Search

Christiaan Theunisse,1,2 Huibert H Ponssen,2 Netty T C de Graaf,1 Maaike Scholten-Bakker,1 Sten P Willemsen,3 David Cheung1 1Department of Pulmonology, Albert Schweitzer Hospital, Dordrecht, the Netherlands; 2Department of Intensive Care, Albert Schweitzer Hospital, Dordrecht, the Netherlands; 3Department of Biostatics, Erasmus University Medical Centre, Rotterdam, the NetherlandsCorrespondence: David CheungDepartment of Pulmonology, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, Dordrecht, AT, NL-3318, the NetherlandsTel +31-78-6523328Fax +31-78-6523354Email d.cheung@asz.nlBackground: The effectiveness of non-invasive home ventilation in patients with severe chronic obstructive pulmonary disease (COPD) is lacking. Non-invasive home ventilation might be more effective when high ventilator settings are used. However, high ventilator settings might reduce patient adherence. We have developed a multidisciplinary approach (ventilation practitioners, 24 hours support of respiratory nurses, physicians) to non-invasive ventilation aimed at optimizing patient adherence using low ventilator settings in severe COPD patients with high disease burden irrespectively having hypercapnia.Methods: We included in a proof of concept, prospective interventional study, 48 GOLD stage III–IV COPD patients with a high disease burden (≥ 2 exacerbations in a year, and Medical Research Council dyspnea scores ≥ 3). Outcome measures included hospital admissions, capillary pCO2, Medical Research Council dyspnea scores (MRC), Clinical COPD Questionnaire scores (CCQ) and Hospital Anxiety and Depression Scale (HADS).Results: After 1 year 32 patients could be evaluated. Hospital admissions decreased by 1.0 admission (mean difference ± SD: 1.0 ± 1.48; p = 0.001). In-hospital days decreased by 10.0 days (10.0 ± 15.48; p = 0.001). Capillary pCO2 decreased by 0.33 kPa (0.33 ± 0.81: p = 0.03). The MRC dyspnea score decreased by 0.66 (0.66 ± 1.35; p = 0.02). The CCQ score decreased by 0.59 (0.59 ± 1.39; p = 0.03). The HADS anxiety score decreased by 1.64 (1.64 ± 3.12; p = 0.01). The HADS depression score decreased by 1.64 (1.64 ± 3.91; p = 0.04).Conclusion: A proof of concept multidisciplinary approach, using low pressure domiciliary non-invasive ventilation, aimed at optimizing patient adherence in severe COPD patients regardless having hypercapnia, reduced hospital admissions and improved symptoms and quality of life measures. This may imply that severe COPD patients with high disease burden, irrespective being hypercapnic, are candidates to be treated with low pressure domiciliary non-invasive ventilation.Keywords: COPD, non-invasive ventilation, domiciliary, hospitalization, compliance

Objective: To investigate whether first‐trimester maternal haemodynamic adaptation impacts placental, embryonic and fetal development as well as birth outcomes in pregnancies with and without placenta‐related complications. Design: Prospective observational cohort. Setting: A Dutch tertiary hospital. Population: Two hundred and fourteen ongoing pregnancies. Methods: At 7, 9 and 11 weeks of gestation, we assessed maternal haemodynamic adaptation (mean arterial blood pressure [MAP], uterine artery [UtA] blood flow) and placental development (placental volume [PV], uteroplacental vascular volume [uPVV]) using three‐dimensional power Doppler ultrasound volumes, and embryonic development (crown–rump length, embryonic volume). At 22 and 32 weeks of gestation, fetal development was assessed by estimated fetal weight. Birth outcomes (birthweight, placental weight) were extracted from medical records. Linear mixed modelling and linear regression analyses were applied. Main outcome measures: Birthweight centile and placental weight. Results: In placenta‐related complications (n= 55, 25.7%), reduced haemodynamic adaptation, i.e. higher UtA pulsatility index (PI) and resistance index (RI) trajectories, was associated with smaller increase in PV (β = −0.559, 95% CI −0.841 to −0.278, P< 0.001; β = −0.579, 95% CI −0.878 to −0.280, P< 0.001) and uPVV trajectories (UtA PI: β = −0.301, 95% CI −0.578 to −0.023, P= 0.034). At birth, reduced haemodynamic adaptation was associated with lower placental weight (UtA PI: β = −0.502, 95% CI −0.922 to −0.082, P= 0.022; UtA RI: β = −0.435, 95% CI −0.839 to −0.032, P= 0.036). In pregnancies without placenta‐related complications, higher MAP trajectories were positively associated with birthweight centile (β = 0.398, 95% CI 0.049–0.748, P= 0.025). Conclusions: Reduced first‐trimester maternal haemodynamic adaptation impacts both placental size and vascularisation and birthweight centile, in particular in pregnancies with placenta‐related complications. Reduced first‐trimester maternal haemodynamic adaptation to pregnancy impairs early placental development. [ABSTRACT FROM AUTHOR]

