Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

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 ß = 0.017, 95% CI [0.009; 0.025], bifurcation points ß = 0.012, 95% CI [0.006; 0.018], crossing points ß = 0.017, 95% CI [0.008; 0.025], vessel points ß = 0.01, 95% CI [0.002; 0.008], and total vascular length ß = 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 ß = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV ß = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV ß = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV ß -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV ß = -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).

Paternal age and first trimester placental size and growth: The Rotterdam Periconceptional Cohort.

INTRODUCTION: Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories. METHODS: Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode. RESULTS: From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%-7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population. DISCUSSION: We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.

Current preconception care practice in the Netherlands - An evaluation study among birth care professionals.

OBJECTIVE: To evaluate the current practice of preconception care in the Netherlands and the perceptions of birth care professionals concerning preconception care. METHODS: We have developed a digital questionnaire and conducted a cross-sectional study by distributing the questionnaire among 102 organisations: 90 primary care midwifery practices and obstetric departments of 12 hospitals in the Southwest region of the Netherlands between December 2020 and March 2021. One birth care professional per organization was asked to complete the questionnaire. Descriptive statistics were used to present the results. FINDINGS: Respondents of eighty-three organisations (81.4 %) filled in the questionnaire, of whom 74 respondents were independent primary care midwives and 9 respondents were obstetricians. Preconception care mostly consisted of an individual consultation in which personalized health and lifestyle advice was given. Among the respondents, 44.4 % reported that the organization had a preconception care protocol. The way in which the consultation was carried out, as well as the health and lifestyle related questions asked, differed between respondents. More than 85 % of the respondents inquire about the following possible risk factors for complications: maternal illnesses, obstetric history, folic acid supplement intake, alcohol intake, smoking, substance abuse, hereditary disease, prescription medication, dietary habits, overweight, and birth defects in the family. The respondents acknowledged that preconception care should be offered to all couples who wish to become pregnant, as opposed to offering preconception care only to those with an increased risk of complications. Still, respondents do not receive many questions regarding the preconception period or requests for preconception care consultations. KEY CONCLUSION: Birth care professionals acknowledge the need for preconception care for all couples. In the Netherlands, preconception care consists mostly of an individual consultation with recommendations for health and lifestyle advice. However, the identification of risk factors varies between birth care professionals and less than half of the respondents indicate that they have a protocol available in their practice. Furthermore, the demand of parents-to-be for preconception care is low. More research, that includes more obstetricians, is necessary to investigate if there is a difference between the care provided by primary care midwives and obstetricians. IMPLICATIONS FOR PRACTICE: To increase the awareness and uptake of preconception care, it would be prudent to emphasize its importance to parents-to-be and professionals, and actively promote the use of widespread, standardized protocols for birth care professionals.

Reported experienced stress during the COVID-19 pandemic and patient preferences for the consultation of periconception blended lifestyle care: a survey among (pre)pregnant women.

PURPOSE: To assess experienced stress on different aspects of life and evaluate patient preferences for the consultation of periconception blended lifestyle care, combining face-to-face counseling with eHealth, during the COVID-19 pandemic among (pre)pregnant women. Using this two-fold aim, we were able to analyze the levels of stress among (pre)pregnant women during the COVID-19 pandemic, and to study whether their preferences for the consultation modality of periconception blended lifestyle care was influenced by the levels of stress. METHODS: A quantitative survey among (pre)pregnant women who received blended periconception lifestyle care between March 2020 and December 2021, from the first until the fourth COVID-19 wave in the Netherlands. The questionnaire used a 5-point Likert scale and measured experienced stress and preferred periconception blended lifestyle care modality. RESULTS: 984 women (response rate: 55.2%) filled out the questionnaire. Experienced stress during the COVID-19 pandemic was relatively low and stable over time. The highest percentage of respondents (31.2%) reported to have experienced stress on fertility and pregnancy. 40.4% (309/764) of the respondents indicated that face-to-face consultations could be replaced by digital consultation. Additionally, the mean experienced stress did not differ between the patients who preferred a video consultation (2.60 ± 1.1), or a telephone consultation (2.57 ± 1.2), either a video or telephone consultation (2.54 ± 1.3), still preferred a face-to-face consultation (2.41 ± 1.4) (p = .83). CONCLUSIONS: Our findings indicate willingness for wide implementation of telemedicine within health care delivery, and reorganizing of periconception blended lifestyle care toward personalized and value-based health care.

