Edward D. Johnstone

Background: Antihypertensive and cardioprotective medications are prescribed to pregnant women and include Ca ²⁺ channel blockers (CCBs; amlodipine, nifedipine), α- (doxazosin) and β-(labetalol, bisoprolol, nebivolol) adrenergic receptor antagonists, and α-adrenergic receptor agonists (methyldopa). These vasoactive drugs enter the fetal circulation, with unknown effects on the fetoplacental vasculature. We aimed to investigate whether cardiovascular medications modulate human fetoplacental vascular tone, which may impair or enhance placental perfusion. Methods: Chorionic plate arteries (CPAs) were obtained from the placentas of women with normotensive pregnancy (N=28), with unmedicated hypertension (N=14), and those chronically medicated (N=61) with either amlodipine, nifedipine, labetalol or bisoprolol, or a combination of CCBs and labetalol. Using wire myography, ex vivo effects of amlodipine, nifedipine, labetalol, methyldopa, doxazosin, bisoprolol and nebivolol were tested in a concentration-dependent manner (10 ^-11 –10 ^-5 M) in pre-constricted CPAs isolated from the placentas of normotensive women. Differences in CPA vascular reactivity in response to chronic exposure to hypertension and/or cardiovascular medications was assessed by vasoconstriction to high potassium physiological solution (KPSS; 120mM) and to the thromboxane A ₂ mimetic (U46619; 10 ^-10 –2×10 ^-6 M), and relaxation to the nitric oxide donor, sodium nitroprusside (SNP; 10 ^-10 –10 ^-5 M). Results: In pre-constricted CPAs isolated from normotensive women, acute exposure to amlodipine, nifedipine, doxazosin and nebivolol promoted significant vasorelaxation (P<0.05). CPAs acutely exposed to labetalol, methyldopa (P<0.05) and bisoprolol (P<0.001) exhibited increased vasoconstriction compared to their respective diluent controls. CPAs from women with chronic hypertension and from those who had chronic labetalol treatment exhibited significantly reduced vasoconstriction to KPSS (P<0.05). CPAs from women with chronic hypertension and exposure to bisoprolol also had significantly attenuated vascular responses to U46619 and SNP (P<0.01 and P<0.01, respectively), compared to normal pregnancy. Conclusions: Maternal hypertension impairs vascular responses of the placenta. Cardiovascular medications prescribed during pregnancy may dysregulate placental vascular function. Further research is warranted to evaluate the relative safety of cardiovascular medications in pregnancy, as their distinct effects on fetoplacental vascular function may have important implications for maternal and fetal outcomes. Mechanistic studies alongside clinical correlations are essential to guide evidence-based prescribing.

The umbilical cord varies widely across placental mammals, yet the functional consequences of this structural diversity remain unclear. We compared cord anatomy across 130 mammal species, reconstructed ancestral states, and combined multimodal imaging with physics-based modelling of oxygen and heat transfer. Reconstructions indicate that the ancestral umbilical cord was uncoiled, with three vessels and an allantoic duct; the human combination of coiling with loss of the duct is rare. Across species, vessel number, duct persistence, and cord length increase with birth weight. Modelling predicts that oxygen delivery remains near maximal across architectures, but that placental heat loss depends more strongly on umbilical flow and on cord length and coiling, suggesting more efficient cooling in larger mammals. Microscopy and ultrasound imaging reveal geometric vessel layouts, including a human triple helix, consistent with configurations predicted to reduce inter-vessel heat shunting. As fetuses must dissipate heat through the mother, these results link cord morphology, evolution, and fetal thermal resilience.

BACKGROUND: Suboptimal fetal growth (SFG), being born small for gestational age (SGA), and catch-up (CU) growth are, individually and together, linked to cardiometabolic risks. However, not all develop adverse outcomes. This study aimed to validate a transcriptomic signature to identify individuals at greatest cardiometabolic risk. METHODS: Using National Heart, Lung and Blood Institute (NHLBI) criteria to define cardiometabolic risk, healthy and prehypertensive 17-year-olds were identified in the Avon Longitudinal Study of Parents and Children (ALSPAC) (UK) childhood cohort. Epigenomic and transcriptomic differences were analyzed. A hypergraph identified functionally related genes, which were used in random forest classification to predict prehypertensive phenotypes. The BabyGRO (UK) cohort included 80 children aged 3–7 years, born at term following pregnancies with SFG risks. Anthropometric and cardiometabolic markers and transcriptomic profiles were collected, fetal and childhood weight trajectories and their relationship to cardiometabolic markers were assessed, and transcriptome was used for prediction. RESULTS: Individuals with CU-SGA in ALSPAC were 1.6 times more likely than all others to be prehypertensive at 17 years ( P < 1 × 10 ^–5 ). A 42-gene hypergraph cluster was highly predictive of prehypertension (AUC 0.984, error rate 5.4%). In BabyGRO, 20 of these genes accurately predicted higher systolic blood pressure (AUC 0.971, error rate 3.6%). This transcriptomic signature could help identify children with adverse pre- and postnatal growth who may develop prehypertension. CONCLUSION: A blood transcriptomic signature exists in childhood which distinguishes those at risk of adult cardiometabolic disease among children with adverse pre- and postnatal growth. TRIAL REGISTRATION: Regional ethics committee reference 17/NW/0153, IRAS project ID 187679. FUNDING: Centre grant to the Maternal and Fetal Health Research Centre by Tommy’s The Pregnancy and Baby Charity, Child Growth Foundation, European Research Council funding as part of the Health and Environment-wide Associations based on Large Population Surveys (HEALS) study