Objective To assess the digit preference for last menstrual period ( LMP) dates, associated determinants and impact on obstetric outcome. Design Retrospective cohort study. Setting University medical centre (the Netherlands). Population Cohort of 24 665 LMP records and a subgroup of 4630 cases with known crown-rump length ( CRL) measurement, and obstetric outcome. Methods Digit preference was determined by comparing the observed to expected counts of each day. Associated determinants were identified by multivariate regression analysis. Differences in obstetric outcome between LMP and CRL dating were analysed. Main outcome measures (Non)deprived neighbourhood, cycle irregularity, certainty of LMP date, maternal age, smoking, body mass index, parity and ultrasound investigator. Preterm and post-term delivery. Results LMP digit preference for the first [odds ratio ( OR), 1.28; 95% confidence interval (95% CI), 1.20-1.36], fifth ( OR, 1.10; 95% CI, 1.03-1.17), 10th ( OR, 1.17; 95% CI, 1.09-1.25), 15th ( OR, 1.31; 95% CI, 1.23-1.40), 20th ( OR, 1.22; 95% CI, 1.15-1.30) and 25th ( OR, 1.08; 95% CI, 1.01-1.15) days of the month occurred more often than expected. Digit preference occurred more frequently in women living in a deprived neighbourhood ( OR, 1.21; 95% CI, 1.06-1.39), with uncertain LMP ( OR, 2.03; 95% CI, 1.63-2.52) or irregular cycle ( OR, 1.24; 95% CI, 1.06-1.44). More post-term (≥42 weeks) deliveries ( OR, 1.27; 95% CI, 1.05-1.54) were observed in LMP dating. This effect was larger in women with a digit preference ( OR, 1.56; 95% CI, 1.03-2.37). Conclusions LMP digit preference occurs more often in women living in deprived neighbourhoods, with uncertain LMP or an irregular cycle. LMP-dated pregnancies are associated with more post-term pregnancies. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between periconception maternal folate status and embryonic size. Design Prospective periconception cohort study. Setting Erasmus University Medical Centre, Rotterdam, the Netherlands. Population Seventy-seven singleton pregnancies recruited in 2009 and 2010. Methods We recruited women before 8 weeks of gestation and performed weekly three-dimensional ultrasound scans from enrolment up to 13 weeks of gestation. As a measure of embryonic growth, crown-rump length ( CRL) measurements were performed using V-Scope software in the BARCO I-Space. Maternal blood was collected to determine first-trimester long-term red blood cell ( RBC) folate status. Non-malformed live births were included in the analysis. We calculated quartiles of RBC folate, square root-transformed CRL data and performed multivariable linear mixed model analyses. Main outcome measures Serial first-trimester CRL measurements. Results In total, 484 ultrasound scans were performed in 77 women, in 440 (90.7%) of which CRLs could be measured. RBC folate in the third quartile (1513-1812 nmol/l) was significantly associated with an increased CRL compared with the first two quartiles (814-1512 nmol/l) and the upper quartile (1813-2936 nmol/l; Poverall = 0.03; adjusted for gestational age, smoking, body mass index and fetal sex). Compared with the third quartile, embryos in the upper quartile were 24.2% smaller at 6+0 weeks [4.1 mm (95% confidence interval 3.5, 4.7) versus 5.4 mm (95% confidence interval 4.8, 6.1)] and 7.6% smaller at 12+0 weeks [55.1 mm (95% confidence interval 52.9, 57.3) versus 59.6 mm (95% confidence interval 57.4, 62.0)] of gestation. Conclusions This study suggests that a very high maternal periconception folate status is associated with reduced embryonic size. Whether these effects are beneficial or harmful requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Although grip and pinch strength provide a more global measure of a large number of digits and muscles, measuring strength of individual fingers or the thumb can provide additional and more detailed information regarding hand strength.Questions/purposes: We developed growth diagrams for individual finger strength in children.Patients and Methods: We measured thumb palmar abduction, thumb opposition, and thumb flexion in the metacarpophalangeal joint, and abduction of the index and little fingers in 101 children (4-12 years old) using a myometer. We recorded hand dominance, gender, height, and weight. All measurements were performed in a randomized order by the same researcher. We developed statistical models for drawing growth diagrams using estimated percentiles for each strength measurement. Separate models for dominant and nondominant hands of boys and girls were developed, in addition to a combined model.Results: Because there was no difference in strength between boys and girls and between dominant and nondominant hands, both hands and genders were combined in one growth diagram for each measurement. The normative data were presented in a table format and in growth diagrams for each myometer measurement.Conclusions: These diagrams can be used for pediatric patients such as patients with congenital malformations or neuromuscular disorders who receive interventions or therapy aimed at function of the hand, fingers, or thumb. The growth diagrams facilitate distinguishing between the effects of growth and intervention on strength development. [ABSTRACT FROM AUTHOR]

RATIONALE: It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves outcome. OBJECTIVES: To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU) patients admitted with a lactate level of greater than or equal to 3.0 mEq/L. METHODS: Patients were randomly allocated to two groups. In the lactate group, treatment was guided by lactate levels with the objective to decrease lactate by 20% or more per 2 hours for the initial 8 hours of ICU stay. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value) during this period. The primary outcome measure was hospital mortality. MEASUREMENTS AND MAIN RESULTS: The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat population (348 patients), hospital mortality in the control group was 43.5% (77/177) compared with 33.9% (58/171) in the lactate group (P = 0.067). When adjusted for predefined risk factors, hospital mortality was lower in the lactate group (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87; P = 0.006). In the lactate group, Sequential Organ Failure Assessment scores were lower between 9 and 72 hours, inotropes could be stopped earlier, and patients could be weaned from mechanical ventilation and discharged from the ICU earlier. CONCLUSIONS: In patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. Clinical trial registered with www.clinicaltrials.gov (NCT00270673). [ABSTRACT FROM AUTHOR]

