Publications by authors named "Kypros H Nicolaides"

355 Publications

Second and third trimester serum levels of HtrA1 in pregnancies affected by pre-eclampsia.

Placenta 2021 Mar 5;106:1-6. Epub 2021 Feb 5.

Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Introduction: Altered placental expression of high temperature requirement factor A1 (HtrA1) is implicated in abnormal trophoblastic invasion and endothelial dysfunction in pre-eclampsia (PE). Serum levels of HtrA1 have been proposed as a novel biomarker to improve the prediction of PE. This study assesses serum HtrA1 levels in prospectively collected samples of women who developed PE compared to normotensive pregnancies.

Methods: This was a case-control study of serum HtrA1 levels in second and third trimester samples in women who later developed preterm or term PE compared to controls. Overall, 300 serum samples were drawn from a prospective observational study of adverse pregnancy outcomes in three different gestational age windows (19-24, 30-34 and 35-37 weeks) at the Fetal Medicine Research Institute, King's College Hospital, London. Serum HtrA1 levels were determined by enzyme-linked immunosorbent assay (ELISA) by a blinded laboratory professional. Median HtrA1 MoM values, adjusted for gestational age and maternal characteristics, were compared between cases and controls at each gestational age group.

Results: Women who later developed PE, compared to controls, had significantly higher maternal weight and more frequently had chronic hypertension or a history of PE in a previous pregnancy. In normotensive pregnancies, serum HtrA1 increased with increasing gestational age, whereas, in PE pregnancies HtrA1 levels remained stable, but were not significantly different from control pregnancies at any gestational age.

Discussion: Serum HtrA1 levels are not significantly different in women who develop PE compared to controls.
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http://dx.doi.org/10.1016/j.placenta.2021.02.003DOI Listing
March 2021

Fetal fraction of cell free DNA in screening for hypertensive disorders at 11-13 weeks.

J Matern Fetal Neonatal Med 2021 Jan 31:1-6. Epub 2021 Jan 31.

Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK.

Objective: To investigate whether first-trimester maternal plasma fetal fraction is altered in women that subsequently develop preeclampsia (PE) or gestational hypertension (GH) and to examine its potential value in improving the performance of screening for PE and GH by maternal factors and maternal serum pregnancy associated plasma protein-A (PAPP-A), mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI).

Methods: The study population of 10,131 pregnancies undergoing cell free fetal DNA testing at 11-13 weeks' gestation included 91 (0.9%) cases with preterm-PE, 222 (2.2%) cases with term-PE, 360 (3.6%) with GH and 9,458 (93.4%) cases unaffected by hypertensive disorders. Maternal plasma fetal fraction levels were expressed as multiples of the median (MoM) after adjustment for maternal factors and crown-rump length. The performance of screening for preterm-PE, term PE and GH by maternal factors and MoM values of fetal fraction, PAPP-A, UtA-PI and MAP was evaluated by receiver operating characteristic (ROC) curves.

Results: The median fetal fraction MoM was significantly lower in the preterm-PE (0.825; IQR 0.689-1.115 MoM,  < .001), term-PE (0.946; IQR 0.728-1.211 MoM,  = .028) and GH (0.928; IQR 0.711-1.182 MoM,  < .001) groups than in the unaffected group (1.002; IQR 0.785-1.251 MoM). However, the performance of screening for PE or GH by maternal factors alone or by maternal factors and PAPP-A, UtA-PI and MAP was not significantly improved by the addition of fetal fraction.

Conclusions: First trimester maternal plasma fetal fraction is not useful in screening for hypertensive disorders of pregnancy.
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http://dx.doi.org/10.1080/14767058.2021.1879043DOI Listing
January 2021

High dose progesterone for prevention of preterm birth in twins.

Am J Obstet Gynecol 2021 Jan 19. Epub 2021 Jan 19.

Fetal Medicine Research Institute, King's College Hospital, 16-20 Windsor Walk, Denmark Hill, London SE5 8BB, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2021.01.009DOI Listing
January 2021

Fully Automated 3D Ultrasound Segmentation of the Placenta, Amniotic Fluid and Fetus for Early Pregnancy Assessment.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Jan 18;PP. Epub 2021 Jan 18.

Volumetric placental measurement using 3D ultrasound has proven clinical utility in predicting adverse pregnancy outcomes. However, this metric can not currently be employed as part of a screening test due to a lack of robust and real-time segmentation tools. We present a multi-class convolutional neural network (CNN) developed to segment the placenta, amniotic fluid and fetus. The ground truth dataset consisted of 2,093 labelled placental volumes augmented by 300 volumes with placenta, amniotic fluid and fetus annotated. A two pathway, hybrid model using transfer learning, a modified loss function and exponential average weighting was developed and demonstrated the best performance for placental segmentation, achieving a Dice similarity coefficient (DSC) of 0.84 and 0.38 mm average Hausdorff distance (HDAV). Use of a dual-pathway architecture, improved placental segmentation by 0.03 DSC and reduced HDAV by 0.27mm when compared with a naïve multi-class model. Incorporation of exponential weighting produced a further small improvement in DSC by 0.01 and a reduction of HDAV by 0.44mm. Per volume inference using the FCNN took 7-8 seconds. This method should enable clinically relevant morphometric measurements (such as volume and total surface area) to be automatically generated for the placenta, amniotic fluid and fetus. Ready availability of such metrics makes a population-based screening test for adverse pregnancy outcomes possible.
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http://dx.doi.org/10.1109/TUFFC.2021.3052143DOI Listing
January 2021

Predicting cesarean delivery for failure to progress as an outcome of labor induction in term singleton pregnancy.

Am J Obstet Gynecol 2021 Jan 4. Epub 2021 Jan 4.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom.

