Lucy Higgins

Obesity and the placenta: A consideration of nutrient exchange mechanisms in relation to aberrant fetal growth

The obesity epidemic, including childhood obesity, is rapidly gaining strength as one of the most significant challenges to the health of the global community in the 21st Century. The proportion of women who are obese at the beginning of pregnancy is also increasing. These women and their babies are at high risk of pregnancy complications, and of programming for metabolic disease in adult life. In particular, maternal obesity is associated with aberrant fetal growth, encompassing both growth restricted and large for gestational age, or macrosomic fetuses. This article considers the potential effect of obesity and adipose tissue on placental nutrient exchange mechanisms in relation to aberrant fetal growth. The review emphasizes the dearth of work on this topic to date despite its importance to current and future healthcare of the population.

Maternal obesity and its effect on placental cell turnover.

Abstract Background: Maternal obesity is a frequent obstetric risk factor, linked with short- and long-term consequences for mother and child, including foetal overgrowth, growth restriction and stillbirth. The mechanisms underlying these pathologies remain unknown but likely involve the placenta. Aims: To study placental cell turnover in relation to maternal body mass index (BMI). Methods: Term placental villous tissue was randomly sampled from 24 pregnancies, with a range of maternal BMI of 19.5–49.6. Immunohistochemistry was performed for human chorionic gonadotropin, Ki67 and M30 and image analysis used to calculate syncytiotrophoblast area and proliferative and apoptotic indices. Results were compared categorically between women of BMI 18.5–24.9 (normal), BMI 30.0–39.9 (obese classes 1and 2) and BMI 40+ (obese class 3) and continuously against BMI; p < 0.05 by the Kruskal–Wallis test or linear regression was considered statistically significant. Results: Increased maternal BMI was associated with categorical (normal versus obese class 3 and obese classes 1 and 2 versus obese class 3, both p < 0.05) and continuous (r2 = 0.24, p = 0.016) reductions in the proliferative index and a continuous reduction (r2 = 0.17, p = 0.047) in the apoptotic index. Discussion: Maternal obesity is associated with a dose-dependent reduction in placental villous proliferation and apoptosis which may increase susceptibility to adverse pregnancy outcomes.

Chorionic plate arterial function is altered in maternal obesity

Objectives To characterise Chorionic Plate Artery (CPA) function in maternal obesity, and investigate whether leptin exposure reproduces the obese CPA phenotype in normal-BMI women. Study design CPA responses to the thromboxane-A2 mimetic U46619 (pre/post leptin incubation), to the nitric oxide donor sodium nitroprusside (SNP) and the occurrence of tone oscillations (pre/post leptin incubation) were assessed in 46 term placentas from women of normal (18.5–24.9) or obese (>30) Body Mass Index (BMI). Outcome measures Area Under the dose response Curve (AUC), maximum response (Vmax), sensitivity (EC50) to U46619 (pre/post leptin) and SNP; average vessel tone, oscillation amplitude and frequency (pre/post leptin). Results U46619 vasoconstriction was similar between BMI categories (p > 0.05), however vasodilatation to SNP was reduced in obesity (AUC p = 0.02, Vmaxp = 0.04) compared to normal-BMI women. Leptin incubation altered responses to U46619 in both normal-BMI (EC50 at 100 ng/ml leptin; p < 0.05) and obese women (AUC at 50 ng/ml; p < 0.05) but vasomotion was unaffected (p > 0.05). Conclusions Maternal obesity is associated with altered placental vascular function which may adversely affect placental oxygen and nutrient transport, placing the fetus at risk. Leptin incubation altered CPA vascular function but did not reproduce the obese phenotype.

Placental Features of Late-Onset Adverse Pregnancy Outcome

Objective Currently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement. Methods Following third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium). Results Placentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10–12) vessels/mm2 vs. normal outcome 13 (12–15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19–50) nM vs. 12 (6–24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11–50) vs. 55 (24–102) mIU/mg, p = 0.007) and human placental lactogen (11 (6–14) vs. 27 (9–50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13–29) vs. 5 (2–15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue. Conclusion These data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.

Intraexaminer and Interexaminer Variability in 3D Fetal Volume Measurements During the Second and Third Trimesters of Pregnancy

To assess intraexaminer and interexaminer reliability of 3‐dimensional fetal sonographic measurements.

