Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort.

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 cm3. 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: ß = 0.39, 95% CI = 0.15;0.64; bifurcation points: ß = 4.64, 95% CI = 0.04;9.25; crossing points: ß = 4.01, 95% CI = 0.65;7.37; total vascular length: ß = 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.

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

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

Gestational hypertensive disorders and blood pressure and childhood cardiac outcomes: A prospective cohort study.

OBJECTIVE: To assess whether gestational hypertensive disorders and higher gestational blood pressure were associated with subclinical changes in offspring cardiac structure and function during childhood. DESIGN: Population-based prospective cohort study. SETTING: Rotterdam, the Netherlands. POPULATION: A cohort of 2502 mother-offspring pairs. METHODS: Maternal blood pressure was measured in early, mid and late pregnancy, and information on gestational disorders were obtained from medical records. Offspring cardiac measurements were assessed by Cardiovascular Magnetic Resonance at 10 years. MAIN OUTCOME MEASURES: Left and right ventricular end-diastolic volumes (LVEDVs and RVEDVs), and ejection fractions, and left ventricular mass (LVM). RESULTS: Offspring exposed to pre-eclampsia had a lower right ventricular ejection fraction (RVEF) (difference, -0.31 SDS; 95% CI -0.60, -0.02); however, no associations with other cardiac outcomes were present. Higher maternal diastolic blood pressure (DBP) in early and late pregnancy was associated with lower LVEDVs and RVEDVs (p < 0.05), with the strongest effect in early pregnancy. No associations of systolic blood pressure (SBP) with offspring outcomes were present. These associations persisted after additional adjustment for birth and child factors. Paternal SBP and DBP were not associated with offspring cardiac outcomes. CONCLUSIONS: No consistent associations of gestational hypertensive disorder status with childhood cardiac outcomes were present. Higher maternal DBP throughout pregnancy was associated with lower childhood LVEDVs and RVEDVs. Stronger maternal-offspring rather than paternal-offspring associations were present, which may suggest that suboptimal maternal gestational haemodynamic adaptations affects offspring cardiac structure through direct intrauterine effects. Further studies are needed to replicate these findings and examine the underlying mechanisms.

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

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

Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients' offspring.

OBJECTIVES: To study pregnancy outcomes in a closely monitored, well-defined cohort of women with rheumatoid arthritis (RA). In particular, pregnancy outcomes of women that used a TNFi during pregnancy. METHODS: Patients were derived from a prospective study on pregnancy and RA (Preconception Counseling in Active RA study) and treated according to a treatment protocol aimed at minimal disease activity. Multivariate linear regression analysis was used to describe which variables influenced birth weight. RESULTS: 188 patients were included, 92 (48.9%) patients with RA used a TNFi during pregnancy. Disease Activity Score in 28 joints C reactive protein (DAS28CRP) was low at all time points during pregnancy (DAS28CRP in the third trimester: 2.17 (SD 0.73). TNFi use was not associated with an increase of adverse pregnancy outcomes such as low birth weight (<2500 g), (emergency) caesarian section, hypertensive disorders or congenital malformations. TNFi use resulted in less children born small-for-gestational age (p=0.05), however, did not increase the risk of large-for-gestational age (p=0.73). Mean birth weight was 173 g higher in women that used a TNFi during pregnancy (3.344 kg vs 3.171 kg, p=0.03). In the multivariate analysis, maternal age (ß -0.023, 95% CI -0.040 to -0.0065, p=0.007), TNFi use (ß 0.20, 95% CI 0.066, 0.34, p=0.004), diabetes mellitus (ß 0.37, 95% CI 0.12, 0.63, p=0.004) and gestational age (ß 0.18, 95% CI 0.15, 0.2, p<0.001) were statistically significant associated with birth weight. CONCLUSIONS: This is the first study to show that TNFi use during pregnancy is associated with increased birth weight of offspring of women with well-controlled RA. The underlying mechanism of TNF-inhibition on birth weight and the long-term consequences for the offspring should be explored in future research.