First-trimester maternal renin-angiotensin-aldosterone system activation and the association with maternal telomere length after natural and IVF/ICSI conceived pregnancies: the Rotterdam periconception cohort.

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.

Embryonic morphological development is delayed in pregnancies ending in a spontaneous miscarriage.

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 (ßCarnegie = -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 (ßCRL = -0.120, 95% CI -0.240; -0.001, P = 0.049) and EV (ßEV = -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 impact of maternal smoking on embryonic morphological development: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is periconceptional maternal smoking associated with embryonic morphological development in ongoing pregnancies? SUMMARY ANSWER: Smoking during the periconceptional period is associated with a delayed embryonic morphological development which is not fully recuperated beyond the first trimester of pregnancy. WHAT IS KNOWN ALREADY: Smoking during pregnancy decreases prenatal growth, increasing the risk of preterm birth, small for gestational age (GA) and childhood obesity. STUDY DESIGN, SIZE, DURATION: Between 2010 and 2018, 689 women with ongoing singleton pregnancies were periconceptionally enrolled in a prospective cohort study with follow-up until 1 year after delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between 7 + 0 and 10 + 3 weeks, GA serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development as assessed by the Carnegie developmental stages was evaluated using Virtual Reality techniques. In the absence of fetal morphology classification methods beyond the embryonic period, fetal ultrasound measurements at around 20 weeks' GA, and birth weight were used to assess fetal growth. Linear mixed models were used to evaluate the association between smoking and the Carnegie stages. Regarding first-trimester morphological development, we additionally stratified our findings for mode of conception. Multiple linear regression models were used to study the association between smoking, fetal growth and birth weight. To investigate to which extent delayed embryonic morphological development mediated the effect of smoking, contemporary mediation analysis was used. Adjustments were made for potential confounders and other covariates. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 689 singleton ongoing pregnancies were included and 1210 Carnegie stages were determined. Maternal periconceptional smoking represented by the number of cigarettes/day was associated with a slight non-significant delay of the Carnegie stages (ßcigarettes/day = -0.058, 95% CI -0.122; 0.007, P = 0.080). Smoking of ≥10 cigarettes/day showed the strongest association (ß≥10 cigarettes/day = -0.352, 95% CI -0.648; -0.057, P = 0.019), as reflected by a 0.9-day delay in reaching the final Carnegie stage. Stratification for mode of conception showed a stronger negative association between the number of cigarettes/day in the IVF/ICSI group (ßcigarettes/day = -0.126, 95% CI -0.200; -0.051, P = 0.001) compared to naturally conceived pregnancies (ßcigarettes/day = 0.009, 95% CI -0.093; 0.111, P = 0.867). In the IVF/ICSI group, periconceptional smoking of ≥10 cigarettes/day was associated with in a 1.6 day delay in reaching the final Carnegie stage (ß≥10 cigarettes/day = -0.510, 95% CI -0.834; -0.186, P = 0.002). In the second trimester, periconceptional smoking was associated with a smaller femur length (ßcigarettes/day = -0.077, 95% CI -0.147; -0.008, P = 0.029) and a larger head circumference (ß1-9 cigarettes/day = 0.290, 95% CI 0.065; 0.514, P = 0.012). Smoking was associated with a lower birth weight, with a dose-response effect (ßcigarettes/day = -0.150, 95% CI -0.233; -0.068, P < 0.001). Furthermore, using the unadjusted model, 40-60% of the association between smoking and fetal ultrasound parameters and 6.3% of the association between smoking and birth weight can be explained by a delayed embryonic morphology. LIMITATIONS, REASONS FOR CAUTION: The study population was recruited from a tertiary referral center. Smoking habits were explored using self-reported questionnaires and checked for consistency by trained researchers. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that the association of periconceptional maternal smoking and human morphological development can already be detected early in the first trimester of pregnancy using embryonic morphology as outcome. One of the key messages of this study is that the delay, or dysregulation, in embryonic morphology is associated with allometric growth reflected by smaller fetal measurements at 20 weeks gestation and lower weight at birth. The delay in embryonic morphology, measured in early pregnancy, cannot be recuperated during the pregnancy. The results of this study emphasize the importance of smoking intervention programs prior to conception. More research is warranted to assess the association between periconceptional smoking cessation and embryonic development. 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.