Background: Induction of labor is one of the most common interventions in modern obstetrics, and its frequency is expected to continue to increase. There is inconsistency as to how failed induction of labor is defined; however, the majority of studies define success as the achievement of vaginal delivery. Induction of labor in nulliparous women poses an additional challenge with a 15% to 20% incidence of failure, ending in emergency operative deliveries. The Bishop score has been traditionally used before decisions for induction of labor. Nonetheless, it is subjective and prone to marked interobserver variation. Several studies have been conducted to find alternative predictors, yet a reliable, objective method still remains to be introduced and validated. Hence, there is still a need for the development of new predictive tools to facilitate informed decision making, optimization of resources, and minimization of potential risks of failure. Furthermore, a peripartum transperineal ultrasound scan has been proven to provide objective, noninvasive assessment of labor.

Objective: This study aimed to assess the feasibility of developing and validating an objective and reproducible model for the prediction of cesarean delivery for failure to progress as an outcome of labor induction in term singleton pregnancies.

Study Design: This was a prospective observational cohort study conducted in Cairo University Hospitals and University of Bologna Hospitals between November 2018 and November 2019. We recruited 382 primigravidae with singleton term pregnancies in cephalic presentation. All patients had baseline Bishop scoring together with various transabdominal and transperineal ultrasound assessments of the fetus, maternal cervix, and pelvic floor. The managing obstetricians were blinded to the ultrasound scan findings. The method and indication of induction of labor, the total duration of stages of labor, mode of birth, and neonatal outcomes were all recorded. Women who had operative delivery for fetal distress or indications other than failure to progress in labor were excluded from the final analysis, leaving a total of 344 participants who were randomly divided into 243 and 101 pregnancies that constituted the model development and cross-validation groups, respectively.

Results: It was possible to perform transabdominal and transperineal scans and assess all the required parameters on all study participants. Univariate and multivariate analyses were used for selection of potential predictors and model fitting. The independent predictive variables for cesarean delivery included maternal age (odds ratio, 1.12; P=.003), cervical length (odds ratio, 1.08; P=.04), angle of progression at rest (odds ratio, 0.9; P=.001), and occiput posterior position (odds ratio, 5.7; P=.006). We tested the performance of the prediction model on our cross-validation group. The calculated areas under the curve for the ability of the model to predict cesarean delivery were 0.7969 (95% confidence interval, 0.71-0.87) and 0.88 (95% confidence interval, 0.79-0.97) for the developed and validated models, respectively.

Conclusion: Maternal age and sonographic fetal occiput position, angle of progression at rest, and cervical length before labor induction are very good predictors of induction outcome in nulliparous women at term.
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http://dx.doi.org/10.1016/j.ajog.2020.12.1212DOI Listing
January 2021

Maternal cardiac adaptation and fetal growth.

Am J Obstet Gynecol 2020 Dec 24. Epub 2020 Dec 24.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom. Electronic address:

Background: Pregnancies with small-for-gestational-age fetuses are at increased risk of adverse maternal-fetal outcomes. Previous studies examining the relationship between maternal hemodynamics and fetal growth were mainly focused on high-risk pregnancies and those with fetuses with extreme birthweights, such as less than the 3rd or 10th percentile and assumed a similar growth pattern in fetuses above the 10th percentile throughout gestation.

Objective: This study aimed to evaluate the trends in maternal cardiac function, fetal growth, and oxygenation with advancing gestational age in a routine obstetrical population and all ranges of birthweight percentiles.

Study Design: This was a prospective, longitudinal study assessing maternal cardiac output and peripheral vascular resistance by bioreactance at 11 to 13, 19 to 24, 30 to 34, and 35 to 37 weeks' gestation, sonographic estimated fetal weight in the last 3 visits and the ratio of the middle cerebral artery by umbilical artery pulsatility indices or cerebroplacental ratio in the last 2 visits. Women were divided into the following 5 groups according to birthweight percentile: group 1, <10th percentile (n=261); group 2, 10 to 19.9 percentile (n=180); group 3, 20 to 29.9 percentile (n=189); group 4, 30 to 69.9 percentile (n=651); and group 5, ≥70th percentile (n=508). The multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables and z scores of the estimated fetal weight and cerebroplacental ratio.

Results: In visit 2, compared with visit 1, in all groups, cardiac output increased, and peripheral vascular resistance decreased. At visit 3, groups 1, 2, and 3, compared with 4 and 5, demonstrated an abrupt decrease in cardiac output and increase in peripheral vascular resistance. From visit 2, group 1 had a constant decline in estimated fetal weight, coinciding with the steepest decline in maternal cardiac output and rise in peripheral vascular resistance. In contrast, in groups 4 and 5, the estimated fetal weight had a stable or accelerative pattern, coinciding with the greatest increase in cardiac output and lowest peripheral vascular resistance. Groups 2 and 3 showed a stable growth pattern with intermediate cardiac output and peripheral vascular resistance. Increasing birthweight was associated with higher cerebroplacental ratio. Groups 3, 4, and 5 had stable cerebroplacental ratio across visits 3 and 4, whereas groups 1 and 2 demonstrated a significant decline (P<.001).

Conclusion: In a general obstetrical population, maternal cardiac adaptation at 32 weeks' gestation parallels the pattern of fetal growth and oxygenation; babies with birthweight<20th percentile have progressive decline in fetal cerebroplacental ratio, decline in maternal cardiac output, and increase in peripheral vascular resistance.
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http://dx.doi.org/10.1016/j.ajog.2020.12.1199DOI Listing
December 2020

Impact of new definitions of preeclampsia at term on identification of adverse maternal and perinatal outcomes.

Am J Obstet Gynecol 2020 Nov 6. Epub 2020 Nov 6.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Institute of Women and Children's Health, King's Health Partners, London, United Kingdom. Electronic address:

Background: Any definition of preeclampsia should identify women and babies at greatest risk of adverse outcomes.

Objective: This study aimed to investigate the ability of the American College of Obstetricians and Gynecologists and International Society for the Study of Hypertension in Pregnancy definitions of preeclampsia at term gestational age (≥37 0/7 weeks) to identify adverse maternal and perinatal outcomes.