Childhood Blood Pressure, Carotid Intima Media Thickness, and Distensibility After In Utero Exposure to Gestational Hypertensive Disorders.

Background Offspring exposed to gestational hypertensive disorders have higher blood pressure and increased risk of stroke in later life. Gestational hypertensive disorders might influence vascular development in the offspring, predisposing them to a higher blood pressure and stroke in later life. Methods and Results In a population-based cohort among 4777 mother-offspring pairs, we examined whether gestational hypertension, preeclampsia, and higher gestational blood pressure across the full blood pressure spectrum were associated with offspring blood pressure, carotid intima media thickness, and distensibility at the age of 10 years. Offspring exposed to gestational hypertension, but not preeclampsia, had higher systolic and diastolic blood pressure (0.17 [95% CI, 0.02-0.31] and 0.23 [95% CI, 0.08-0.38] increases in standard deviation scores, respectively), whereas no associations with intima media thickness and distensibility were present. Higher maternal systolic and diastolic blood pressure in early, mid, and late pregnancy were associated with higher offspring systolic and diastolic blood pressure and lower distensibility (P values <0.05), but not with intima media thickness. The associations were not explained by maternal, birth, or child factors. Paternal systolic and diastolic blood pressure were also associated with these offspring outcomes (P values <0.05), with a comparable strength as maternal-offspring associations. Conclusions Gestational hypertension and higher gestational blood pressure, even below the diagnostic threshold for gestational hypertensive disorders, are associated with higher offspring blood pressure and lower carotid distensibility. No associations were found for preeclampsia with offspring vascular outcomes. As maternal-offspring and paternal-offspring associations were comparable, these associations are more likely driven by genetic predisposition and shared lifestyle rather than by a direct intrauterine effect.

Innovative approach for first-trimester fetal organ volume measurements using a Virtual Reality system: The Generation R Next Study.

INTRODUCTION: To investigate the reproducibility of first-trimester fetal organ volume measurements using three-dimensional (3D) ultrasound and a Virtual Reality system. METHODS: Within a population-based prospective cohort study, 3D ultrasound datasets of 25 first-trimester fetuses were collected by three sonographers. We used the V-scope application to perform Virtual Reality volume assessments of the fetal heart, lungs, and kidneys. All measurements were performed by two independent researchers. RESULTS: Intraobserver analyses for volume measurements of the fetal heart, lungs, and kidneys showed intraclass correlation coefficients ≥0.86, mean differences ≤8.3%, and coefficients of variation ≤22.8%. Interobserver analyses showed sufficient agreement for right lung volume measurements, but consistent measurement differences between observers for left lung, heart, and kidney volume measurements (p-values <0.05). CONCLUSION: We observed sufficient intraobserver reproducibility, but overall suboptimal interobserver reproducibility for first-trimester fetal heart, lung, and kidney volume measurements using an innovative Virtual Reality approach. In the current stage, these measurements might be promising for the use in research settings. The reproducibility of the measurements might be further improved by novel post-processing algorithms.

Toward more accurate prediction of future pregnancy outcome in couples with unexplained recurrent pregnancy loss: taking both partners into account.

OBJECTIVE: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy. DESIGN: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020. SETTING: Two academic centers in the Netherlands. PATIENTS: Clinical data from 526 couples with unexplained RPL were used in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve). RESULTS: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age. CONCLUSIONS: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice.

Associations of dietary glycemic index and load during pregnancy with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders.