First-trimester utero-placental (vascular) development and embryonic and fetal growth: The Rotterdam periconception cohort.

INTRODUCTION: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. METHODS: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. RESULTS: PV trajectories were positively associated with CRL (ßadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (ßadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (ßadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (ßadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). DISCUSSION: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

Time-lapse imaging of human embryos fertilized with testicular sperm reveals an impact on the first embryonic cell cycle.

Testicular sperm is increasingly used during in vitro fertilization treatment. Testicular sperm has the ability to fertilize the oocyte after intracytoplasmic sperm injection (ICSI), but they have not undergone maturation during epididymal transport. Testicular sperm differs from ejaculated sperm in terms of chromatin maturity, incidence of DNA damage, and RNA content. It is not fully understood what the biological impact is of using testicular sperm, on fertilization, preimplantation embryo development, and postimplantation development. Our goal was to investigate differences in human preimplantation embryo development after ICSI using testicular sperm (TESE-ICSI) and ejaculated sperm. We used time-lapse embryo culture to study these possible differences. Embryos (n = 639) originating from 208 couples undergoing TESE-ICSI treatment were studied and compared to embryos (n = 866) originating from 243 couples undergoing ICSI treatment with ejaculated sperm. Using statistical analysis with linear mixed models, we observed that pronuclei appeared 0.55 h earlier in TESE-ICSI embryos, after which the pronuclear stage lasted 0.55 h longer. Also, significantly more TESE-ICSI embryos showed direct unequal cleavage from the 1-cell stage to the 3-cell stage. TESE-ICSI embryos proceeded faster through the cleavage divisions to the 5- and the 6-cell stage, but this effect disappeared when we adjusted our model for maternal factors. In conclusion, sperm origin affects embryo development during the first embryonic cell cycle, but not developmental kinetics to the 8-cell stage. Our results provide insight into the biological differences between testicular and ejaculated sperm and their impact during human fertilization.

Sharing primary percutaneous coronary intervention care: first experiences with South Limburg ST-elevation myocardial infarction network.

BACKGROUND: In the region of South Limburg, the Netherlands, a shared ST-elevation myocardial infarction (STEMI) networking system (SLIM network) was implemented. During out-of-office hours, two percutaneous coronary intervention (PCI) centres-Maastricht University Medical Centre and Zuyderland Medical Centre-are supported by the same interventional cardiologist. The aim of this study was to analyse performance indicators within this network and to compare them with contemporary European Society of Cardiology guidelines. METHODS: Key time indicators for an all-comer STEMI population were registered by the emergency medical service and the PCI centres. The time measurements showed a non-Gaussian distribution; they are presented as median with 25th and 75th percentiles. RESULTS: Between 1 February 2018 and 31 March 2019, a total of 570 STEMI patients were admitted to the participating centres. The total system delay (from emergency call to needle time) was 65 min (53-77), with a prehospital system delay of 40 min (34-47) and a door-to-needle time of 22 min (15-34). Compared with in-office hours, out-of-office hours significantly lengthened system delays (55 (47-66) vs 70 min (62-81), p < 0.001), emergency medical service transport times (29 (24-34) vs 35 min (29-40), p < 0.001) and door-to-needle times (17 (14-26) vs 26 min (18-37), p < 0.001). CONCLUSIONS: With its effective patient pathway management, the SLIM network was able to meet the quality criteria set by contemporary European revascularisation guidelines.

Effective psychological therapies to improve lifestyle behaviors in (pre)pregnant women: A systematic review.