Maternal perception of fetal movements in late pregnancy is affected by type and duration of fetal movement

Abstract Objective: A reduction in fetal movements has been proposed to identify pregnancies at risk of stillbirth. The utility of this approach is limited by variability in maternal perception of fetal movements. We aimed to determine the proportion of fetal movements observed by ultrasound that were maternally perceived and identify factors that affected maternal perception. Method: During 30-min recordings, women (n = 21) depressed a trigger upon perception of a fetal movement, while an ultrasound operator recorded observed movements according to the fetal parts involved. Results: Women perceived between 2.4% and 81.0% (median 44.8%) of movements observed on scan. Synchronous movement of the fetal trunk and limbs was more likely to be recognized than either part in isolation (60.5% versus 37.5% and 30%, respectively). The ultrasound operator judged the fetus to be moving for a significantly greater proportion of the time than mothers (median 1.5% of total recording time versus 0.7%). There was no significant relationship between the ability to perceive fetal activity and placental site, parity, amniotic fluid index or maternal body mass index. Conclusion: Variations in maternal perception of fetal movements may affect detection of a clinically significant reduction in fetal movements for some women.

Persistent inaccuracies in completion of medical certificates of stillbirth: A cross-sectional study

Abstract Background The UK Medical Certificate of Stillbirth (MCS) records information relevant to the cause of stillbirth of infants ≥24 weeks’ gestation. A cross‐sectional audit demonstrated widespread inaccuracies in MCS completion in 2009 in North West England. A repeat study was conducted to assess whether practice had improved following introduction of a regional care pathway. Methods 266 MCS issued in 14 North West England obstetric units during 2015 were studied retrospectively. Cause of death was assigned following review of information available at the time of MCS completion. This was compared to that documented on the MCS, and to data from 2009. Results Twenty‐three certificates were excluded (20 inadequate data, 3 late miscarriages). 118/243 (49%) MCS contained major errors. Agreement between the MCS and adjudicated cause of stillbirth was fair (Kappa 0.31; 95% CI 0.24, 0.38) and unchanged from 2009 (0.29). In 2015, excluding 34 terminations of pregnancy, the proportion of MCSs documenting “unexplained” stillbirths (113/211; 54%) was reduced compared to 2009 (158/213; 74%); causality could be assigned after case note review in 78% cases. Recognition of fetal growth restriction (FGR) as a cause of stillbirth improved (2015: 30/211; 14% vs 2009: 1/213; 0.5%), although 71% cases were missed. 47% MCSs following termination of pregnancy documented an iatrogenic primary cause of death. Conclusions Completion of MCSs remains inaccurate, particularly in recognition of FGR as a cause of stillbirth. Detailed case note review before issuing the MCS could dramatically improve the usefulness of included information; evaluation of practitioner education programmes/internal feedback systems are recommended.

Cell free hemoglobin in the fetoplacental circulation: A novel cause of fetal growth restriction?

Cell free hemoglobin impairs vascular function and blood flow in adult cardiovascular disease. In this study, we investigated the hypothesis that free fetal hemoglobin (fHbF) compromises vascular integrity and function in the fetoplacental circulation, contributing to the increased vascular resistance associated with fetal growth restriction (FGR). Women with normal and FGR pregnancies were recruited and their placentas collected freshly postpartum. FGR fetal capillaries showed evidence of erythrocyte vascular pacκing and extravasation. Fetal cord blood fHbF levels were higher in FGR than in normal pregnancies (P < 0.05) and the elevation of fHbF in relation to heme oxygenase‐1 suggests a failure of expected catabolic compensation, which occurs in adults. During ex vivo placental perfusion, pathophysiological fHbF concentrations significantly increased fetal‐side microcirculatory resistance (P < 0.05). fHbF sequestered NO in acute and chronic exposure models (P <0.001), and fHbF‐primed placental endothelial cells developed a proinflammatory phenotype, demonstrated by activation of NF‐κB pathway, generation of IL‐1ä and TNF‐ä (both P < 0.05), uncontrolled angiogenesis, and disruption of endothelial cell flow alignment. Elevated fHbF contributes to increased fetoplacental vascular resistance and impaired endothelial protection. This unrecognized mechanism for fetal compromise offers a novel insight into FGR as well as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.—Brooκ, A., Hoaκsey, A., Gurung, R., Yoong, E. E. C., Sneyd, R., Baynes, G. C., Bischof, H., Jones, S., Higgins, L. E., Jones, C., Greenwood, S. L., Jones, R. L., Gram, M., Lang, I., Desoye, G., Myers, J., Schneider, H., Hansson, S. R., Crocκer, I. P., Brownbill, P. Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction? FASEB J. 32, 5436–5446 (2018). www.fasebj.org

A mixed‐methods evaluation of continuous electronic fetal monitoring for an extended period

Continuous fetal monitoring is used to objectively record the fetal heart rate and fetal activity over an extended period of time; however, its feasibility and acceptability to women is currently unknown. The study addressed the hypothesis that continuous fetal monitoring is feasible and acceptable to pregnant women.