PURPOSE: The aim of this study was to examine the associations of dietary glycemic index and load with gestational blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. METHODS: In a population-based cohort among 3378 pregnant Dutch women, dietary glycemic index and load were assessed from food frequency questionnaires at median 13.4 (95% range 9.9-22.9) weeks gestation. Blood pressure was measured in early-, mid- and late-pregnancy. Placental hemodynamic parameters were measured in mid- and late-pregnancy by ultrasound. Data on gestational hypertensive disorders was acquired from medical records. RESULTS: Mean dietary glycemic index (SD) was 58 (3) and mean dietary glycemic load (SD) was 155 (47). Dietary glycemic index was not associated with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. Higher dietary glycemic load SDS was associated with a higher diastolic blood pressure in early-pregnancy, remaining after adjustment for socio-demographic and lifestyle factors ((0.98 (95% CI 0.35-1.61) mmHg per SDS increase in glycemic load). No other associations of glycemic load with blood pressure or placental hemodynamic parameters and the risk of gestational hypertensive disorders were present. No significant associations of dietary glycemic index and load quartiles with longitudinal blood pressure patterns from early to late-pregnancy were present. CONCLUSION: Within this low-risk pregnant population, we did not find consistent associations of dietary glycemic index and load with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. Further studies need to assess whether the effects on gestational hemodynamic adaptations are more pronounced among high-risk women with an impaired glucose metabolism.

Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice.

OBJECTIVES: Lupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice. METHODS: In this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018. RESULTS: During the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-ß2 glycoprotein I (ß2GPI) IgG compared with patients with other indications. CONCLUSION: The prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-ß2GPI IgG and aCL IgG, which should be confirmed in future studies.

Corpus luteum number and the maternal renin-angiotensin-aldosterone system as determinants of utero-placental (vascular) development: the Rotterdam Periconceptional Cohort.

BACKGROUND: Pregnancies with > 1 corpus luteum (CL) display a hyperdynamic circulation and an increased risk of small-for-gestational age deliveries. Among the factors released by the CL is prorenin, the inactive precursor of renin. Since the renin-angiotensin-aldosterone system (RAAS) is involved in early hemodynamic pregnancy adaptation, we linked both CL number and first-trimester concentrations of prorenin (as an indicator of RAAS activity) and the aldosterone/renin ratio (as an indicator of angiotensin-independent aldosterone effectiveness) to non-invasive markers of utero-placental (vascular) development, measured longitudinally from the first trimester onwards. METHODS: A total of 201 women, who conceived naturally or after in-vitro fertilization treatment (with 0 (n = 8), 1 (n = 143), or > 1 (n = 51) CL), were selected from the Rotterdam Periconceptional Cohort. Maternal RAAS components were determined at 11 weeks gestation. Placental volume and utero-placental vascular volume were measured from transvaginal 3D ultrasound scans at 7, 9 and 11 weeks gestation, pulsatility and resistance indices of the uterine arteries were assessed by pulsed wave Doppler ultrasounds at 7, 9, 11, 13, 22 and 32 weeks gestation. At birth placental weight was obtained using standardized procedures. RESULTS: Pregnancies without a CL show lower uterine artery indices throughout gestation than 1 CL and > 1 CL pregnancies, while parameters of placental development are comparable among the CL groups. After adjustment for patient- and treatment-related factors, first-trimester prorenin concentrations are positively associated with uterine artery pulsatility and resistance indices (ß 0.06, 95% CI 0.01;0.12, p = 0.04 and ß 0.10, 95% CI 0.01;0.20, p = 0.04, respectively), while high prorenin concentrations are negatively associated with first-trimester utero-placental vascular volume (ß -0.23, 95% CI -0.44;-0.02, p = 0.04) and placental weight (ß -93.8, 95%CI -160.3;-27.4, p = 0.006). In contrast, the aldosterone/renin ratio is positively associated with first-trimester placental volume (ß 0.12, 95% CI 0.01;0.24, p = 0.04). CONCLUSIONS: The absence of a CL, resulting in low prorenin concentrations, associates with low uterine artery pulsatility and resistance, while high prorenin concentrations associate with a low utero-placental vascular volume and weight. These data support a scenario in which excess prorenin, by upregulating angiotensin II, increases uterine resistance, thereby preventing normal placental (vascular) development, and increasing the risk of small-for-gestational age deliveries. Simultaneously, high aldosterone concentrations, by ensuring volume expansion, exert the opposite.

Periconceptional maternal and paternal homocysteine levels and early utero-placental (vascular) growth trajectories: The Rotterdam periconception cohort.