Unlabelled: Grip strength dynamometers often are used to assess hand function in children. The use of normative grip strength data at followup is difficult because of the influence of growth and neuromuscular maturation. As an alternative, infant welfare centers throughout the world use growth diagrams to observe normative growth. The aim of this study was to develop similar growth diagrams for grip strength in children. We measured the grip strength, hand dominance, gender, height, and weight of 225 children, 4 to 12 years old. We developed separate statistical models for both hands of boys and girls for drawing growth curves. Grip strength increased with age for both hands. For the whole group, the dominant hand produced higher grip strength than the nondominant hand and boys were stronger than girls. The grip strength of boys and girls differed between 2 and 19 N for the different age groups. Because grip strength measurements are accompanied by a rather large variance, the growth diagrams (presenting a continuum in grip strength) make it possible to better observe grip strength development with time corresponding to a more exact age. Depending on the accuracy needed, the use of one combined diagram could be considered.Level Of Evidence: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy. METHODS: In a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mother's smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan-Meier curve analyses were performed to examine the association between medication use and gestational age at delivery. RESULTS: Data from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean +/- SD birth weight (3,379 +/- 564 gm) and the mean +/- SD birth weight standard deviation score (SDS; +0.1 +/- 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004). CONCLUSION: Pregnancy outcome in women with well-controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune-mediated mechanism. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of glucosamine sulfate as a symptom and disease modifier for osteoarthritis is still under debate.Objective: To assess whether glucosamine sulfate has an effect on the symptoms and structural progression of hip osteoarthritis during 2 years of treatment.Design: Randomized, controlled trial.Setting: Primary care in the Netherlands.Patients: 222 patients with hip osteoarthritis who were recruited by their general practitioner. Patients were eligible if they met the American College of Rheumatology clinical criteria for hip osteoarthritis.Intervention: 2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily.Measurements: Primary outcome measures were Western Ontario and McMaster Universities (WOMAC) pain and function subscales over 24 months and joint space narrowing after 24 months. The main secondary outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months.Results: At baseline, both groups were similar in demographic and clinical variables. Overall, WOMAC pain did not differ (mean difference [glucosamine sulfate minus placebo], -1.54 [95% CI, -5.43 to 2.36]), nor did WOMAC function (mean difference, -2.01 [CI, -5.38 to 1.36]). Joint space narrowing also did not differ after 24 months (mean difference, -0.029 [CI, -0.122 to 0.064]). Only 1 of the sensitivity analyses, based on extreme assumptions regarding missing assessments due to total hip replacement, provided results consistent with a glucosamine effect.Limitations: Twenty patients had total hip replacement during the trial. Half of the patients had a Kellgren and Lawrence score of 1.Conclusion: Glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis. International Standard Randomised Controlled Trial Number: ISRCTN54513166. [ABSTRACT FROM AUTHOR]