Study Design: In this prospective cohort study at 2 maternity hospitals in England, women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment that included history; ultrasonographic estimated fetal weight; Doppler measurements of the pulsatility index in the uterine, umbilical, and fetal middle cerebral arteries; and serum placental growth factor-to-soluble fms-like tyrosine kinase-1 ratio. Obstetrical records were examined for all women with chronic hypertension and those who developed new-onset hypertension, with preeclampsia (de novo or superimposed on chronic hypertension) defined in 5 ways: traditional, based on new-onset proteinuria; American College of Obstetricians and Gynecologists 2013 definition; International Society for the Study of Hypertension in Pregnancy maternal factors definition; International Society for the Study of Hypertension in Pregnancy maternal factors plus fetal death or fetal growth restriction definition, defined according to the 35 0/7 to 36 6/7 weeks' gestation scan as either estimated fetal weight <3rd percentile or estimated fetal weight at the 3rd to 10th percentile with any of uterine artery pulsatility index >95th percentile, umbilical artery pulsatility index >95th percentile, or middle cerebral artery pulsatility index <5th percentile; and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance definition, defined as placental growth factor <5th percentile or soluble fms-like tyrosine kinase-1-to-serum placental growth factor >95th percentile. Detection rates for outcomes of interest (ie, severe maternal hypertension, major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit admission ≥48 hours, and birthweight <10th percentile) were compared using the chi-square test, and P<.05 was considered significant.

Results: Among 15,248 singleton pregnancies, the identification of women with preeclampsia varied by definition: traditional, 15 of 281 (1.8%; 248); American College of Obstetricians and Gynecologists, 15 of 326 (2.1%; 248); International Society for the Study of Hypertension in Pregnancy maternal factors, 15 of 400 (2.6%; 248); International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, 15 of 434 (2.8%; 248); and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, 15 of 500 (3.3%; 248). Compared with the traditional definition of preeclampsia, the International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance best identified the adverse outcomes: severe hypertension (40.6% [traditional] vs 66.9% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P<.0001], 59.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.004], 56.2% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.013], 46.1% [American College of Obstetricians and Gynecologists, P=.449]); P<.0001); composite maternal severe adverse event (72.2% [traditional] vs 100% for all others; P=.046); composite of perinatal mortality and morbidity (46.9% [traditional] vs 71.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.002], 62.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.06], 59.8% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.117], 49.4% [American College of Obstetricians and Gynecologists, P=.875]); neonatal unit admission for ≥48 hours (51.4% [traditional] vs 73.4% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.001], 64.5% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.070], 60.7% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.213], 53.3% [American College of Obstetricians and Gynecologists, P=.890]); birthweight <10th percentile (40.5% [traditional] vs 78.7% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P<.0001], 70.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal, P<.0001], 51.3% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.064], 46.3% [American College of Obstetricians and Gynecologists, P=.349]).

Conclusion: Our findings present an evidence base for the broad definition of preeclampsia. Our data suggest that compared with a traditional definition, a broad definition of preeclampsia can better identify women and babies at risk of adverse outcomes. Compared with the American College of Obstetricians and Gynecologists definition, the more inclusive International Society for the Study of Hypertension in Pregnancy definition of maternal end-organ dysfunction seems to be more sensitive. The addition of uteroplacental dysfunction to the broad definition optimizes the identification of women and babies at risk, particularly when angiogenic factors are included.
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http://dx.doi.org/10.1016/j.ajog.2020.11.004DOI Listing
November 2020

Serum leukotriene B4 and hydroxyeicosatetraenoic acid in the prediction of pre-eclampsia.

Placenta 2021 Jan 10;103:76-81. Epub 2020 Oct 10.

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Introduction: Pre-eclampsia (PE) affects 2-8% of pregnancies worldwide. Despite identification of numerous possible biomarkers, accurate prediction and early diagnosis of PE remain challenging. We examined the potential of leukotriene B4 (LTB4) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE) as biomarkers of PE by comparing serum levels at three gestational age (GA) groups between normotensive pregnancies and asymptomatic women who subsequently developed preterm or term-PE.

Methods: This is a case-control study drawn from a prospective study of adverse pregnancy outcomes with serum samples collected at 19-24 weeks (n = 48), 30-34 weeks (n = 101) and 35-37 weeks (n = 54) GA. LTB4 and 15(S)-HETE levels were determined by ELISA. Serum level multiples of the median (MoM) were compared between normal and PE-pregnancies. Association between LTB4 and 15(S)-HETE and GA at delivery was investigated with Cox proportional-hazards models.

Results: Serum LTB4 levels were lower in women of East-Asian ethnicity, higher in women with PE history, and increased with GA in normotensive pregnancies, but not in PE. LTB4 was elevated at 19-24 weeks in women who developed preterm-PE. There was a negative association between LTB4 MoM and interval between sampling and delivery with PE at 19-24 weeks only. Serum 15(S)-HETE levels were not influenced by GA at testing and were elevated in women of South-Asian ethnicity. Median 15(S)-HETE levels were unchanged in preterm and term-PE at any GA.

Discussion: LTB4 was higher at 19-24 weeks in pregnancies that developed preterm-PE versus unaffected pregnancies, suggesting it is a potentially useful predictive marker of preterm PE in the second trimester.
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http://dx.doi.org/10.1016/j.placenta.2020.10.007DOI Listing
January 2021

First trimester biomarkers for prediction of gestational diabetes mellitus.

Placenta 2020 11 6;101:80-89. Epub 2020 Sep 6.

ASPRE Project, Telemarpe Ltd, 41 Beit El St, Tel Aviv 699126, Israel and Hy-Laboratories Ltd, Rehovot, 7670606, Israel. Electronic address:

Purpose: To develop a first trimester prediction model for gestational diabetes mellitus (GDM) using obesity, placental, and inflammatory biomarkers.

