Evaluating antenatal risk in twin pregnancies-A feasibility study to identify modifiable factors associated with adverse pregnancy outcomes.

INTRODUCTION: Twin pregnancies have significantly higher rates of perinatal morbidity and mortality compared to singleton pregnancies; current attempts to reduce perinatal mortality have been less successful in twin pregnancies. The paucity of information about modifiable risk factors for adverse neonatal outcomes in twin pregnancies, as well as independent effects of chorionicity may have contributed to this outcome. This study aimed to explore the feasibility of an observational study to identify modifiable factors associated with adverse neonatal outcomes in twin pregnancies. MATERIAL AND METHODS: Patients pregnant with twins at six UK hospitals between December 2019-March 2021 completed researcher-administered questionnaires at approximately 20-, 28- and 36-weeks' gestation, recording a wide range of self-reported social, lifestyle and demographic factors, alongside prospectively recorded clinical data from maternity records. Descriptive statistics were used to describe frequencies of exposures; logistic regression was used to determine whether factors were associated with a composite measure of adverse neonatal outcome. RESULTS: Data were collected from 65% (181/277) of eligible participants. A total of 98% (175) of participants had positive views about their participation. Some exposures, including cigarette smoking, supine sleep position and reduced fetal movements were less frequent in twin pregnancies compared to singletons, whereas fertility treatment was more common. Furthermore, different patterns of exposure were seen between monochorionic and dichorionic twins. This pilot study found some associations with adverse neonatal outcomes including: low BMI (OR 8.36, 95% CI: 1.02-68.87), maternal age ≥41 years (OR 9.0 95% CI: 1.07-75.84), maternally perceived high-stress levels (OR 1.96, 95% CI: 1.03-3.75) and inadequate antenatal screening (OR 1.44, 95% CI: 1.01-2.06). Sleep duration ≥9 h and right-sided going to sleep position were more frequent among pregnancies with adverse outcomes. Participants who reported receiving no information on fetal movement and reduced maternal perception of movements were more likely to have an adverse outcome, but sample size prohibited analysis based upon chorionicity. CONCLUSIONS: An observational study of modifiable factors in twin pregnancy is feasible. Differences in the frequencies of exposures between twin and singleton pregnancies highlight the need for twin-specific studies to identify modifiable factors and develop preventative strategies for morbidity and mortality in twin pregnancies.

Effect of encouraging awareness of reduced fetal movement and subsequent clinical management on pregnancy outcome: a systematic review and meta-analysis.

OBJECTIVE: Reduced fetal movement, defined as a decrease in the frequency or strength of fetal movements as perceived by the mother, is a common reason for presentation to maternity care. Observational studies have demonstrated an association between reduced fetal movement and stillbirth and fetal growth restriction related to placental insufficiency. However, individual intervention studies have described varying results. This systematic review and meta-analysis aimed to determine whether interventions aimed at encouraging awareness of reduced fetal movement and/or improving its subsequent clinical management reduce the frequency of stillbirth or other important secondary outcomes. DATA SOURCES: Searches were conducted in MEDLINE, Embase, CINAHL, The Cochrane Library, Web of Science, and Google Scholar. Guidelines, trial registries, and gray literature were also searched. Databases were searched from inception to January 20, 2022. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and controlled nonrandomized studies were eligible if they assessed interventions aimed at encouraging awareness of fetal movement or fetal movement counting and/or improving the subsequent clinical management of reduced fetal movement. Eligible populations were singleton pregnancies after 24 completed weeks of gestation. The primary review outcome was stillbirth; a number of secondary maternal and neonatal outcomes were specified in the review. METHODS: Risk of bias was assessed using the Cochrane Risk of Bias 2 and Risk of Bias in Non-Randomized Studies I tools for randomized controlled trials and nonrandomized studies, respectively. Variation caused by heterogeneity was assessed using I2. Data from studies employing similar interventions were combined using random effects meta-analysis. RESULTS: A total of 1609 citations were identified; 190 full-text articles were evaluated against the inclusion criteria, 18 studies (16 randomized controlled trials and 2 nonrandomized studies) were included. The evidence is uncertain about the effect of encouraging awareness of fetal movement on stillbirth when compared with standard care (2 studies, n=330,084) with a pooled adjusted odds ratio of 1.19 (95% confidence interval, 0.96-1.47). Interventions for encouraging awareness of fetal movement may be associated with a reduction in neonatal intensive care unit admissions and Apgar scores of <7 at 5 minutes of age and may not be associated with increases in cesarean deliveries or induction of labor. The evidence is uncertain about the effect of encouraging fetal movement counting on stillbirth when compared with standard care with a pooled odds ratio of 0.69 (95% confidence interval, 0.18-2.65) based on data from 3 randomized controlled trials (n=70,584). Counting fetal movements may increase maternal-fetal attachment and decrease anxiety when compared with standard care. When comparing combined interventions of fetal movement awareness and subsequent clinical management with standard care (1 study, n=393,857), the evidence is uncertain about the effect on stillbirth (adjusted odds ratio, 0.86; 95% confidence interval, 0.70-1.05). CONCLUSION: The effect of interventions for encouraging awareness of reduced fetal movement alone or in combination with subsequent clinical management on stillbirth is uncertain. Encouraging awareness of fetal movement may be associated with reduced adverse neonatal outcomes without an increase in interventions in labor. The meta-analysis was hampered by variations in interventions, outcome reporting, and definitions. Individual studies are frequently underpowered to detect a reduction in severe, rare outcomes and no studies were included from high-burden settings. Studies from such settings are needed to determine whether interventions can reduce stillbirth.