Poor lifestyle behaviors impact (pre)pregnant women by affecting pregnancy outcomes and offspring health. This systematic review provides an overview of psychological therapies to support lifestyle behavior changes among (pre)pregnant women. Scientific databases were searched from their inception to 20 December 2020 for studies investigating the effects of psychological therapies on improvements in lifestyle behaviors. Studies were eligible if they included (pre)pregnant women, examined the effects of a psychological therapy on at least one lifestyle behavior and used a control group receiving usual pregnancy care or a non-psychological intervention. Lifestyle behaviors of interest were dietary intake, physical activity, smoking, alcohol consumption, drug use, body weight loss and body weight gain during pregnancy. Pregnancy complications were included as outcome measures. Motivational interviewing (MI) (n = 21), cognitive behavioral therapy (CBT) (n = 8), incentive-based contingency management (IBCM) (n = 9), mindfulness (n = 1) and hypnosis (n = 1) were investigated as lifestyle behavior interventions. The findings revealed that MI was effective in reducing (self-reported) smoking and alcohol consumption and restricting gestational weight gain (GWG). CBT was only studied as an intervention to restrict GWG and the results predominantly confirmed its effectiveness. IBCM showed the strongest effect on reducing smoking and substance use. The studies using hypnosis or mindfulness to reduce smoking or restrict GWG, respectively, showed no associations. The use of psychological therapies to improve lifestyle behaviors among (pre)pregnant women is new and the scientific proof is promising. Before wide implementation is legitimated, more evidence is needed on the consequences of lifestyle change for pregnancy outcomes.

Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients.

BACKGROUND: The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against COVID-19 has resulted in an ongoing discussion about the effectivity and toxicity of these drugs. Recent studies report no effect of (H)CQ on 28-day mortality. We investigated the effect of HCQ and CQ in hospitalized patients on the non-ICU COVID-ward. METHODS: A nationwide, observational cohort study was performed in The Netherlands. Hospitals were given the opportunity to decide independently on the use of three different COVID-19 treatment strategies: HCQ, CQ, or no treatment. We compared the outcomes between these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer to the intensive care unit (ICU). RESULTS: The analysis included 1064 patients from 14 hospitals: 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensity-matched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality on the COVID ward. However, HCQ was associated with a significantly decreased risk of transfer to the ICU (hazard ratio (HR) = 0.47, 95% CI = 0.27-0.82, p = 0.008) when compared with controls. This effect was not found in the CQ group (HR = 0.80, 95% CI = 0.55-1.15, p = 0.207), and remained significant after competing risk analysis. CONCLUSION: The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU mortality. However, we show that the use of HCQ - but not CQ - is associated with a 53% reduction in risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent prospective studies have reported on 28-day, all-cause mortality only; therefore, additional prospective data on the early effects of HCQ in preventing transfer to the ICU are still needed.

Differences in DNA methylation of insulin-like growth factor 2 and cadherin 13 in patients with preeclampsia.

OBJECTIVES: In a previous mass spectrometry study of our research group, 25 proteins were found to be differentially expressed in cerebrospinal fluid of patients with preeclampsia compared to controls. The objective of the current study was to investigate DNA methylation of the genes encoding for the former mentioned proteins in an independent dataset. STUDY DESIGN: In a nested case-control study of the Rotterdam Periconceptional Cohort, placental tissue, umbilical cord white blood cells and human umbilical vein endothelial cells (HUVEC) were obtained of 13 patients with early-onset preeclampsia, 16 patients with late-onset preeclampsia and 83 normotensive controls (27 patients with fetal growth restriction, 20 patients with spontaneous preterm birth and 36 uncomplicated pregnancies). DNA methylation of 783 CpGs in regions of 25 genes was measured. MAIN OUTCOME MEASURES: DNA methylation of selected candidate genes in early- and late-onset preeclampsia compared to fetal growth restriction, spontaneous preterm birth and uncomplicated controls. RESULTS: From the 783 CpGs of the 25 selected genes, 15 CpGs were differentially methylated between early-onset preeclampsia and spontaneous preterm birth (3.80 E-5 ≤ p ≤ 0.036). Four CpGs were differentially methylated between early-onset preeclampsia and fetal growth restriction (0.0002 ≤ p ≤ 0.037) and 13 CpGs were differentially methylated between early onset preeclampsia and uncomplicated controls (0.0001 ≤ p ≤ 0.04). CONCLUSION: Differences in DNA methylation were found in placental tissue, umbilical cord white blood cells and HUVEC of patients with early onset preeclampsia compared to (un)complicated controls, but not in patients with late-onset preeclampsia. The genes showing the largest differential methylation encode insulin-like growth factor 2 binding protein and receptor and cadherin 13.