Methods: We used a first trimester dataset of the ASPRE study to evaluate clinical and biochemical biomarkers. All biomarkers levels (except insulin) were transformed to gestational week-specific medians (MoMs), adjusted for maternal body mass index (BMI), maternal age, and parity. The MoM values of each biomarker in the GDM and normal groups were compared and used for the development of a prediction model assessed by area under the curve (AUC).

Results: The study included 185 normal and 20 GDM cases. In the GDM group, compared to the normal group BMI and insulin (P = 0.003) were higher (both P < 0.003). The MoM values of uterine artery pulsatility index (UtA-PI) and soluble (s)CD163 were higher (both P < 0.01) while pregnancy associated plasma protein A (PAPP-A), placental protein 13 (PP13), and tumor-necrosis factor alpha (TNFα) were lower (all P < 0.005). There was no significant difference between the groups in placental growth factor, interleukin 6, leptin, peptide YY, or soluble mannose receptor (sMR/CD206). In screening for GDM in obese women the combination of high BMI, insulin, sCD163, and TNFα yielded an AUC of 0.95, with detection rate of 89% at 10% false positive rate (FPR). In non-obese women, the combination of sCD163, TNFα, PP13 and PAPP-A yielded an AUC of 0.94 with detection rate of 83% at 10% FPR.

Conclusion: A new model for first trimester prediction of the risk to develop GDM was developed that warrants further validation.
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http://dx.doi.org/10.1016/j.placenta.2020.08.020DOI Listing
November 2020

The value of three-dimensional ultrasound in identifying Mullerian anomalies at risk of adverse pregnancy outcomes.

J Matern Fetal Neonatal Med 2020 Sep 1:1-8. Epub 2020 Sep 1.

Fetal Medicine Research Institute, King's College London, London, UK.

Objective: To examine the reliability of three-dimensional ultrasound (3 D-US) in the differentiation between subseptate and arcuate uteri, due to the different associated pregnancy outcomes; refine the existing 3 D-US parameters and evaluate the concordance between 3 D-US and MRI in diagnosing these anomalies.

Study Design: This was a prospective cohort study of 455 women suspected of having a Mullerian anomaly. The diagnosis of subseptate, bicornuate or arcuate uterus was made by 3 D-US in 55 women. Two independent examiners manipulated the 3 D-US volume datasets and recorded the internal intercornual distance, indentation length, indentation tip angle, and myometrial wall thickness in the coronal plane of the uterus. Subsequently, 48 women underwent MRI which was used as the reference test for diagnosis. We calculated the degree of correlation between the two ultrasound assessors' 3 D-US measurements using interclass correlation coefficient and as well as a Bland-Altman plot. The mean values of the four parameters were used to create receiver operating characteristic curves for determining the best cutoff values for differentiation between subseptate and arcuate uterui. We used the Cohen's Kappa test to measure the level of agreement between 3 D-US and MRI.

Results: There was good interobserver agreement between the two 3 D-US assessors for all four parameters. There was a substantial level of agreement between 3 D-US and MRI in differentiating between bicornuate, subseptate and arcuate uteri with a kappa value of 0.727 (95% CI 0.443-0.856). Distinction between subseptate and arcuate uterus was improved when using an indentation length ≥12.5 mm (AUC 0.99) and indentation tip angle ≤89.25 degrees (AUC 0.97) as cutoffs for diagnosis but not the internal intercornual distance or myometrial wall thickness.

Conclusion: 3 D-US evaluation of the coronal view of the uterus can be relied upon to make a noninvasive, accurate differentiation between subseptate and arcuate uteri. The fundal indentation length and indentation tip angle cut offs of ≥12.5 mm and ≤88 mm, respectively were found to be most accurate for distinction. Thus, allowing for individualizing pre-pregnancy management plans and patient-informed healthcare choices. Highlights There are no agreed upon criteria for differentiating arcuate from subseptate uteri. Such differentiation is critical for counseling and management due to the substantial difference in pregnancy outcome. We aimed to propose cut off values for ultrasound measurements standardized against MRI diagnostic criteria for accurate differentiation between arcuate and subseptate uteri. We demonstrated substantial agreement between 3D-US and MRI in differentiating between bicornuate, subseptate and arcuate uteri. 3D-US evaluation of the coronal view of the uterus is reliable to make an accurate differentiation between subseptate and arcuate uteri. Using the indentation length ≥12.5 mm and indentation tip angle ≤89.25 degrees as parameters to be measured on the coronal view by 3D-US increases its diagnostic accuracy for distinction between arcuate and subseptate uteri.
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http://dx.doi.org/10.1080/14767058.2020.1815189DOI Listing
September 2020

Galectin-7 Impairs Placentation and Causes Preeclampsia Features in Mice.

Hypertension 2020 10 31;76(4):1185-1194. Epub 2020 Aug 31.

From the Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC, Australia (E.M., W.Z., L.L.S., T.S., E.D.).

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, , and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8-E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1β, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15313DOI Listing
October 2020

Prevention of preeclampsia with aspirin.

Am J Obstet Gynecol 2020 Aug 21. Epub 2020 Aug 21.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, the Hong Kong Special Administrative Region of the People's Republic of China. Electronic address:

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is an important cause of maternal and perinatal morbidity and mortality, particularly when of early onset. Although a significant amount of research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively unchanged in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely understood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32 weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.
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http://dx.doi.org/10.1016/j.ajog.2020.08.045DOI Listing
August 2020

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.

Am J Obstet Gynecol 2021 01 26;224(1):86.e1-86.e19. Epub 2020 Jun 26.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom. Electronic address:

Background: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy.

Objective: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24 and 33 weeks.

Study Design: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24 and 33 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24 and 33 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth.

Results: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24 and 33 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69).

Conclusion: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24 and 33 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.
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http://dx.doi.org/10.1016/j.ajog.2020.06.050DOI Listing
January 2021

Maternal Cardiac Assessment at 35 to 37 Weeks Improves Prediction of Development of Preeclampsia.

Hypertension 2020 08 22;76(2):514-522. Epub 2020 Jun 22.