Worth the paper it's written on? A cross-sectional study of Medical Certificate of Stillbirth accuracy in the UK.

BACKGROUND: The Medical Certificate of Stillbirth (MCS) records data about a baby's death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in two UK-based regional studies. METHODS: A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual 'ideal MCSs' and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors. RESULTS: There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated 'substantial' agreement [K = 0.73 (95% CI 0.70-0.76)]. Primary cause of death (COD) showed 'fair' agreement [K = 0.26 (95% CI 0.24-0.29)]. Major errors [696/1120; 62.1% (95% CI 59.3-64.9%)] included certificates issued for fetal demise at <24 weeks' gestation [23/696; 3.3% (95% CI 2.2-4.9%)] or neonatal death [2/696; 0.3% (95% CI 0.1-1.1%)] or incorrect primary COD [667/696; 95.8% (95% CI 94.1-97.1%)]. Of 540/1246 [43.3% (95% CI 40.6-46.1%)] 'unexplained' stillbirths, only 119/540 [22.0% (95% CI 18.8-25.7%)] remained unexplained; the majority were redesignated as either fetal growth restriction [FGR: 195/540; 36.1% (95% CI 32.2-40.3%)] or placental insufficiency [184/540; 34.1% (95% CI 30.2-38.2)]. Overall, FGR [306/1246; 24.6% (95% CI 22.3-27.0%)] was the leading primary COD after review, yet only 53/306 [17.3% (95% CI 13.5-22.1%)] FGR cases were originally attributed correctly. CONCLUSION: This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory.

Placental volume in gestational week 27 measured by three-dimensional ultrasound and magnetic resonance imaging.

INTRODUCTION: Ultrasound is the diagnostic tool of choice in pregnancy. We lack valid ultrasound methods for placental size measurements. Our aim was therefore to compare three-dimensional (3D) ultrasound with magnetic resonance imaging (MRI) for measurements of placental volume. MATERIAL AND METHODS: We measured placental volume by 3D ultrasound and MRI in 100 unselected pregnancies at 27 weeks of gestation (25+4 -28+4  weeks). The 3D ultrasound acquisitions were analyzed offline, and the placental outline was manually traced using the virtual organ computer-aided analysis (VOCAL) 30° rotational technique. The MRI examinations included a T2-weighted gradient echo sequence in the sagittal plane, with 5-mm slices through the entire uterus. The placental outline was manually traced in each slice. The correlation between 3D ultrasound and MRI placental volumes was estimated by intraclass correlation coefficients. Bland-Altman analysis was applied to visualize systematic bias and limits of agreement, in which the ratio MRI placental volume/3D ultrasound placental volume was plotted against the average of the two methods. RESULTS: The intraclass correlation coefficient between 3D ultrasound and MRI measurements was 0.49 (95% confidence interval 0.33-0.63). In general, 3D ultrasound measured smaller placental volumes (median 373 cm3 , interquartile range 309-434 cm3 ) than MRI (median 507 cm3 , interquartile range 429-595 cm3 ) and the systematic bias was 1.44. The 95% limits of agreement between the two methods were wide (0.68-2.21). CONCLUSIONS: We found poor to moderate correlation between 3D ultrasound and MRI placental volume measurements. Generally, 3D ultrasound measured smaller placental volumes than MRI, suggesting that 3D ultrasound failed to visualize the entire placenta. Our findings may hopefully contribute to the improvement of ultrasound methods for placental measurements.