Background: People use lumbar supports to prevent low back pain. Secondary analyses from primary preventive studies suggest benefit among workers with previous low back pain, but definitive studies on the effectiveness of supports for the secondary prevention of low back pain are lacking.Objective: To determine the effectiveness of lumbar supports in the secondary prevention of low back pain.Design: Randomized, controlled trial.Setting: Home care organization in the Netherlands.Patients: 360 home care workers with self-reported history of low back pain.Intervention: Short course on healthy working methods, with or without patient-directed use of 1 of 4 types of lumbar support.Measurements: Primary outcomes were the number of days of low back pain and sick leave over 12 months. Secondary outcomes were the average severity of low back pain and function (Quebec Back Pain Disability scale) in the previous week.Results: Over 12 months, participants in the lumbar support group reported an average of -52.7 days (CI, -59.6 to -45.1 days) fewer days with low back pain than participants who received only the short course. However, the total sick days in the lumbar support group did not decrease (-5 days [CI, -21.1 to 6.8 days]). Small but statistically significant differences in pain intensity and function favored lumbar support.Limitations: Study participants were unblinded, and a substantial amount of missing data required imputation. Objective data on sick days due to low back pain were not available.Conclusion: Adding patient-directed use of lumbar supports to a short course on healthy working methods may reduce the number of days when low back pain occurs, but not overall work absenteeism, among home care workers with previous low back pain. Further study of lumbar supports is warranted. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy (HDP) are a significant cause of maternal and perinatal mortality and morbidity. Knowledge on the placenta-related pathophysiology of HDP is increasing. Since maternal tryptophan metabolites are involved in placentation, we investigated associations between first-trimester tryptophan metabolites and utero-placental (vascular) development, and the occurrence of HDP., Methods: 911 women were included from a prospective tertiary hospital cohort. Serum tryptophan metabolites were determined at 8.1 ± 1.4 weeks gestation. Placental volume (PV) and utero-placental vascular volume (uPVV) were determined at 7, 9 and 11 weeks gestation. HDP, including hypertension in early pregnancy, gestational hypertension, and preeclampsia, were retrieved from medical records. Associations with PV- and uPVV-trajectories were assessed using mixed models, and HDP risks were estimated by logistic regression models, adjusted for confounders. A mediation analysis was performed to evaluate whether blood pressure was a mediator in the associations with utero-placental (vascular) development., Results: A negative association between kynurenine and PV-trajectories was found (β = -0.129, 95%CI = -0.220 to -0.039), which was not mediated by blood pressure. No significant associations between other tryptophan metabolites and PV- and uPVV-trajectories were observed. Higher 5-hydroxytryptophan was associated with hypertension in early pregnancy (OR = 1.405, 95%CI = 1.210-1.681), and with an increased risk of preeclampsia in these women. No associations between tryptophan metabolites and other HDP were found., Conclusions: Higher first-trimester kynurenine concentrations were associated with impaired utero-placental (vascular) development. Higher first-trimester 5-hydroxytryptophan concentrations were associated with early pregnancy hypertension, and an increased risk of preeclampsia, indicating its clinical potential as biomarker for future prediction, prevention and treatment of HDP., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: An inadequate intake of calcium in pregnancy is associated with higher risks of maternal hypertensive pregnancy disorders, premature birth and intrauterine growth restriction. An evidence based and clinically applicable tool to efficiently estimate the adequacy of calcium intake in pregnant women currently does not exist. The aim of this study is to develop an effective and simple digital screening tool for calcium intake in pregnancy., Study Design: We extracted all data from the Rotterdam Periconceptional cohort (PREDICT study) conducted at the Erasmus MC, University Medical Centre in Rotterdam, the Netherlands, between November 2014 and December 2020. Data was extracted from food frequency questionnaires. The estimated average requirement of 750 m/day was defined as the lower limit for an adequate calcium intake. We created a prediction model, using multivariable binary logistic regression with backward stepwise selection, predicting the probability of adequate calcium intake. We developed a simple screening tool based on the prediction model., Results: 694 participants are included, of which 201 (29 %) had an adequate calcium intake. Total daily or weekly intakes of cheese, milk, and yogurt or curd were selected as predictors for the prediction model. The model had excellent discrimination (AUC 0.858), a good fit (Brier score 0.136, HL statistic p = 0.499) and satisfactory calibration. The test accuracy measures were: sensitivity 80.9 %, specificity 77.1 %, PPV 89.7 %, NPV 62.2 %. A colour coded digital screening tool was developed for use in clinical practice., Conclusions: This evidence-based and simple screening tool is a reliable and efficient instrument to predict inadequate calcium intakes in pregnancy, which can easily be incorporated in daily clinical practice and existing pregnancy coaching platforms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Maternal lifestyle behaviours can affect blood pressure with consequences for maternal and offspring health. The aim of this study was to investigate the effectiveness of the Smarter Pregnancy digital lifestyle coaching program on maternal blood pressure during the first trimester., Methods: The study was conducted on data of the Rotterdam Periconception Cohort from 2010 to 2019 (analysis completed in 2024). The intervention group included 132 pregnant women using Smarter Pregnancy for 6 to 24 weeks, within 30 months before study entry. The control group included 1,091 pregnant women that did not use Smarter Pregnancy. Outcomes included changes in systolic, diastolic and mean arterial blood pressures between baseline and first trimester. Lifestyle behaviours were tracked in the intervention group at 12 and 24 weeks of the program, using lifestyle risk score for vegetables, fruits, smoking and alcohol., Results: Using multivariable analysis, the intervention group showed reductions in systolic (β adj -2.34 mmHg, 95%CI -4.67 to -0.01), diastolic (β adj -2.00 mmHg, 95%CI -3.57 to -0.45) and mean arterial blood pressures (β adj -2.22 mmHg, 95%CI -3.81 to -0.52) compared with the control group. When stratifying for conception mode, reductions were observed in diastolic (β adj -2.38, 95%CI -4.20 to -0.56) and mean arterial blood pressures (β adj -2.63, 95%CI -4.61 to -0.56) only in women who underwent assisted reproduction (n=91). Smarter Pregnancy use was associated with a reduction in lifestyle risk score, indicating improved lifestyle behaviours, after 12 (β -0.84, 95%CI -1.19 to -0.49) and 24 weeks (β -1.07, 95%CI -1.44 to -0.69). The lifestyle risk score was also significantly reduced in ART and natural pregnancy subgroups., Conclusions: The use of Smarter Pregnancy is associated with consistent but small reductions in maternal blood pressure during the first trimester, supporting further implementation in health care., Competing Interests: Declaration of competing interest AD is founder and employee of BioTalentum Ltd and declares no conflict of interest. All other authors report no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Study Question: Is the degree of maternal vulnerability positively associated with stress biomarkers (stress hormones, C-reactive protein, tryptophan metabolites, and one-carbon metabolites), and does long-term exposure to stress hormones reduce first-trimester growth?, Summary Answer: The maternal vulnerability risk score is positively associated with concentrations of hair cortisol and cortisone and negatively with tryptophan, while higher hair cortisol concentrations are associated with reduced first-trimester growth without mediation of tryptophan., What Is Known Already: A high degree of maternal vulnerability during the periconception period is associated with impaired first-trimester growth and pregnancy complications, with consequences for long-term health of the child and future life course. However, due to the challenges of early identification of vulnerable women, the uptake of periconception care is low in this target group., Study Design, Size, Duration: Between June 2022 and June 2023, this study was conducted in a sub-cohort of 160 pregnant women participating in the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective tertiary hospital-based cohort., Participants/materials, Setting, Methods: One hundred and thirty-two women with ongoing pregnancies and available stress biomarker data were included in the analysis. Data on periconceptional social, lifestyle, and medical risk factors were collected via self-administered questionnaires, and these factors were used for the development of a composite maternal vulnerability risk score. Stress biomarkers, including stress hormones (hair cortisol and cortisone) and inflammatory and oxidative stress biomarkers (C-reactive protein, total homocysteine, and tryptophan metabolites) were determined in the first trimester of pregnancy. First-trimester growth was assessed by crown-rump length (CRL) and embryonic volume (EV) measurements at 7, 9, and 11 weeks gestation by making use of an artificial intelligence algorithm and virtual reality techniques using 3D ultrasound data sets. The associations between the maternal vulnerability risk score and stress biomarkers were identified using linear regression models, and between stress hormones and CRL- and EV-trajectories using mixed models. A mediation analysis was performed to assess the contribution of tryptophan. All associations were adjusted for potential confounders, which were identified using a data-driven approach. Several sensitivity analyses were performed to check the robustness of the findings., Main Results and the Role of Chance: The maternal vulnerability risk score was positively associated with concentrations of hair cortisol and cortisone (pg/mg) (β = 0.366, 95% CI = 0.010-0.722; β = 0.897, 95% CI = 0.102-1.691, respectively), and negatively with tryptophan concentrations (µmol/L) (β = -1.637, 95% CI = -2.693 to -0.582). No associations revealed for C-reactive protein and total homocysteine. Higher hair cortisol concentrations were associated with reduced EV-trajectories (3√EV: β = -0.010, 95% CI = -0.017 to -0.002), while no associations were found with CRL-trajectories. Mediation by tryptophan was not shown., Limitations, Reasons for Caution: Residual confounding cannot be ruled out, and the external validity may be limited due to the study's single-center observational design in a tertiary hospital., Wider Implications of the Findings: There is mounting evidence that a high degree of maternal vulnerability negatively affects maternal and perinatal health, and that of the future life course. The results of our study emphasize the need to identify highly vulnerable women as early as possible, at least before conception. Our findings suggest that the chronic stress response and alterations of the maternal tryptophan metabolism are involved in maternal vulnerability, affecting first-trimester growth, with potential impact on the long-term health of the offspring., Study Funding/competing Interest(s): This study was funded by the Departments of Obstetrics and Gynecology and Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Junior Award granted by the De Snoo-van 't Hoogerhuijs Foundation in March 2022. There are no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Is early embryonic size and growth in the first trimester of pregnancy associated with adverse birth outcomes?, Summary Answer: Larger embryonic crown-rump length (CRL) and embryonic volume (EV) are associated with lower odds of adverse birth outcomes, especially small for gestational age (SGA)., What Is Already Known: Preterm birth, SGA, and congenital anomalies are the most prevalent adverse birth outcomes with lifelong health consequences as well as high medical and societal costs. In the late first and second trimesters of pregnancy, fetuses at risk for adverse birth outcomes can be identified using 2-dimensional ultrasonography (US)., Study Design, Size, Duration: Between 2009 and 2018, singleton pregnancies were enrolled in this ongoing prospective Rotterdam Periconception Cohort., Participants/materials, Setting, Methods: This study included 918 pregnant women from a tertiary hospital in the Netherlands. Pregnancy dating was based on either a regular menstrual cycle (for natural pregnancies) or a conception date (for ART pregnancies). CRL and EV were measured using Virtual Reality software on 3-dimensional (3D) ultrasound scans, repeatedly performed around 7, 9, and 11 weeks of gestation. The main outcome measure was adverse birth outcome, defined as the composite of SGA (birth weight <10th percentile), preterm birth (<37th week of gestation), congenital anomalies (Eurocat criteria), stillbirth (>16th week of pregnancy), or early neonatal mortality (≤7 days of life). Reference curves for CRL and EV were constructed. Cross-sectional (CRL/EV <20th percentile at 7, 9, and 11 weeks of gestation) and longitudinal (CRL/EV growth trajectories between 6th and 13th weeks) regression analyses were performed, with adjustments for the participants' educational level, smoking, parity, age, BMI, geographical background, mode of conception, and fetal sex., Main Results and the Role of Chance: Of the 918 pregnant women included, the median age was 32.3 years, and 404 (44%) pregnancies had been conceived via ART. In 199 (22%) pregnancies, there was an adverse birth outcome. Regression analyses showed that at 7 weeks of gestation onwards, embryos with a CRL <20th percentile had an ∼2-fold increased odds of adverse birth outcome (adjusted odds ratio (aOR) 2.03, 95% CI 1.21-3.39, P = 0.007). Similar associations were found for EV <20th percentile but were not statistically significant. These findings were mainly driven by the strong association between embryonic size and SGA (e.g. 7-week CRL: aOR 2.18 (1.16-4.09), P = 0.02; 9-week EV: aOR 2.09 (1.10-3.97, P = 0.02). Longitudinal growth trajectories of CRL, but not of EV, were associated with adverse birth outcomes. Both CRL and EV growth trajectories were associated with SGA., Limitations, Reasons for Caution: The tertiary hospital population and the availability of sophisticated 3D-ultrasound techniques limit the generalizability of this study to general populations and settings., Wider Implications of the Findings: Already very early in the first trimester of pregnancy, embryos with increased risks of an adverse birth outcome can be identified by using 3D-US and Virtual Reality. This expands the window of opportunity to enable the development of future interventions to potentially improve pregnancy outcomes and offspring health during their life-course., Study Funding/competing Interest(s): This work was funded by the Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest., Trial Registration Number: NL4115., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Pilonidal sinus disease impacts a patient's quality of life. In the Netherlands, it is often treated with excision and secondary wound healing, which is associated with high recurrence rates and poor wound healing. The Bascom cleft lift, an alternative technique, has shown favorable healing times and recurrence rates., Objective: The present study compares successful wound healing, time to healing, complications, and recurrence rate between excision with secondary wound healing and Bascom cleft lift., Design: This is a multicenter retrospective study., Settings: Three institutions in the Rotterdam region of the Netherlands participated in the study., Patients: Patients who underwent excision with secondary wound healing or Bascom cleft lift between July 2015 and August 2021 were included., Main Outcome Measures: Primary end points included the rate of successful wound healing and the time to achieve healing. Secondary end points included postoperative complications and the recurrence rate within 12 months after surgery., Results: Of 272 patients, 128 underwent Bascom cleft lift and 144 patients underwent excision and secondary wound healing. Recurrent pilonidal sinus disease (47.7% vs 22.2%) and abscess history (53.1% vs 40.3%) were more common in the Bascom cleft lift group compared to excision with secondary wound healing. The median follow-up period at the outpatient clinic was 43 days. The wound healing rate was 84.4% after Bascom cleft lift versus 32.6% after excision and secondary wound healing ( p < 0.001), with a median time to wound healing of 55 and 101 days, respectively ( p < 0.001). Complications were 28.9% for Bascom cleft lift versus 13.2% for excision and secondary wound healing ( p = 0.003). The rate of recurrent disease was 6.3% after Bascom cleft lift and 11.8% after excision and secondary wound healing ( p = 0.113)., Limitations: This study used a retrospective design, which makes it prone to selection bias and residual confounding. In addition, the short follow-up period adds to these limitations because a longer follow-up period may better identify true recurrence rates. The absence of collected patient satisfaction data, which is currently a common scientific issue, is also a deficiency., Conclusions: This retrospective study shows that Bascom cleft lift is superior to excision and secondary wound healing, given the higher percentage of patients with successful wound healing within a shorter time. See Video Abstract ., Resultados Posoperatorios De La Elevacin De La Hendidura Tipo Bascom Versus La Escisin Con Cicatrizacin De La Herida Por Segunda Intensin Para La Enfermedad De Seno Pilonidal Un Anlisis Retrospectivo Multicntrico: ANTECEDENTES:La enfermedad de seno pilonidal afecta la calidad de vida del paciente. En los Países Bajos, a menudo se trata con escisión y cicatrización por segunda intensión, lo que se asocia con altas tasas de recurrencia y mala cicatrización de las heridas. La elevación de la hendidura de Bascom, una técnica alternativa, ha mostrado tiempos de curación y tasas de recurrencia favorables.OBJETIVO:El presente estudio tiene como objetivo comparar la cicatrización exitosa de la herida, el tiempo de cicatrización, las complicaciones y la tasa de recurrencia entre la escisión con cicatrización secundaria de la herida y la elevación de hendidura tipo Bascom.DISEÑO:Este es un estudio retrospectivo multicéntrico.AJUSTES:Tres instituciones en la región de Rotterdam de los Países Bajos participaron en el estudio.PACIENTES:Se incluyeron pacientes sometidos a escisión con cicatrización secundaria o elecación de la hendidura tipo Bascom entre julio de 2015 y agosto de 2021.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios incluyeron la tasa de curación exitosa de la herida y el tiempo para lograr la curación. Los resultados secundarios incluyeron complicaciones posoperatorias y tasa de recurrencia dentro de los doce meses posteriores a la cirugía.RESULTADOS:De 272 pacientes, 128 se sometieron a elevación de hendidura tipo Bascom y 144 pacientes a escisión y cicatrización secundaria. La ESP recurrente (47.7% frente a 22.2%) y los abscesos (53.1% frente a 40.3%) fueron más comunes en el grupo de elevación tipo Bascom en comparación con la escisión con cicatrización secundaria de la herida. La mediana del período de seguimiento en la consulta externa fue de 43 días. La cicatrización de la herida fue del 84.4 % después del lifting de Bascom frente al 32.6 % después de la escisión y la cicatrización secundaria (p < 0.001), con una mediana de tiempo hasta la cicatrización de la herida de 55 días y 101 días, respectivamente (p < 0.001). Las complicaciones fueron del 28.9% para el lifting tipo Bascom frente al 13.2% para la escisión y cicatrización secundaria (p = 0.003). La enfermedad recurrente fue del 6.3% después del lifting de hendidura tipo Bascom y del 11.8% después de la escisión y cicatrización secundaria (p = 0.113).LIMITACIONES:Diseño retrospectivo que lo hace propenso a sesgos de selección y confusión residual. Adicionalmente, el corto período de seguimiento del estudio aumenta aún más estas limitaciones, ya que un seguimiento más prolongado puede identificar mejor las verdaderas tasas de recurrencia. Por último, una deficiencia es la ausencia de datos recopilados sobre la satisfacción del paciente, lo que hoy en día es un problema científico común.CONCLUSIONES:Este estudio retrospectivo muestra que la elevación de hendidura tipo Bascom es superior a la escisión y cicatrización secundaria dado el mayor porcentaje de pacientes con curación exitosa de la herida en un tiempo más corto. (Traducción-Dr. Jorge Silva Velazco )., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Objective (s): Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature., Methods: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm 3 . The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories., Results: Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development., Conclusion(s): Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval The authors report no conflicts of interest. This research was conducted in accordance with the ethical principles for medical research set out in the Declaration of Helsinki and was approved by the Institutional Review Board of the Erasmus Medical Centre on 2 June 2015 (MEC 2015–494).This study was registered at the Dutch Trial Register: NTR6854., (© 2024. The Author(s).)