INTRODUCTION: Maternal elevated plasma total homocysteine (tHcy) is involved in the origin of several placenta-related pregnancy complications. The first trimester is the most sensitive period for placentation influenced by maternal and paternal health. The aim is to study associations between periconceptional parental tHcy levels and utero-placental growth trajectories in the first trimester of pregnancy. METHODS: Pregnant women and their partners were enrolled before 10 weeks of gestation in the Virtual Placenta study as subcohort of the Rotterdam periconception cohort (Predict study). A total of 190 women with a singleton pregnancy, of which 109 conceived naturally and 81 after IVF/ICSI treatment, were included. We measured serial utero-placental vascular volumes (uPVV) and placental volumes (PV) at 7, 9 and 11 weeks of gestation. First-trimester trajectories of PV were also measured in 662 pregnancies from the total Predict study. RESULTS: Comparing all participants of the virtual placenta study, no association between maternal tHcy and uPVV was observed. However, in IVF/ICSI pregnancies sub-analyses showed significantly negative associations between maternal tHcy in the 3rd and 4th quartile and uPVV trajectories (beta: -0.38 (95%CI -0.74 to -0.02) and beta: -0.42 (95% CI -0.78 to -0.05), respectively) with the 1st quartile as reference. Analysis in the total Predict cohort showed similar negative associations for the total study population. DISCUSSION: Periconceptional high maternal tHcy levels are associated with smaller placental growth trajectories depicted as PV and uPVV in the first trimester of pregnancy. The stronger negative associations with uPVV in IVF/ICSI pregnancies underline the need for further investigation.

First trimester fetal proportion volumetric measurements using a Virtual Reality approach.

OBJECTIVE: To establish feasibility and reproducibility of fetal proportion volumetric measurements, using three-dimensional (3D) ultrasound and a Virtual Reality (VR) system. METHODS: Within a population-based prospective birth cohort, 3D ultrasound datasets of 50 fetuses in the late first trimester were collected by three ultrasonographers in a single research center. V-scope software was used for volumetric measurements of total fetus, extremities, head-trunk, head, trunk, thorax, and abdomen. All measurements were performed independently by two researchers. Intraobserver and interobserver reproducibility were analyzed using Bland and Altman methods. RESULTS: Intraobserver and interobserver analyses of volumetric measurements of total fetus, head-trunk, head, trunk, thorax and abdomen showed intraclass correlation coefficients above 0.979, coefficients of variation below 7.51% and mean difference below 3.44%. The interobserver limits of agreement were within the ±10% range for volumetric measurements of total fetus, head-trunk, head and trunk. The interobserver limits of agreement for extremities, thorax and abdomen were -26.09% to 4.77%, -14.14% to 10.00% and -14.47% to 8.83%, respectively. CONCLUSION: First trimester fetal proportion volumetric measurements using 3D ultrasound and VR are feasible and reproducible, except volumetric measurements of the fetal extremities. These novel volumetric measurements may be used in future research to enable detailed studies on first trimester fetal development and growth.

Evaluation of embryonic posture using four-dimensional ultrasound and virtual reality.

AIM: To assess the possibility of embryonic posture evaluation (=feasibility, reproducibility, variation) at rest at 9 weeks' (+0-6 days) gestational age (GA) using four-dimensional ultrasound and virtual reality (VR) techniques. Moreover, it is hypothesized that embryonic posture shows variation at the same time point in an uneventful pregnancy. METHODS: In this explorative prospective cohort study, 23 pregnant women were recruited from the Rotterdam periconceptional cohort. A transvaginal four-dimensional ultrasound examination of 30 min per pregnancy was performed between 9 and 10 weeks' GA. The acquired datasets were offline evaluated longitudinally (i.e. per frame) using VR techniques. RESULTS: The ultrasound data of 16 (70%) out of 23 pregnancies were eligible for evaluation. At rest the analysis of the embryonic posture was feasible and showed a strong (>80%) intraobserver and interobserver reproducibility for most body parts. The majority of the body parts were in similar anatomic positions at rest. However, variations in anatomic positions (e.g. 6% rotated head, 9% laterally bent spine), within and between embryos, were seen at 9 weeks' GA. CONCLUSION: In this unique study, we showed for the first time that embryonic posture measurements at rest can be performed in a reliable way using state-of-the-art four-dimensional ultrasound and VR techniques. Already early in prenatal life there are differences regarding posture within and between embryos.