Intra-placental arterial Doppler: A marker of fetoplacental vascularity in late-onset placental disease?

INTRODUCTION: Late-gestation adverse pregnancy outcome is associated with reduced placental villous vascularity but rarely with a frankly abnormal umbilical artery Doppler waveform. The clinical utility of umbilical artery Doppler velocimetry in late gestation is limited by poor understanding of what aspect(s) of placental structure and function the impedance reflects. We hypothesized that placental arterial circulation impedance reflects placental vascularity and arterial function. MATERIAL AND METHODS: This was a secondary analysis of data from the FEMINA2 study, a study of pregnancy outcome after reduced fetal movement. Forty-three pregnancies that delivered within 7 days of ultrasound assessment were examined. Impedance was quantified by pulsatility index (PI) from umbilical, chorionic plate arteries, and intra-placental arteries. Site-specific PI was compared with villous vascularity (CD31 immunostaining) and placental arterial function (wire myography) by regression analysis (P < .01) where factor analysis suggested potential co-variance (Eigen value > 2). RESULTS: Pulsatility index decreased with proximity to the placental microvasculature (P < .0001). Intra-placental artery PI correlated significantly with vessel number (R2  = 0.40, P = .0007). No significant relations between umbilical or chorionic plate artery PI and villous vascularity were found (P ≥ .11 and P ≥ .042). No significant co-variance was suggested between PI at any Doppler sampling site and ex vivo placental arterial function indices. Measurement reliability (intraclass correlation coefficient) was highest in the umbilical artery (PI 0.75 and 0.50 for intra- and interoperator reliability, respectively) and lowest in the intra-placental arteries (PI 0.55 and 0.41, respectively). Systematic bias in umbilical artery PI was observed between observers, but not at other Doppler sampling sites. CONCLUSIONS: More vascular placentas ex vivo are associated with reduced intra-placental artery Doppler impedance in utero. Although umbilical (but not intra-placental) artery Doppler PI is associated with adverse outcome after reduced fetal movement, this predictive ability does not appear to be through assessment of placental vascularity or chorionic plate arterial function. The inferior reliability of intra-placental artery Doppler, although similar to previously published reliability of umbilical artery Doppler, impairs its ability to detect subtle differences in placental vascularity, and must be significantly improved before it could be considered a clinically useful test.

Antenatal placental assessment in the prediction of adverse pregnancy outcome after reduced fetal movement.