Context: Several challenges still exist to adopt the anti-müllerian hormone (AMH) as a marker of polycystic ovary morphology, as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the past few years, these studies have mainly been conducted in normo-ovulatory or infertile women., Objective: To develop an age-specific percentile distribution of AMH in patients with polycystic ovary syndrome (PCOS) measured by 3 different assays., Design: Retrospective cross-sectional study., Patients: A total of 2725 women aged 20 to 40 years with PCOS diagnosis were included., Interventions: Serum AMH measurement by the Gen II (Beckman Coulter), the picoAMH (Ansh Labs), and the Elecsys (Roche) assays., Main Outcome Measures: Age-specific percentile curves for all the assays and correlations between AMH, clinical, hormonal, and ultrasound characteristics., Results: Age-related nomograms for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of AMH were calculated using the Lambda-Mu-Sigma method for all the assays. AMH levels were significantly different between PCOS phenotypes. AMH levels were positively correlated to LH, LH/FSH ratio, testosterone, androstenedione, free androgen index, mean follicular number, and mean ovarian volume., Conclusion: To our knowledge, this is the first study reporting age-specific percentile nomograms of serum AMH levels measured by the Gen II, the picoAMH, and the Elecsys assays in a large population of women with PCOS. These findings may help to interpret AMH levels in patients with PCOS and facilitate the use of AMH as a diagnostic tool across age ranges., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Study Question: Is periconceptional multiple-micronutrient supplement (MMS) use including folic acid (FA) compared to FA use only associated with increased embryonic growth, development, and birth weight in a high-risk population?, Summary Answer: Women with MMS intake show no significant differences in first-trimester morphological embryo development, but increased first-trimester embryonic growth trajectories and fewer neonates born small for gestational age (SGA), less than the 3rd percentile (