Associations of DASH Diet in Pregnancy With Blood Pressure Patterns, Placental Hemodynamics, and Gestational Hypertensive Disorders.

Background The Dietary Approaches to Stop Hypertension (DASH) diet improves blood pressure in nonpregnant populations. We hypothesized that adherence to the DASH diet during pregnancy improves hemodynamic adaptations, leading to a lower risk of gestational hypertensive disorders. Methods and Results We examined whether the DASH diet score was associated with blood pressure, placental hemodynamics, and gestational hypertensive disorders in a population-based cohort study among 3414 Dutch women. We assessed DASH score using food-frequency questionnaires. We measured blood pressure in early-, mid-, and late pregnancy (medians, 95% range: 12.9 [9.8-17.9], 20.4 [16.6-23.2], 30.2 [28.6-32.6] weeks gestation, respectively), and placental hemodynamics in mid- and late pregnancy (medians, 95% range: 20.5 [18.7-23.1], 30.4 [28.5-32.8] weeks gestation, respectively). Information on gestational hypertensive disorders was obtained from medical records. Lower DASH score quartiles were associated with a higher mid pregnancy diastolic blood pressure, compared with the highest quartile (P<0.05). No associations were present for early- and late pregnancy diastolic blood pressure and systolic blood pressure throughout pregnancy. Compared with the highest DASH score quartile, the lower DASH score quartiles were associated with a higher mid- and late pregnancy umbilical artery pulsatility index (P≤0.05) but not with uterine artery resistance index. No associations with gestational hypertensive disorders were present. Conclusions A higher DASH diet score is associated with lower mid pregnancy diastolic blood pressure and mid- and late pregnancy fetoplacental vascular function but not with uteroplacental vascular function or gestational hypertensive disorders within a low-risk population. Further studies need to assess whether the effects of the DASH diet on gestational hemodynamic adaptations are more pronounced among higher-risk populations.

Associations of maternal age at the start of pregnancy with placental function throughout pregnancy: The Generation R Study.

OBJECTIVE: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight. STUDY DESIGN: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound. RESULTS: Compared to women aged 25-29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30-34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25-29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30-3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight. CONCLUSIONS: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications.

Second and third trimester fetal ultrasound population screening for risks of preterm birth and small-size and large-size for gestational age at birth: a population-based prospective cohort study

BACKGROUND: Preterm birth, small size for gestational age (SGA) and large size for gestational age (LGA) at birth are major risk factors for neonatal and long-term morbidity and mortality. It is unclear which periods of pregnancy are optimal for ultrasound screening to identify fetuses at risk of preterm birth, SGA or LGA at birth. We aimed to examine whether single or combined second and third trimester ultrasound in addition to maternal characteristics at the start of pregnancy are optimal to detect fetuses at risk for preterm birth, SGA and LGA. METHODS: In a prospective population-based cohort among 7677 pregnant women, we measured second and third trimester estimated fetal weight (EFW), and uterine artery pulsatility and umbilical artery resistance indices as placenta flow measures. Screen positive was considered as EFW or placenta flow measure < 10th or > 90th percentile. Information about maternal age, body mass index, ethnicity, parity, smoking, fetal sex and birth outcomes was available from questionnaires and medical records. Screening performance was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC) along with sensitivity at different false-positive rates. RESULTS: Maternal characteristics only and in combination with second trimester EFW had a moderate performance for screening for each adverse birth outcome. Screening performance improved by adding third trimester EFW to the maternal characteristics (AUCs for preterm birth 0.64 (95%CI 0.61 to 0.67); SGA 0.79 (95%CI 0.78 to 0.81); LGA 0.76 (95%CI 0.75; 0.78)). Adding third trimester placenta measures to this model improved only screening for risk of preterm birth (AUC 0.72 (95%CI 0.66 to 0.77) with sensitivity 37% at specificity 90%) and SGA (AUC 0.83 (95%CI 0.81 to 0.86) with sensitivity 55% at specificity 90%). Combining second and third trimester fetal and placental ultrasound did not lead to a better performance as compared to using only third trimester results. CONCLUSIONS: Combining single third trimester fetal and placental ultrasound results with maternal characteristics has the best screening performance for risks of preterm birth, SGA and LGA. As compared to second trimester screening, third trimester screening may double the detection of fetuses at risk of common adverse birth outcomes.