OBJECTIVE: To assess the value of in utero placental assessment in predicting adverse pregnancy outcome after reported reduced fetal movements (RFM). METHOD: A non-interventional prospective cohort study of women (N = 300) with subjective RFM at ≥28 weeks' gestation in singleton non-anomalous pregnancies at a UK tertiary maternity hospital. Clinical, sonographic (fetal weight, placental size and maternal, fetal and placental arterial Doppler) and biochemical (maternal serum hCG, hPL, progesterone, PlGF and sFlt-1) assessment was conducted. Multiple logistic regression identified combinations of measurements (models) most predictive of adverse pregnancy outcome (perinatal mortality, birth weight <10th centile, five minute Apgar score <7, umbilical arterial pH <7.1 or base excess <-10, neonatal intensive care admission). Models were compared by test performance characteristics (ROC curve, sensitivity, specificity, positive/negative predictive value, positive/negative likelihood ratios) against baseline care (estimated fetal weight centile, amniotic fluid index and gestation at presentation). RESULTS: 61 (20.6%) pregnancies ended in adverse outcome. Models incorporating PlGF/sFlt-1 ratio and umbilical artery free loop Doppler impedance demonstrated modest improvement in ROC area for adverse outcome (baseline care 0.69 vs. proposed models 0.73-0.76, p<0.05). However, there was little improvement in other test characteristics (baseline vs. best proposed model: sensitivity 21.7% [95% confidence interval 13.1-33.6] vs. 35.8%% [24.4-49.3], specificity 96.6% [93.4-98.3] vs. 94.7% [90.7-97.0], PPV 61.9% [40.9-79.3] vs. 63.3% [45.5-78.1], NPV 82.8% [77.9-86.8] vs. 85.2% [80.0-89.2], positive LR 6.3 [2.8-14.6] vs. 6.7 [3.4-3.3], negative LR 0.81 [0.71-0.93] vs. 0.68 [0.55-0.83]) and wide confidence intervals. Negative post-test probability remained high (16.7% vs. 14.0%). CONCLUSION: Antenatal placental assessment may improve identification of RFM pregnancies at highest risk of adverse pregnancy outcome but further work is required to understand and refine currently available outcome definitions and diagnostic techniques to improve clinical utility.

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

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.

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

INTRODUCTION: 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. MATERIAL AND METHODS: Pregnant participants (n = 22) were monitored using a continuous fetal electrocardiography device, the Monica AN24. Signal quality, duration of recording and cardiotocography findings were correlated with maternal and fetal factors. Participants' change in anxiety before and after monitoring was assessed using validated questionnaires. Participants' experiences were explored through a questionnaire (n = 20) and semi-structured interview (n = 13). RESULTS: Recordings were successfully obtained in 19 of the 22 participants (86.3%). The mean recording quality of fetal heart rate was 69.0% (range 17.4%-99.4%) and maternal heart rate was 99.0% (90.9%-100.0%). Recording quality was positively correlated with gestational age (P = 0.05) and negatively correlated with uterine activity and maternal movement (P < 0.001). Overall, participants were satisfied with their experience of continuous fetal monitoring; 30% considered it preferable to intermittent monitoring. Continuous fetal monitoring did not significantly increase maternal anxiety, with a trend towards a reduction in Pregnancy Specific Anxiety score (P = 0.07). Qualitative analysis grouped women's responses into three themes: (a) reassurance and anxiety, (b) the physical device and (c) future developments in continuous fetal monitoring. CONCLUSIONS: Continuous fetal monitoring is a feasible and acceptable form of monitoring to pregnant women although further practical improvements could be incorporated. Further research is required to assess the ability of continuous fetal monitoring to detect fetal compromise.

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 packing 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-1α and TNF-α (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.-Brook, A., Hoaksey, 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., Crocker, I. P., Brownbill, P. Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction?

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

OBJECTIVES: To assess intraexaminer and interexaminer reliability of 3-dimensional fetal sonographic measurements. METHODS: Three-dimensional fetal organ volumes (head, kidney, total thigh volume, and fractional thigh volume) were acquired during the second and third trimesters, with the addition of placental volume in the second trimester, by 2 different experienced, blinded sonographers. Fifty-eight fetuses were examined from 21 to 39 weeks' gestation. Intraexaminer and Interexaminer reliability was assessed with Bland-Altman plots, and their 95% limits of agreement and intraclass correlation coefficients. RESULTS: The most significant interexaminer error was observed in the second-trimester kidney volume (95% limits of agreement, ± 110%), and the best agreement was for the third-trimester fractional thigh volume (95% limits of agreement, ± 25%) and second-trimester head volume (95% limits of agreement, -7%-25%). Second- and third-trimester intraclass correlation coefficient results were all greater than 0.75, apart from second-trimester kidney volume intraexaminer (0.374) and interexaminer (0.061) measurements, second-trimester placenta interexaminer measurements (0.390), and third-trimester kidney interexaminer measurements (0.647). CONCLUSIONS: Three-dimensional fetal sonographic volumes of the head, kidney, total thigh, and placenta have limited reproducibility, and improvements in measurement techniques are needed before they can be used routinely to assess fetal growth. The 3-dimensional fractional thigh volume can be reliably obtained in the late third trimester.

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

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.

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.