Background: The vital role of the maternal tryptophan (TRP) metabolism in maternal health and pregnancy is well established. However, non-medical maternal determinants influencing the TRP metabolism have been poorly investigated. We hypothesise that periconceptional maternal non-medical determinants alter the TRP metabolism, affecting both kynurenine (KP) and serotonin pathway (SP) metabolite concentrations. Therefore, we investigated the influence of non-medical maternal determinants on the TRP metabolism during the periconception period., Methods: About 1916 pregnancies were included from the Rotterdam Periconceptional Cohort between November 2010 and December 2020. Data on periconceptional non-medical maternal determinants were collected through questionnaires. Serum samples were collected at 8.5 (SD = 1.6) weeks of gestation and TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), 5-HT (5-hydroxytryptamine) and 5-hydroxyindole acetic acid (5-HIAA) were determined using validated liquid chromatography (tandem) mass spectrometry. Mixed models were used to determine associations between periconceptional non-medical maternal determinants and these metabolites., Results: In total 11 periconceptional non-medical maternal determinants were identified. Protein intake was positively associated with TRP ( β  = .12, 95% CI = 0.07-0.17), while age, energy intake and body mass index (BMI) ( β  = -.24, 95% CI = -0.37 to -0.10) were negatively associated with TRP. Age, BMI and total homocysteine were associated with higher KYN, whereas non-western geographical origin was associated with lower KYN ( β  = -.09, 95% CI = -0.16 to -0.03). Protein intake and total homocysteine ( β  = .07, 95% CI = 0.03-0.11) had a positive association with 5-HTP, while a negative association was found for energy intake. A non-western geographical origin and drug use were associated with higher 5-HT, and BMI with lower 5-HT ( β  = -6.32, 95% CI = -10.26 to -2.38). Age was positively associated with 5-HIAA ( β  = .92, 95% CI = 0.29-1.56), and BMI negatively., Conclusions: Periconceptional non-medical maternal determinants, including age, geographical origin, drug use, energy and protein intake, BMI and total homocysteine, influence KP and SP metabolite concentrations., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