The umbilical cord plays a critical role in delivering nutrients and oxygen from the placenta to the fetus through the umbilical vein, while the two umbilical arteries carry deoxygenated blood with waste products back to the placenta. Although solute exchange in the placenta has been extensively studied, exchange within the cord tissue has not been investigated. Here, we explore the hypothesis that the coiled structure of the umbilical cord could strengthen diffusive coupling between the arteries and the vein, resulting in a functional shunt. We calculate the diffusion of solutes, such as oxygen, and heat in the umbilical cord to quantify how this shunt is affected by vascular configuration within the cord. We demonstrate that the shunt is enhanced by coiling and vessel proximity. Furthermore, our model predicts that typical vascular configurations of the human cord tend to minimize shunting, which could otherwise disrupt thermal regulation of the fetus. We also show that the exchange, amplified by coiling, can provide additional oxygen supply to the cord tissue surrounding the umbilical vessels.

Background: Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods: The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22⁺⁰ and 29⁺⁶ weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31⁺⁶ weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26⁺⁰ or at 26⁺⁰ weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results: Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion: Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration: This trial is registered as ISRCTN39133303. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

Introduction Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin Methods and analysis The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women’s preference, clinician’s preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents’ and Clinicians’ Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15–25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3. Ethics and dissemination This study has received ethical approval from the Health Research Authority (HRA) South West—Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies. Trial registration number This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201).

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) of the human placenta is potentially a sensitive marker of in vivo oxygenation. This methodological study shows that full coverage of the placenta is possible using 3D mapping of the change in longitudinal relaxation rate (ΔR₁), in a group of healthy pregnant subjects breathing elevated levels of oxygen. Twelve pregnant subjects underwent a comparison of 2D and 3D OE-MRI. ΔR₁ was mapped for a single 2D slice (ss-2D), a single matched-slice from the 3D volume (ss-3D) and the full 3D volume (vol-3D). The group-average median ΔR₁ values for ss-3D (0.023 s^-1) and vol-3D (0.022 s^-1) do not differ significantly from ss-2D (0.020 s^-1), when compared using a two-tailed paired t-test (ss-3D (p = 0.58) and vol-3D (p = 0.70)). However, median baseline T₁ (T_1b) for ss-2D was higher (1603 ms) than T_1b for ss-3D (1540 ms, p = 0.07) and significantly higher than vol-3D (1515 ms, p = 0.02), when compared using a two-tailed paired t-test. In contrast with previous studies, no correlation of median ΔR₁ with gestation age at scan for the normal group (N = 10) was observed for ss-2D, likely due to the smaller gestational range. Full volume OE-MRI maps reveal sensitivity to changes in ΔR₁, with some participants showing an enhanced gradient in the intermediate space between the fetal and maternal sides of the placenta in the 3D data. This study shows that it is feasible to acquire whole placental volume OE-MRI data in women with healthy pregnancy.

Low-cost personal exposure monitors (PEMs) to measure personal exposure to air pollution are potentially promising tools for health research. However, their adoption requires robust validation. This study evaluated the performance of twenty-one Plume Lab Flow2s (PLFs) by comparing its air pollutant measurements, particulate matter with a diameter of 2.5 μm or less (PM_2.5), 10 μm or less (PM₁₀), and nitrogen dioxide (NO₂), against several high-quality air pollution monitors under field conditions (at indoor, outdoor, and roadside locations). Correlation and regression analysis were used to evaluate measurements obtained by different PLFs against reference instrumentation. For all measured pollutants, the overall correlation coefficient between the PLFs and the reference instruments was often weak (r < 0.4). Moderate correlation was observed for one PLF unit at the indoor location and two units at the roadside location when measuring PM_2.5, but not for PM₁₀ and NO₂ concentration. During periods of particularly higher pollution, 11 PLF tools showed stronger regression results (R² values > 0.5) with one-hour and 9 PLF units with one-minute time interval. Results show that the PLF cannot be used robustly to determine high and low exposure to poor air. Therefore, the use of PLFs in research studies should be approached with caution if data quality is important to the research outputs.

Low-cost personal exposure monitors (PEMs) to measure personal exposure to air pollution are potentially promising tools for health research. However, their adoption requires robust validation. This study evaluated the performance of twenty-one Plume Lab Flow2 (PLF) by comparing its air pollutant measurements, particulate matter with a diameter of 2.5 μm or less (PM2.5), 10 μm or less (PM10), and nitrogen dioxide (NO2), against several high-quality air pollution monitors under field conditions (at indoor, outdoor, and roadside locations). Correlation and regression analysis were used to evaluate measurements obtained by different PLFs against reference instrumentation. For all measured pollutants, the overall correlation coefficient between the PLFs and the reference instruments was often weak (r 0.5) with one-hour and 9 PLF units with one-minute time interval. Results show that the PLF cannot be used robustly to determine high and low exposure to poor air. Therefore, the use of PLFs in research studies should be approached with caution if data quality is important to the research outputs.