BACKGROUND: The IMPACT BCN trial-a parallel-group randomized clinical trial where 1221 pregnant women at high risk for small-for-gestational age (SGA) newborns were randomly allocated at 19- to 23-week gestation into three groups: Mediterranean diet, Mindfulness-based Stress reduction or non-intervention-has demonstrated a positive effect of Mediterranean diet and Stress reduction in the prevention of SGA. However, the mechanism of action of these interventions remains still unclear. The aim of this study is to investigate the effect of Mediterranean diet and Stress reduction on placental volume and perfusion.
METHODS: Participants in the Mediterranean diet group received monthly individual and group educational sessions, and free provision of extra-virgin olive oil and walnuts. Women in the Stress reduction group underwent an 8-week Stress reduction program adapted for pregnancy, consisting of weekly 2.5-h and one full-day sessions. Non-intervention group was based on usual care. Placental volume and perfusion were assessed in a subgroup of randomly selected women (n = 165) using magnetic resonance (MR) at 36-week gestation. Small placental volume was defined as MR estimated volume <10th centile. Perfusion was assessed by intravoxel incoherent motion.
RESULTS: While mean MR placental volume was similar among the study groups, both interventions were associated with a lower prevalence of small placental volume (3.9% Mediterranean diet and 5% stress reduction vs. 17% non-intervention; p = 0.03 and p = 0.04, respectively). Logistic regression showed that small placental volume was significantly associated with higher risk of SGA in both study groups (OR 7.48 [1.99-28.09] in Mediterranean diet and 20.44 [5.13-81.4] in Stress reduction). Mediation analysis showed that the effect of Mediterranean diet on SGA can be decomposed by a direct effect and an indirect effect (56.6%) mediated by a small placental volume. Similarly, the effect of Stress reduction on SGA is partially mediated (45.3%) by a small placental volume. Results on placental intravoxel incoherent motion perfusion fraction and diffusion coefficient were similar among the study groups.
CONCLUSIONS: Structured interventions during pregnancy based on Mediterranean diet or Stress reduction are associated with a lower proportion of small placentas, which is consistent with the previously observed beneficial effects of these interventions on fetal growth.

BACKGROUND: Our goal was to evaluate the potential utility of magnetic resonance imaging (MRI) placental volume as an assessment of placental insufficiency.
METHODS: Secondary analysis of a prospective cohort undergoing serial placental MRIs at two academic tertiary care centers. The population included 316 participants undergoing MRI up to three times throughout gestation. MRI was used to calculate placental volume in milliliters (ml). Placental-mediated adverse pregnancy outcome (cAPO) included preeclampsia with severe features, abnormal antenatal surveillance, and perinatal mortality. Serial measurements were grouped as time point 1 (TP1) <22 weeks, TP2 22 0/7-29 6/7 weeks, and TP3 ≥30 weeks. Mixed effects models compared change in placental volume across gestation between cAPO groups. Association between cAPO and placental volume was determined using logistic regression at each TP with discrimination evaluated using area under receiver operator curve (AUC). Placental volume was then added to known clinical predictive variables and evaluated with test characteristics and calibration.
RESULTS: 59 (18.7 %) of 316 participants developed cAPO. Placental volume growth across gestation was slower in the cAPO group (p < 0.001). Placental volume was lower in the cAPO group at all time points, and alone was moderately predictive of cAPO at TP3 (AUC 0.756). Adding placental volume to clinical variables had moderate discrimination at all time points, with strongest test characteristics at TP3 (AUC 0.792) with sensitivity of 77.5 % and specificity of 75.3 % at a predicted probability cutoff of 15 %.
CONCLUSIONS: MRI placental volume warrants further study for assessment of placental insufficiency, particularly later in gestation.

BACKGROUND: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown.
METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction.
RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7).
CONCLUSIONS: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.

BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA.
METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders.
RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025).
CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.

BACKGROUND: Unfavorable lipid profile is associated with pregnancy disorders characterized by uteroplacental dysfunction, including hypertensive disorders of pregnancy, preterm birth and fetal growth restriction. None of current tools used to predict the risk of pregnancy complications include lipid levels.
OBJECTIVE: In this study, we examined the association of preconception lipid profile with pregnancy disorders characterized by uteroplacental dysfunction in a multi-ethnic population, aiming to improve the identification of women at high risk for uteroplacental dysfunction using current prediction models.
METHODS: We conducted a linkage study combining lipid profile collected in the multi-ethnic HELIUS study (Amsterdam, 2011-2015), linked with national perinatal registry data on pregnancy complications after inclusion until 2019. We included 1177 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan origin. Associations were studied using Poisson regression. The discriminative ability was assessed for different pregnancy complications of significantly associated lipid parameters when added to commonly used prediction tools for preeclampsia.
RESULTS: Preconception triglyceride level was associated with prevalence of hypertensive disorders of pregnancy (e^triglyceride level (mmol/L) adjusted prevalence ratio 1.07, 95% CI 1.00 to 1.14). Age-adjusted prevalence of hypertensive disorders of pregnancy was also higher among women with high LDL-C level, high TC/HDL-C or ≥4 adverse lipid parameters, but most of these findings were not statistically significant when adjusted for demographic, lifestyle and medical characteristics. Addition of triglyceride level and other lipid parameters to the NICE guideline criteria and to the EXPECT prediction tool did not improve discriminative ability for hypertensive disorders of pregnancy, preterm birth or fetal growth restriction.
CONCLUSIONS: Lipid profile did not aid in the identification of women at high risk for pregnancy disorders characterized by uteroplacental dysfunction. Further studies are needed to improve preconception prediction models for hypertensive disorders of pregnancy and other pregnancy disorders characterized by uteroplacental dysfunction using biomarkers or other easily available measurements.