From the Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom; School of Biomedical Engineering and Imaging Sciences, King's College London, United Kingdom; and Cardiology Unit, Hammersmith Hospital, Imperial College London, United Kingdom.

Preeclampsia at term accounts for half of maternal deaths from hypertensive disorders. We aimed to assess differences in maternal cardiac indices at 35 to 36 weeks' gestation between women who subsequently developed preeclampsia at term compared with those with uncomplicated pregnancy and to evaluate whether cardiac indices offer incremental prognostic value to the available screening algorithm for preeclampsia. We recruited 1602 women with singleton pregnancies who attended for a routine hospital visit at 35 to 36 weeks' gestation between April and November 2018. We recorded maternal characteristics and preeclampsia-risk-score derived from a competing risks model and measured cardiac indices. Preeclampsia developed in 3.12% (50/1602) of participants. Women with preeclampsia, compared with those without, had increased mean arterial pressure (97.6, SD, 5.53 versus 87.9, SD, 6.82 mm Hg), systemic vascular resistance (1500, interquartile range, 1393-1831 versus 1400, interquartile range, 1202-1630 PRU) and preeclampsia-risk-score (23.4, interquartile range, 9.13-40 versus 0.9, interquartile range, 0.32-3.25). Multivariable analysis demonstrated independent association between the incidence of preeclampsia and E/e' (hazard ratio, 1.19/unit [95% CI, 1.03-1.37]; =0.018) as well as left ventricular mass indexed for body surface area (hazard ratio, 1.03/[g·m] [95% CI, 1.003-1.051]; =0.029). Women with E/e' ≥7.3 and left ventricular mass indexed for body surface area ≥63.2 g/m had an increased risk for developing preeclampsia, despite low preeclampsia-risk-score <5% (hazard ratio, 20.1 [95% CI, 10.5-38.7], <0.001). Increased left ventricular mass and E/e' offer incremental information to available scoring systems and better stratify women at risk of developing preeclampsia at term.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14643DOI Listing
August 2020

Paired maternal and fetal cardiac functional measurements in women with gestational diabetes mellitus at 35-36 weeks' gestation.

Am J Obstet Gynecol 2020 10 23;223(4):574.e1-574.e15. Epub 2020 Apr 23.

Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College London, London, United Kingdom; School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.

Background: Gestational diabetes mellitus is associated with early-onset cardiovascular disease and increased incidence of adverse cardiovascular outcomes in mothers and their offspring. Few studies with a limited number of patients have reported subclinical cardiac changes in association with gestational diabetes mellitus; however, it remains unclear whether the mother and the fetus respond in a similar fashion to gestational diabetes mellitus; thus, by assessing the heart of one, we can estimate or predict changes in the other.

Objective: This study aimed to compare maternal and fetal cardiovascular functions in the third trimester between women with gestational diabetes mellitus and women with uncomplicated pregnancy and to explore whether gestational diabetes mellitus affects to the same extent the maternal and fetal heart.

Study Design: This was a cross-sectional study of maternal and fetal echocardiography for assessment of cardiovascular function in the third trimester in women with singleton pregnancies who received a diagnosis of gestational diabetes mellitus and the control group with uncomplicated pregnancies.

Results: In this study, we included 161 women with gestational diabetes mellitus and 483 women with uncomplicated pregnancies. Compared with women in the control group, women with gestational diabetes mellitus were older (34.5, standard deviation, 5.3 years] vs 32.5, standard deviation, 4.8 years]; P<.001), had higher body mass index (31.3 kg/m [standard deviation, 5.8] vs 28.6 kg/m [standard deviation, 4.4]; P<.001), had lower weight gain during pregnancy (8.3 [interquartile range, 4.8-11 kg] vs 10.8 [interquartile range, 8.2-13.5 kg]; P<.001), and delivered babies with lower birthweight (P<.001). After multivariable analysis, accounting for differences in maternal characteristics and fetal weight, mothers with gestational diabetes mellitus had lower left ventricular diastolic and systolic (tissue Doppler systolic [s'] wave) functional indices (P<.01 for both) compared with those of mothers in the control group. The noted cardiac changes did not fulfill the adult criteria for clinical cardiac dysfunction. No differences in hemodynamic indices (cardiac output and peripheral vascular resistance) and left ventricular mass were noted between the groups. Fetuses of mothers with gestational diabetes mellitus had more globular-shaped hearts with increased right and left ventricular sphericity indices (P<.001 for both) and reduced global longitudinal right and left ventricular systolic functional indices (P<.001 for both). The effect of gestational diabetes mellitus on maternal and fetal hearts was different, and there was no clear association between the two.

Conclusion: In the third trimester, in pregnancies with gestational diabetes mellitus, there were subclinical cardiac changes in both the mother and the fetus, but there was no significant difference in any of the fetal cardiac parameters between women with and women without unfavorable cardiac profile. This suggests that the stimulus for cardiovascular responses in the mother and fetus may not be the same in pregnancies with gestational diabetes mellitus.
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http://dx.doi.org/10.1016/j.ajog.2020.04.019DOI Listing
October 2020

Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta-analysis.

Am J Obstet Gynecol 2020 07 3;223(1):42-65.e2. Epub 2020 Feb 3.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

Background: Randomized controlled trials that have assessed the efficacy of cervical pessary to prevent preterm birth in asymptomatic high-risk women have reported conflicting results.

Objective: To evaluate the efficacy and safety of cervical pessary to prevent preterm birth and adverse perinatal outcomes in asymptomatic high-risk women.

Data Sources: MEDLINE, EMBASE, POPLINE, CINAHL, and LILACS (from their inception to October 31, 2019), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.

Study Eligibility Criteria: Randomized controlled trials that compared cervical pessary with standard care (no pessary) or alternative interventions in asymptomatic women at high risk for preterm birth.