Design and rationale of ischaemia-driven complete revascularisation versus usual care in patients with non-ST-elevation myocardial infarction and multivessel coronary disease: the South Limburg Myocardial Infarction (SLIM) trial.

AIMS: To compare ischaemia-driven complete coronary revascularisation by percutaneous coronary intervention (PCI) with usual care in patients with non-ST-elevation myocardial infarction (non-STEMI) and multivessel disease (MVD). METHODS: The South Limburg Myocardial Infarction (SLIM) trial (NCT03562572) is an investigator-initiated, prospective, multicentre, randomised controlled trial that compares fractional flow reserve (FFR)-guided complete revascularisation during the index procedure with usual care in non-STEMI patients with MVD. A total of 414 patients will be randomised in a 1:1 fashion. The primary endpoint is the composite of all-cause mortality, non-fatal myocardial infarction, and any revascularisation and stroke (MACCE) at 12 months. The secondary endpoints are: MACCE at 24 and 36 months, and the composite of cardiac death, myocardial infarction, any revascularisation, stroke, major bleeding and left ventricular ejection fraction below 45% at 12, 24 and 36 months. Furthermore, quality of life will be assessed by the Patient Health Questionnaire (PHQ-9) and the Short Form (36) Health Survey (SF-36) at 1 and 12 months of follow-up. CONCLUSION: The SLIM trial aims to provide evidence whether FFR-guided complete revascularisation by PCI is superior to usual care with respect to clinical outcomes (major adverse cardiovascular events) in non-STEMI patients with MVD.

Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): A cross-sectional study.

OBJECTIVE: To compare vitamin D status in women with PCOS versus fertile women and subsequently evaluate the association between vitamin D status and metabolic disturbances in PCOS women. METHODS: We conducted a cross-sectional comparison study of 639 women with PCOS and 449 fertile women. Serum 25-hydroxyvitamin D (25(OH)D) was stratified into a severe deficient (< 25 nmol/l), insufficient (25-50 nmol/l), moderate (50-75 nmol/l) and adequate (> 75 nmol/l) status. The main outcome measures were the difference in vitamin D status between PCOS and fertile women, and the association between serum 25(OH)D and metabolic disturbances in PCOS women only. RESULTS: Serum 25(OH)D was significantly lower in PCOS women compared to fertile controls (mean 25(OH)D of 49.0 nmol/l versus 64.5 nmol/l). An adjusted significant difference was seen between serum 25(OH)D and homeostasis model assessment (HOMA-IR) (ß = 0.76; 95% CI: 0.63-0.91; p < 0.01), HDL-cholesterol (ß = 0.20; 95% CI: 0.05-0.60, p < 0.01) and apolipoprotein A1 (ß = 26.2; 95% CI: 7.5-45.0, p < 0.01) between the highest vitamin D group compared to the lowest vitamin D group. CONCLUSIONS: This study demonstrates that women with PCOS have a significantly lower serum 25(OH)D compared to fertile controls. A compromised vitamin D status in PCOS women is associated with a higher HOMA-IR and an unfavourable lipid profile. Large randomized controlled trials are necessary to explore the causality of this linkage.

A compromised maternal vitamin D status is associated with congenital heart defects in offspring.