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary\'s Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (β = 0.003, p < 0.05). When comparing the normal growth and asymmetric FGR groups, the asymmetric FGR group showed significantly higher maternal and fetal BPA levels compared to the normal growth group (maternal urine BPA, 3.99 μg/g creatinine vs. 1.71 μg/g creatinine [p < 0.05]; cord blood BPA, 1.96 μg/L vs. -0.86 μg/L [p < 0.05]). In conclusion, fetal exposure levels of BPA show linear associations with asymmetric fetal growth patterns. High maternal and fetal exposure to BPA might be associated with asymmetric FGR.

BACKGROUND: To longitudinally and cross-sectionally study the differences in the uterine artery pulsatility index (UTPI), umbilical artery pulsatility index (UAPI) and placental vascularization indices (PVIs, derived from 3-dimensional power Doppler) between normal and placental insufficiency pregnancies throughout gestation.
METHODS: UTPI, UAPI and PVI were measured 6 times at 4- to 5- week intervals from 11 to 13+6 weeks-36 weeks. Preeclampsia (PE) and fetal growth restriction (FGR) were defined as placental insufficiency. Comparisons of UTPI, UAPI and PVI between normal and insufficiency groups were performed by one-way repeated measures analysis of variance.
RESULTS: A total of 125 women were included: monitored regularly from the first trimester to 36 weeks of gestation: 109 with normal pregnancies and 16 with placental insufficiency. Longitudinal study of the normal pregnancy group showed that UTPI and UAPI decreased significantly every 4 weeks, while PVIs increased significantly every 8 weeks until term. In the placental insufficiency group however, this decrease occurred slower at 8 weeks intervals and UTPI stabilized after 24 weeks. No significant difference was noted in PVIs throughout pregnancy. Cross-sectional study from different stages of gestation showed that UTPI was higher in the insufficiency group from 15 weeks onward and PVIs were lower after 32 weeks.
CONCLUSIONS: Compared to high-risk pregnancies with normal outcome, UTPI and UAPI needed a longer time to reach a significant change in those with clinical confirmation of placental insufficiency pregnancies and no significant change was found in PVI throughout gestation. UTPI was the earliest factor in detecting adverse outcome pregnancies.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age.
OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial.
METHODS: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion.
RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups.
CONCLUSIONS: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

BACKGROUND: Prospective data about the risks of thrombotic and severe haemorrhagic complications during pregnancy and post partum are unavailable for women with antiphospholipid syndrome. We aimed to assess thrombotic and haemorrhagic events in a prospective cohort of pregnant women with antiphospholipid syndrome.
METHODS: This multicentre, prospective, observational study was done at 76 centres in France. To be eligible for this study, women had to have diagnosis of antiphospholipid syndrome; have conceived before April 17, 2020; have an ongoing pregnancy that had reached 12 weeks of gestation; and be included in the study before 18 weeks of gestation. Exclusion criteria were active systemic lupus erythematosus nephropathy, or a multifetal pregnancy. Severe haemorrhage was defined as the need for red blood cell transfusion or maternal intensive care unit admission because of bleeding or invasive procedures, defined as interventional radiology or surgery, to control bleeding. The GR2 study is registered with ClinicalTrials.gov, NCT02450396.
RESULTS: Between May 26, 2014, and April 17, 2020, 168 pregnancies in 27 centres met the inclusion criteria for the study. 89 (53%) of 168 women had a history of thrombosis. The median term at inclusion was 8 weeks gestation. 16 (10%) of 168 women (95%CI 5-15) had a thrombotic (six [4%] women; 95% CI 1-8) or severe haemorrhagic event (12 [7%] women; 95% CI 4-12). There were no deaths during the study. The main risk factors for thrombotic events were lupus anticoagulant positivity at inclusion (six [100%] of six women with thrombosis vs 78 [51%] of 152 of those with no thrombosis; p=0·030) and placental insufficiency (four [67%] of six women vs 28 [17%] of 162 women; p=0·013). The main risk factors for severe haemorrhagic events were pre-existing maternal hypertension (four [33%] of 12 women vs 11 [7%] of 156 women; p=0·014), lupus anticoagulant positivity at inclusion (12 [100%] of 12 women vs 72 [49%] of 146 women; p<0·0001) and during antiphospholipid history (12 [100%] of 12 women vs 104 [67%] of 156 women; p=0·019), triple antiphospholipid antibody positivity (eight [67%] of 12 women vs 36 [24%] of 147 women; p=0·0040), placental insufficiency (five [42%] of 12 women vs 27 [17%] of 156 women; p=0·038), and preterm delivery at 34 weeks or earlier (five [45%] of 11 women vs 12 [8%] of 145 women; p=0·0030).
CONCLUSIONS: Despite treatment adhering to international recommendations, a proportion of women with antiphospholipid syndrome developed a thrombotic or severe haemorrhagic complication related to pregnancy, most frequently in the post-partum period. Lupus anticoagulant and placental insufficiency were risk factors for these life-threatening complications. These complications are difficult to prevent, but knowledge of the antenatal characteristics associated with them should increase awareness and help physicians manage these high-risk pregnancies.
BACKGROUND: Lupus France, association des Sclérodermiques de France, association Gougerot Sjögren, Association Francophone contre la Polychondrite chronique atrophiante, AFM-Telethon, the French Society of Internal Medicine and Rheumatology, Cochin Hospital, the French Health Ministry, FOREUM, the Association Prix Veronique Roualet, and UCB.