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: β = 1.31, 95% CI = 0.38-2.23). Analysis stratified for BMI classification showed comparable associations in normal weight participants (adjusted: β = 1.07, 95% CI = 0.06-2.07); however, no significant association in participants with overweight (adjusted: β = 0.06, 95% CI = - 0.95-1.07) and obesity (adjusted: β = 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., (© 2024. The Author(s).)

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: β = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: β = -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 Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles?, Summary Answer: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles., What Is Known Already: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown., Study Design, Size, Duration: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018., Participants/materials, Setting, Methods: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no)., Main Results and the Role of Chance: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β = 0.017, 95% CI [0.009; 0.025], bifurcation points β = 0.012, 95% CI [0.006; 0.018], crossing points β = 0.017, 95% CI [0.008; 0.025], vessel points β = 0.01, 95% CI [0.002; 0.008], and total vascular length β = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV β = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV β = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV β -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV β = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically., Limitation, Reasons for Caution: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship., Wider Implications of the Findings: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction., 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)., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Objective: To investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ)., Design: Randomised controlled non-inferiority trial., Setting: One academic and one regional hospital in the Netherlands., Population: Thirty-five women with rrCIN were included in the study between May 2016 and May 2021., Methods: Women were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment)., Main Outcome Measures: The primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high-risk human papilloma virus (hr-HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored., Results: Treatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow-up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow-up., Conclusions: This is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr-HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC., Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data., Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth., Trial Registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019., (© 2024. The Author(s).)

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., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI., Methods: In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA., Results: A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies., Conclusion: The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation.

Background: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age., Methods: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle., Discussion: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants., Trial Registration: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort., Methods: The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes., Results: This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED 30 ; - 0.13 (95% CI; - 0.22; - 0.04), ED 36 ; - 0.14 (95% CI; - 0.25; - 0.04)) and a smaller abdominal circumference (ED 36 ; - 0.09 (95% CI; - 0.18; - 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED 30 ; - 0.14 (95% CI; - 0.25; - 0.02), ED 36 ; - 0.22 (95% CI; - 0.37; - 0.06)) and a smaller estimated fetal weight (ED 36 ; - 0.22 (95% CI; - 0.38; - 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED 30 ; - 0.49 (95% CI; - 0.86; - 0.12), ED 36 ; - 0.70 (95% CI; - 1.22; - 0.17)) and estimated fetal weight (ED 30 ; - 0.54 (95% CI; - 0.94; - 0.14), ED 36 ; - 0.69 (95% CI; - 1.25; - 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth., Conclusions: This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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 (β - 12.6 µm 2 /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 µm 2 versus discarded 9679 ± 673 µm 2 , 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 OR used 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 β - 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., (© 2023. The Author(s).)