Study Appraisal And Synthesis Methods: The systematic review was conducted according to the Cochrane Handbook guidelines. The primary outcome was spontaneous preterm birth <34 weeks of gestation. Secondary outcomes included adverse pregnancy, maternal, and perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology.

Results: Twelve studies (4687 women and 7167 fetuses/infants) met the inclusion criteria: 8 evaluated pessary vs no pessary in women with a short cervix, 2 assessed pessary vs no pessary in unselected multiple gestations, and 2 compared pessary vs vaginal progesterone in women with a short cervix. There were no significant differences between the pessary and no pessary groups in the risk of spontaneous preterm birth <34 weeks of gestation among singleton gestations with a cervical length ≤25 mm (relative risk, 0.80; 95% confidence interval, 0.43-1.49; 6 trials, 1982 women; low-quality evidence), unselected twin gestations (relative risk, 1.05; 95% confidence interval, 0.79-1.41; 1 trial, 1177 women; moderate-quality evidence), twin gestations with a cervical length <38 mm (relative risk, 0.75; 95% confidence interval, 0.41-1.36; 3 trials, 1128 women; low-quality evidence), and twin gestations with a cervical length ≤25 mm (relative risk; 0.72, 95% confidence interval, 0.25-2.06; 2 trials, 348 women; low-quality evidence). Overall, no significant differences were observed between the pessary and no pessary groups in preterm birth <37, <32, and <28 weeks of gestation, and most adverse pregnancy, maternal, and perinatal outcomes (low- to moderate-quality evidence for most outcomes). There were no significant differences in the risk of spontaneous preterm birth <34 weeks of gestation between pessary and vaginal progesterone in singleton gestations with a cervical length ≤25 mm (relative risk, 0.99; 95% confidence interval, 0.54-1.83; 1 trial, 246 women; low-quality evidence) and twin gestations with a cervical length <38 mm (relative risk, 0.73; 95% confidence interval, 0.46-1.18; 1 trial, 297 women; very low-quality evidence). Vaginal discharge was significantly more frequent in the pessary group than in the no pessary and vaginal progesterone groups (relative risks, ∼2.20; high-quality evidence).

Conclusion: Current evidence does not support the use of cervical pessary to prevent preterm birth or to improve perinatal outcomes in singleton or twin gestations with a short cervix and in unselected twin gestations.
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http://dx.doi.org/10.1016/j.ajog.2019.12.266DOI Listing
July 2020

Placental function and fetal weight are associated with maternal hemodynamic indices in uncomplicated pregnancies at 35-37 weeks of gestation.

Am J Obstet Gynecol 2020 06 15;222(6):604.e1-604.e10. Epub 2020 Jan 15.

Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College London, London, United Kingdom; School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.

Background: Over the years, there has been an increasing interest in the assessment of maternal hemodynamic responses during pregnancy. With the use of both noninvasive devices and/or maternal echocardiography, it has been shown that mothers who have pregnancy complications have altered hemodynamics compared with those who have uncomplicated pregnancies. It also has been suggested that preexisting maternal cardiac changes might drive the development of complications in pregnancy that are associated with impaired placentation. To understand, however, this potential link in complicated pregnancies, it is important to clarify whether placental function is associated with maternal cardiac functional indices in normal pregnancies.

Objective: To determine whether placental function, perfusion, and fetal weight are associated with maternal cardiac hemodynamic responses at 35-36 weeks of gestation in normal pregnancies.

Study Design: Prospective screening of women attending Kings' College Hospital for routine hospital visit at 35-37 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, uterine artery pulsatility index, sonographic estimated fetal weight, and serum placental growth factor and soluble fms-like tyrosine kinase 1. We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function, including global longitudinal systolic function and left ventricular mass indexed to body surface area.

Results: We studied 1386 women. Maternal characteristics were associated with both maternal hemodynamics and functional and structural indices. Uterine artery pulsatility index was associated with left ventricular mass (P=.03) and global longitudinal systolic function (P=.017). There were significant nonlinear associations between placental growth factor and cardiac output and peripheral vascular resistance (P<.001 for both) and between soluble fms-like tyrosine kinase 1 and peripheral vascular resistance (P=.018). Estimated fetal weight was associated with maternal cardiac output (mean increase=0.186, 95% confidence interval, 0.133-0.238, P<.001) and peripheral vascular resistance (mean decrease=-0.164, 95% confidence interval, -0.217 to -0.111, P<.001). No association was noted between placental and fetal parameters and maternal cardiac functional and structural indices. In multivariable analysis, placental growth factor remained strongly associated with maternal cardiac output and peripheral vascular resistance (P=.002 for both) over and above maternal characteristics and estimated fetal weight. Estimated fetal weight was associated with left ventricular mass (0.102, 95% confidence interval, 0.044-0.162, P=.001).

Conclusion: The results of this study suggest a strong link between maternal hemodynamic responses and fetoplacental needs across the whole spectrum in normal pregnancies. These findings would also indicate that to diagnose maternal cardiac dysfunction in pregnancies complicated by impaired placentation a more extensive echocardiographic assessment might be needed rather than relying on hemodynamics which are strongly associated with fetoplacental indices.
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http://dx.doi.org/10.1016/j.ajog.2020.01.011DOI Listing
June 2020

Pregnancy in Liver Transplantation.

Liver Transpl 2020 04;26(4):564-581

Institute of Liver Studies, King's College Hospital, London, United Kingdom.

Pregnancy after liver transplantation (LT) is increasingly common and is a frequent scenario that transplant physicians, obstetricians, and midwives encounter. This review summarizes the key issues surrounding preconception, pregnancy-related outcomes, immunosuppression, and breastfeeding in female LT recipients. Prepregnancy counseling in these patients should include recommendations to delay conception for at least 1-2 years after LT and discussions about effective methods of contraception. Female LT recipients are generally recommended to continue immunosuppression during pregnancy to prevent allograft rejection; however, individual regimens may need to be altered. Although pregnancy outcomes are overall favorable, there is an increased risk of maternal and fetal complications. Pregnancy in this cohort remains high risk and should be managed vigilantly in a multidisciplinary setting. We aim to review the available evidence from national registries, population-based studies, and case series and to provide recommendations for attending clinicians.
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http://dx.doi.org/10.1002/lt.25717DOI Listing
April 2020

Establishing a Differential Marker Profile for Pregnancy Complications Near Delivery.