OBJECTIVE: To investigate the relationship of umbilical vein flow (UVF) measured close to term with abnormal fetal growth and adverse perinatal outcome in a cohort of pregnancies at low risk of placental insufficiency.
METHODS: This was a prospective multicenter observational study conducted across two tertiary maternity units. Patients with a singleton appropriate-for-gestational-age fetus between 35 and 38 weeks\' gestation were included. Pregnancies at higher risk of placental insufficiency or with fetal anomalies were excluded. At ultrasound examination, the abdominal circumference (AC), umbilical vein diameter and peak velocity of the umbilical vein were measured, and, using these variables, a new variable, UVF/AC, was calculated. The primary outcome was the occurrence of severely stunted fetal growth, defined as a greater than 40-percentile drop between estimated fetal weight at the third-trimester ultrasound and birth weight. The occurrence of adverse perinatal outcome (defined as one of the following: neonatal acidosis (umbilical artery pH < 7.15 and/or base excess > 12 mmol/L) at birth, 5-min Apgar score < 7, neonatal resuscitation or neonatal intensive care unit admission) was analyzed as a secondary outcome.
RESULTS: Between April 2021 and March 2023, 365 women were included in the study. The mean UVF/AC at enrolment was 6.4 ± 2.6 mL/min/cm, and 35 (9.6%) cases were affected by severely stunted fetal growth. Severely stunted fetal growth was associated with a lower mean UVF/AC (5.4 ± 2.6 vs 6.5 ± 2.6 mL/min/cm; P = 0.02) and a higher frequency of UVF/AC < 10th percentile (8/35 (22.9%) vs 28/330 (8.5%); P = 0.01). Moreover, UVF/AC showed an area under the receiver-operating-characteristics curve (AUC) of 0.65 (95% CI, 0.55-0.75; P = 0.004) in predicting the occurrence of severely stunted fetal growth, and the optimal cut-off value of UVF/AC for discriminating between normal and severely stunted fetal growth was 7.2 mL/min/cm. This value was associated with a sensitivity and specificity of 0.77 (95% CI, 0.60-0.90) and 0.33 (95% CI, 0.28-0.39), and positive and negative predictive values of 0.11 (95% CI, 0.07-0.15) and 0.93 (95% CI, 0.87-0.97), respectively. Regarding the occurrence of adverse perinatal outcome, this was associated independently with maternal age (adjusted odds ratio (aOR), 0.93 (95% CI, 0.87-0.99); P = 0.04), UVF/AC Z-score (aOR, 0.53 (95% CI, 0.30-0.87); P = 0.01) and augmentation of labor (aOR, 2.69 (95% CI, 1.28-5.69); P = 0.009). UVF/AC showed an AUC of 0.65 (95% CI, 0.56-0.73; P = 0.005) in predicting the occurrence of adverse perinatal outcome, and the optimal cut-off value of UVF/AC for discriminating between normal and adverse perinatal outcome was 6.7 mL/min/cm. This value was associated with a sensitivity and specificity of 0.70 (95% CI, 0.54-0.83) and 0.40 (95% CI, 0.34-0.45), and positive and negative predictive values of 0.14 (95% CI, 0.09-0.19) and 0.91 (95% CI, 0.85-0.95), respectively.
CONCLUSIONS: Our data demonstrate an association between reduced UVF close to term, severely stunted fetal growth and adverse perinatal outcome in a cohort of low-risk pregnant women, with a moderate ability to rule out and a poor ability to rule in either outcome. Further studies are needed to establish whether the assessment of UVF can improve the identification of fetuses at risk of subclinical placental insufficiency and adverse perinatal outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.