what would motivate them to change their lifestyle. Therefore, this study - conducted in women with a vulnerable health status - aimed to identify their preferences towards a nudge, provided via a mobile application that aims to help them adopt healthy lifestyle behaviours by offering rewards.  METHODS: We conducted semi-structured interviews with twelve women with a vulnerable health status. A framework approach was used to analyse the data. A thematic content analysis was conducted on five themes: (1) "Usefulness of an app as an integral information source", (2) "Permissibility and effects of offering rewards", (3) "Preferences regarding content", (4) "Preferences regarding type of rewards and system of allocation", and (5) "Barriers". RESULTS: Of the 12 participants, 11 deemed an app as integral information source concerning the preconception period useful. None of the participants objected to being nudged i.e., being rewarded for healthy behaviour. All participants stated that they would like the app to contain information on healthy nutrition and 8 participants wanted to know how to get pregnant quickly. Furthermore, participants stated that the freedom to choose the timing and content of the reward would increase the probability of successful behavioural change, and having to pay or contact a healthcare provider to access the app may prevent women using the app. CONCLUSIONS: These insights into the preferences of women with a vulnerable health status towards nudging will inform the design of an effective app-based nudge. This may help to improve prepregnancy health as investment in health of current and future generations.