Fetal Diagn Ther 2020 28;47(6):471-484. Epub 2019 Nov 28.

Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Ljubljana, Slovenia.

Objective: The aim of this work was to define a differential marker profile for pregnancy complications near delivery.

Methods: We enrolled pregnant women who were referred to the outpatient pregnancy clinic of the University Medical Center, Ljubljana, Slovenia, due to symptoms of pregnancy complications and women with a history of pregnancy complications attending the high-risk hospital clinic for close surveillance. They were evaluated for prior risk and were tested for biophysical and biochemical markers at the time of enrolment. Biochemical markers included the pro- and anti-angiogenic markers, along with additional previously reported markers of potential value, all tested by various formats of immuno-diagnostics. Biophysical markers included blood pressure, sonographic markers, and EndoPAT. Statistical differences were determined with Kruskal-Wallis and Mann-Whitney tests for continuous parameters, and Pearson χ2 for categorical values. p < 0.05 was considered significant.

Results: The cohort included 125 pregnant patients, 31 developed preeclampsia (PE) alone (13 were <34 weeks' gestation), 16 had intrauterine growth restriction (IUGR) alone (12 were <34 weeks), 42 had both IUGR and PE (22 were <34 weeks), and 15 had an iatrogenic preterm delivery (PTD; 6 were <34 weeks). Twenty-one were unaffected and delivered a healthy baby at term. Mean arterial blood pressure and proteinuria were significantly higher in PE and PE+IUGR but not in pure IUGR or PTD. In PE, IUGR, and PE+IUGR, the levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were significantly higher, while placental growth factor (PlGF) was very low compared to unaffected controls and PTD. PE, IUGR, and PE+IUGR also had a high anti-angiogenic ratio (sFlt-1/PlGF) and a low proangiogenic ratio of PlGF/(sFlt-1+Eng). Levels of inhibin A were significantly higher in pure PE across subgroups but had many extreme values, which made it a poor differentiator. Higher uterine artery Doppler pulsatility indexes were detected in PE, IUGR, and PE+IUGR, with similar resistance indexes and peaks of systolic velocity. A significantly different marker level between PE and IUGR was found using arterial stiffness that was 10 times higher in PE; concurrently with an increase of the reactive hyperemia index, both were accompanied by a slight increase in placental protein 13. Higher tumor necrosis factor alpha (TNFα) differentially identified iatrogenic very early PTD (<34 weeks).

Conclusion: Arterial stiffness can serve as a major marker to differentiate PE (with/without IUGR) from pure IUGR near delivery. TNFα can differentiate iatrogenic early PTD from other complications of pregnancy and term IUGR.
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http://dx.doi.org/10.1159/000502177DOI Listing
April 2021

The competing risk approach for prediction of preeclampsia.

Am J Obstet Gynecol 2020 07 13;223(1):12-23.e7. Epub 2019 Nov 13.

Harris Birthright Research Centre for Fetal Medicine, King's College, London, UK. Electronic address:

The established method of the assessment of the risk for development of preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors, the patient is classified as high risk and in their absence as low risk. Although this approach is simple to perform, it has poor performance of the prediction of preeclampsia and does not provide patient-specific risks. This review describes a new approach that allows the estimation of patient-specific risks of delivery with preeclampsia before any specified gestational age by maternal demographic characteristics and medical history with biomarkers obtained either individually or in combination at any stage in pregnancy. In the competing risks approach, every woman has a personalized distribution of gestational age at delivery with preeclampsia; whether she experiences preeclampsia or not before a specified gestational age depends on competition between delivery before or after the development of preeclampsia. The personalized distribution comes from the application of Bayes theorem to combine a previous distribution, which is determined from maternal factors, with likelihoods from biomarkers. As new data become available, what were posterior probabilities take the role as the previous probability, and data collected at different stages are combined by repeating the application of Bayes theorem to form a new posterior at each stage, which allows for dynamic prediction of preeclampsia. The competing risk model can be used for precision medicine and risk stratification at different stages of pregnancy. In the first trimester, the model has been applied to identify a high-risk group that would benefit from preventative therapeutic interventions. In the second trimester, the model has been used to stratify the population into high-, intermediate-, and low-risk groups in need of different intensities of subsequent monitoring, thereby minimizing unexpected adverse perinatal events. The competing risks model can also be used in surveillance of women presenting to specialist clinics with signs or symptoms of hypertensive disorders; combination of maternal factors and biomarkers provide patient-specific risks for preeclampsia that lead to personalized stratification of the intensity of monitoring, with risks updated on each visit on the basis of biomarker measurements.
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http://dx.doi.org/10.1016/j.ajog.2019.11.1247DOI Listing
July 2020

Prenatal incidence of isolated right aortic arch and double aortic arch.

J Matern Fetal Neonatal Med 2019 Oct 16:1-6. Epub 2019 Oct 16.

Harris Birthright Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital , London , UK.

To define the incidence of variants of aortic arch sidedness in fetuses undergoing routine first trimester ultrasound examination. The data for this study were derived from prospective routine ultrasound examination at 11 to 13 weeks' gestation in singleton pregnancies examined in a local population between January 2014 and March 2018. We examined the incidence of isolated right aortic arch (RAA) and double aortic arch (DAA) in the local, screened population and compared the groups with and without these abnormalities. The study population of 33,202 pregnancies included 18 (5.4 per 10,000) cases with isolated RAA and 5 (1.5 per 10,000) with DAA. In the group with isolated RAA or DAA, compared to those without, the median maternal age was higher and the incidence of conceptions from fertilization (IVF) was eight-fold higher. The prevalence of 22q11microdeletion was 5% in patients with RAA from this local population. The incidence of isolated RAA and DAA in a local population undergoing routine first-trimester ultrasound examination is 2-3-fold higher than that reported in postnatal studies and the risk for these abnormalities is substantially increased in fetuses conceived by IVF.
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http://dx.doi.org/10.1080/14767058.2019.1676413DOI Listing
October 2019

Reasons for accepting or declining participation in the ASPRE trial: A qualitative study with women at high risk of preterm pre-eclampsia.