Study Question: Is there a difference in embryonic morphological development between ongoing pregnancies and live pregnancies ending in a miscarriage?, Summary Answer: Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage compared to ongoing pregnancies., What Is Known Already: Pregnancies ending in a miscarriage tend to have smaller embryos and slower heart rates., Study Design, Size, Duration: Between 2010 and 2018, 644 women with singleton pregnancies, in the periconception period, were enrolled in a prospective cohort study with follow up until 1 year after delivery. A miscarriage was registered as a non-viable pregnancy before 22 weeks gestational age, defined by an absent heartbeat by ultrasound for a previously reported live pregnancy., Participants/materials, Setting, Methods: Pregnant women with live singleton pregnancies were included and serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development was assessed by the Carnegie developmental stages and evaluated using virtual reality techniques. The embryonic morphology was compared to clinically used growth parameters (i.e. crown-rump length (CRL) and embryonic volume (EV)). Linear mixed models were used to evaluate the association between miscarriage and the Carnegie stages. Logistic regression with generalized estimating equations was used to calculate the odds of a miscarriage after a delay in Carnegie stages. Adjustments were made for potential confounders or covariates and include age, parity, and smoking status., Main Results and the Role of Chance: A total of 611 ongoing pregnancies and 33 pregnancies ending in a miscarriage were included between 7 + 0 and 10 + 3 weeks gestational age, resulting in 1127 assigned Carnegie stages for evaluation. Compared to an ongoing pregnancy, a pregnancy ending in a miscarriage is associated with a lower Carnegie stage (βCarnegie = -0.824, 95% CI -1.190; -0.458, P < 0.001). A live embryo of a pregnancy ending in a miscarriage will reach the final Carnegie stage with a delay of 4.0 days compared to an ongoing pregnancy. A pregnancy ending in a miscarriage is associated with a smaller CRL (βCRL = -0.120, 95% CI -0.240; -0.001, P = 0.049) and EV (βEV = -0.060, 95% CI -0.112; -0.007, P = 0.027). The delay in Carnegie stage increases the odds of a miscarriage by 1.5% per delayed Carnegie stage (ORCarnegie = 1.015, 95% CI 1.002; 1.028, P = 0.028)., Limitations, Reasons for Caution: We included a relatively small number of pregnancies ending in a miscarriage from a study population that is recruited from a tertiary referral centre. Furthermore, results of genetic testing on the products of the miscarriages or information on the karyotype of the parents were not available., Wider Implications of the Findings: Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage. In the future, embryonic morphology may be used to estimate the likelihood of a pregnancy continuing to the delivery of a healthy baby. This is of crucial importance for all women but in particular for those at risk of a recurrent pregnancy loss. As part of supportive care, both women and their partners may benefit from information on the prospective outcome of the pregnancy and the timely identification of a miscarriage., Study Funding/competing Interest(s): The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Importance: Quantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification., Objective: To systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification., Data Sources: A systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022., Study Selection: Studies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline., Data Extraction and Synthesis: Data extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome., Main Outcomes and Measures: The main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications., Results: Ten studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of -14 μmol/L, with pooled 95% CBs of -106 to 78 μmol/L. For the Bilistick, the pooled mean difference was -17 μmol/L (95% CBs, -114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB., Conclusions and Relevance: Despite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

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 (β 64.45 µm2, 95% CI 3.26; 125.64, P = 0.04), and faster progression from five-cell stage onwards (e.g. β8-cell -1.37 h, 95% CI -2.48; -0.26, P = 0.02). Prorenin associated positively with pre-transfer outcomes (e.g. βfertilized oocytes 2.09, 95% CI 1.43; 2.75, P < 0.001) and implantation (odds ratio+β-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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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 R 2 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., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

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 (beta EV 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 (beta EV 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 (beta EV 0.040 3√ml [95% CI 0.012-0.069], P = 0.005). This association was most pronounced in male embryos (beta EV 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., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

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)., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Congenital cardiac outflow defects (COD) are the largest group of congenital heart defects, with ventricular septal defect (VSD) as the most prevalent phenotype. Increased maternal age, excessive oxidative stress and inflammation are involved in the pathophysiology of COD and enhance telomere length (TL) shortening. We investigated the association between periconception maternal TL and the risk of having a child with COD., Methods: From a multicentre case-control trial, 306 case mothers of a child with COD and 424 control mothers of a child without a congenital malformation were selected. Relative TL was measured by qPCR. Multivariable logistic regression was used to compute crude and adjusted odds ratios, per standard deviation decrease, between maternal T/S ratio and COD and VSD risk. Adjustments were made for maternal age. Additional adjustments were made in a second model., Results: Shorter maternal relative TL was significantly associated with an OR of 1.29 (95% CI 1.04-1.61), p = .02, for the risk of VSD in offspring, which remained significant after an adjustment for maternal age (adjOR 1.25(95% CI 1.01-1.55), p = .04). No association between maternal TL and the risk of overall COD in offspring was observed., Conclusion: Shorter maternal relative TL is associated with an approximately 1.3-OR for the risk, per SD in relative TL shortening, of VSD in the offspring. These findings need further confirmation in other studies on the predictive value of maternal TL., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

To study the impact of culture media on preimplantation morphokinetics used for predicting clinical outcomes. All IVF and ICSI cycles performed between 2012 and 2017 with time-lapse information available were included. In November 2014, culture medium was changed from Vitrolife G-1 PLUS to SAGE 1-Step. Each embryo was retrospectively assigned a morphokinetic-based KIDScore for prediction of implantation. Clinical outcomes were retrieved from medical records. Linear mixed models were used to study differences in morphokinetic parameters, a proportional odds model for KIDScore ranking and logistic regression for differences in clinical outcomes. All analyses were adjusted for patient and treatment characteristics. In 253 (63.1%) cycles, embryos (n = 671) were cultured in Vitrolife, and in 148 (36.9%) cycles, embryos (n = 517) were cultured in SAGE. All cleavage divisions occurred earlier for SAGE embryos than for Vitrolife embryos (2-cell: -2.28 (95%CI: -3.66, -0.89), 3-cell: -2.34 (95%CI: -4.00, -0.64), 4-cell: -2.41 (95%CI: -4.11, -0.71), 5-cell: -2.54 (95%CI: -4.90, -0.18), 6-cell: -3.58 (95%CI: -6.08, -1.08), 7-cell: -5.62 (95%CI: -8.80, -2.45) and 8-cell: -5.32 (95%CI: -9.21, -1.42) hours, respectively). Significantly more embryos cultured in SAGE classified for the highest KIDScore compared to embryos cultured in Vitrolife (p < 0.001). No differences were observed in clinical outcomes. Our results demonstrate an impact of culture medium on preimplantation embryo developmental kinetics, which affects classification within the KIDScore algorithm, while pregnancy outcomes were comparable between the groups. This study underscores the need to include the type of culture medium in the development of morphokinetic-based embryo selection tools., (© 2022. The Author(s).)