Associations of Maternal Early-Pregnancy Glucose Concentrations With Placental Hemodynamics, Blood Pressure, and Gestational Hypertensive Disorders.

BACKGROUND: Gestational diabetes mellitus is associated with increased risks of gestational hypertension and preeclampsia. We hypothesized that high maternal glucose concentrations in early pregnancy are associated with adverse placental adaptations and subsequently altered uteroplacental hemodynamics during pregnancy, predisposing to an increased risk of gestational hypertensive disorders. METHODS: In a population-based prospective cohort study from early pregnancy onwards, among 6,078 pregnant women, maternal early-pregnancy non-fasting glucose concentrations were measured. Mid and late pregnancy uterine and umbilical artery resistance indices were assessed by Doppler ultrasound. Maternal blood pressure was measured in early, mid, and late pregnancy and the occurrence of gestational hypertensive disorders was assessed using hospital registries. RESULTS: Maternal early-pregnancy glucose concentrations were not associated with mid or late pregnancy placental hemodynamic markers. A 1 mmol/l increase in maternal early-pregnancy glucose concentrations was associated with 0.71 mm Hg (95% confidence interval 0.22-1.22) and 0.48 mm Hg (95% confidence interval 0.10-0.86) higher systolic and diastolic blood pressure in early pregnancy, respectively, but not with blood pressure in later pregnancy. Also, maternal glucose concentrations were not associated with the risks of gestational hypertension or preeclampsia. CONCLUSIONS: Maternal early-pregnancy non-fasting glucose concentrations within the normal range are associated with blood pressure in early pregnancy, but do not seem to affect placental hemodynamics and the risks of gestational hypertensive disorders.

Population screening for gestational hypertensive disorders using maternal, fetal and placental characteristics: A population-based prospective cohort study.

OBJECTIVE: To determine screening performance of maternal, fetal and placental characteristics for selecting pregnancies at risk of gestational hypertension and preeclampsia in a low-risk multi-ethnic population. METHOD: In a prospective population-based cohort among 7124 pregnant women, we collected maternal characteristics including body mass index, ethnicity, parity, smoking and blood pressure in early-pregnancy. Fetal characteristics included second and third trimester estimated fetal weight and sex determined by ultrasound. Placental characteristics included first and second trimester placental growth factor concentrations and second and third trimester uterine artery resistance indices. RESULTS: Maternal characteristics provided the best screening result for gestational hypertension (area-under-the-curve [AUC] 0.79 [95% Confidence interval {CI} 0.76-0.81]) with 40% sensitivity at 90% specificity. For preeclampsia, the maternal characteristics model led to a screening performance of AUC 0.74 (95% CI 0.70-0.78) with 33% sensitivity at 90% specificity. Addition of second and third trimester placental ultrasound characteristics only improved screening performance for preeclampsia (AUC 0.78 [95% CI 0.75-0.82], with 48% sensitivity at 90% specificity). CONCLUSION: Routinely measured maternal characteristics, known at the start of pregnancy, can be used in screening for pregnancies at risk of gestational hypertension or preeclampsia within a low-risk multi-ethnic population. Addition of combined second and third trimester placental ultrasound characteristics only improved screening for preeclampsia.