BACKGROUND: Interactions between genetic and environmental factors, including modifiable maternal nutrition and lifestyle, play a significant role in the pathogenesis of most congenital heart defects (CHD). The aim of this study was to investigate associations between periconceptional maternal vitamin D status and the prevalence of CHD in offspring. METHODS: A case-control study was performed in 345 mothers of a child with CHD and 432 mothers of a child without CHD from four tertiary hospitals in the Netherlands between 2003 and 2005. Approximately 15months after pregnancy mothers filled out questionnaires regarding general characteristics and periconceptional lifestyle. Maternal blood was obtained to determine serum 25-hydroxyvitamin D and lipid concentrations. The 25-hydroxyvitamin D concentration was stratified into a deficient <50nmol/l, moderate 50-75nmol/l and adequate >75nmol/l status. Logistic regression was performed to study associations between vitamin D status and CHD risk, adjusted for maternal age, body mass index, ethnicity, smoking and total cholesterol concentration. RESULTS: Case mothers less often had an adequate vitamin D status compared with controls (27% vs. 38%; p=0.002). The use of multivitamin supplements, ethnicity, season and body mass index were associated with vitamin D concentrations. A moderate (odds ratio 1.58, [95%CI 1.08, 2.32]) and deficient (odds ratio 2.15, [95%CI 1.44-3.19]) vitamin D status were associated with CHD in offspring. CONCLUSION: A compromised maternal vitamin D status is associated with an approximately two-fold increased prevalence of CHD in offspring. Therefore, improvement of the periconceptional maternal vitamin D status is recommended.

New imaging markers for preconceptional and first-trimester utero-placental vascularization.

INTRODUCTION: The availability of imaging makers of early placental circulation development is limited. This study aims to develop a feasible and reliable method to assess preconceptional and early first-trimester utero-placental vascular volumes using three-dimensional power Doppler (3D PD) ultrasound on two different Virtual Reality (VR) systems. METHODS: 3D PD ultrasound images of the uterine and placental vasculature were obtained in 35 women, either preconceptionally (n = 5), or during pregnancy at 7 (n = 10), 9 (n = 10) or 11 (n = 10) weeks of gestation. Preconceptional uterine vascular volume (UVV), first-trimester placental vascular volume (PVV) and embryonic vascular volume (EVV) were measured by two observers on two VR systems, i.e., a Barco I-Space and VR desktop. Intra- and inter-observer agreement and intersystem agreement were assessed by intra-class correlation coefficients (ICC) and absolute and relative differences. RESULTS: Uterine-, embryonic- and placental vascular volume measurements showed good to excellent intra- and inter-observer agreement and inter-system reproducibility with most ICC above 0.80 and relative differences of less than 20% preconceptionally and almost throughout the entire gestational age range. Inter-observer agreement of PVV at 11 weeks gestation was suboptimal (ICC 0.69, relative difference 50.1%). DISCUSSION: Preconceptional and first-trimester 3D PD ultrasound utero-placental and embryonic vascular volume measurements using VR are feasible and reliable. Longitudinal cohort studies with repeated measurements are needed to further validate this and assess their value as new imaging markers for placental vascular development and ultimately for the prediction of placenta-related pregnancy complications.

Foetal fractional thigh volume: an early 3D ultrasound marker of neonatal adiposity.

BACKGROUND: The predisposition for obesity is suggested to originate in the prenatal period. Prenatal markers are needed to identify foetuses at risk for neonatal adiposity, as early marker of childhood obesity. OBJECTIVE: The aim of this study is to assess the association between foetal fractional thigh volume (TVol) and neonatal percentage fat mass from mid-gestation onward. METHODS: In this perinatal cohort study, singleton pregnancies with term born infants were included. Foetal TVol was measured on three-dimensional ultrasound scans (3D US) obtained at 22, 26 and 32 weeks of gestation. Neonatal body composition measurement (percentage body fat (%BF)) was planned between 42+0 and 42+6 -week postmenstrual age. Cross-sectional and longitudinal linear regression analyses were performed. RESULTS: Seventy-nine mother-child pairs were included. Median (interquartile range) TVol increased from 7.6 (7.1; 8.5) cm3 at 22 weeks to 36.5 (33.8; 40.9) cm3 at 32 weeks. Median neonatal %BF was 14.3% (11.7; 17.0). TVol at 22 weeks (ß = -1.58, 95% CI -2.45; -0.70, explained variance 31%) was negatively associated with %BF, but no associations were found at 26 and 32 weeks of gestation. TVol growth between 22 and 32 weeks of gestation (explained variance 18%) was also statistically significantly negatively associated with %BF. CONCLUSIONS: Foetal TVol is a promising 3D US marker for prediction of neonatal adiposity from mid-gestation onward.