Prenat Diagn 2019 11 13;39(12):1127-1135. Epub 2019 Sep 13.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

Objective: To identify factors that affected the decision of pregnant women at high risk for pre-eclampsia (PE) in accepting or declining participation in a medicated clinical trial (ASPRE) for the prevention of preterm PE.

Method: This was a qualitative, cross-sectional study. A purposive sample of 14 participants and 13 decliners of the ASPRE trial were interviewed using semi-structured interviews. Data were analysed using template analysis.

Results: For participants, their high-risk status seems to have motivated them to take part in the trial. This was enabled by their perception that the trial drug aspirin was commonly used, the safety of the procedure, and the belief that they will be in receipt of extra monitoring in pregnancy. Decliners expressed discomfort about taking medications in pregnancy, and about the presence of the placebo arm; they seemed to be motivated by desire to reduce harm. Satisfaction with the information provided by the medical professionals was also influential in women's decision making, and so were the views of their partners and other trusted individuals.

Conclusion: Pregnant women's motivation to take part or to decline participation in a medicated trail can be understood as an attempt to cope with the threat posed by their high-risk status.
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http://dx.doi.org/10.1002/pd.5554DOI Listing
November 2019

Reply.

Am J Obstet Gynecol 2019 12 8;221(6):659. Epub 2019 Aug 8.

King's College Hospital, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2019.08.007DOI Listing
December 2019

Reply.

Am J Obstet Gynecol 2019 11 5;221(5):534-535. Epub 2019 Aug 5.

Harris Birthright Research Centre for Fetal Medicine, King's College, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2019.07.048DOI Listing
November 2019

The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention.

Int J Gynaecol Obstet 2019 05;145 Suppl 1:1-33

Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Pre‐eclampsia (PE) is a multisystem disorder that typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low‐resource countries are at a higher risk of developing PE compared with those in high‐resource countries. Although a complete understanding of the pathogenesis of PE remains unclear, the current theory suggests a two‐stage process. The first stage is caused by shallow invasion of the trophoblast, resulting in inadequate remodeling of the spiral arteries. This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder. Accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early enough to improve placentation and thus prevent or at least reduce the frequency of its occurrence. Furthermore, identification of an “at risk” group will allow tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE has been previously defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened. Now the internationally agreed definition of PE is the one proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). According to the ISSHP, PE is defined as systolic blood pressure at ≥140 mm Hg and/or diastolic blood pressure at ≥90 mm Hg on at least two occasions measured 4 hours apart in previously normotensive women and is accompanied by one or more of the following new‐onset conditions at or after 20 weeks of gestation: 1.Proteinuria (i.e. ≥30 mg/mol protein:creatinine ratio; ≥300 mg/24 hour; or ≥2 + dipstick); 2.Evidence of other maternal organ dysfunction, including: acute kidney injury (creatinine ≥90 μmol/L; 1 mg/dL); liver involvement (elevated transaminases, e.g. alanine aminotransferase or aspartate aminotransferase >40 IU/L) with or without right upper quadrant or epigastric abdominal pain; neurological complications (e.g. eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, and persistent visual scotomata); or hematological complications (thrombocytopenia–platelet count <150 000/μL, disseminated intravascular coagulation, hemolysis); or 3.Uteroplacental dysfunction (such as fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or stillbirth). It is well established that a number of maternal risk factors are associated with the development of PE: advanced maternal age; nulliparity; previous history of PE; short and long interpregnancy interval; use of assisted reproductive technologies; family history of PE; obesity; Afro‐Caribbean and South Asian racial origin; co‐morbid medical conditions including hyperglycemia in pregnancy; pre‐existing chronic hypertension; renal disease; and autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome. These risk factors have been described by various professional organizations for the identification of women at risk of PE; however, this approach to screening is inadequate for effective prediction of PE. PE can be subclassified into: 1.Early‐onset PE (with delivery at <34+0 weeks of gestation); 2.Preterm PE (with delivery at <37+0 weeks of gestation); 3.Late‐onset PE (with delivery at ≥34+0 weeks of gestation); 4.Term PE (with delivery at ≥37+0 weeks of gestation). These subclassifications are not mutually exclusive. Early‐onset PE is associated with a much higher risk of short‐ and long‐term maternal and perinatal morbidity and mortality. Obstetricians managing women with preterm PE are faced with the challenge of balancing the need to achieve fetal maturation in utero with the risks to the mother and fetus of continuing the pregnancy longer. These risks include progression to eclampsia, development of placental abruption and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. On the other hand, preterm delivery is associated with higher infant mortality rates and increased morbidity resulting from small for gestational age (SGA), thrombocytopenia, bronchopulmonary dysplasia, cerebral palsy, and an increased risk of various chronic diseases in adult life, particularly type 2 diabetes, cardiovascular disease, and obesity. Women who have experienced PE may also face additional health problems in later life, as the condition is associated with an increased risk of death from future cardiovascular disease, hypertension, stroke, renal impairment, metabolic syndrome, and diabetes. The life expectancy of women who developed preterm PE is reduced on average by 10 years. There is also significant impact on the infants in the long term, such as increased risks of insulin resistance, diabetes mellitus, coronary artery disease, and hypertension in infants born to pre‐eclamptic women. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to discuss and evaluate current knowledge on PE and develop a document to frame the issues and suggest key actions to address the health burden posed by PE. FIGO's objectives, as outlined in this document, are: (1) To raise awareness of the links between PE and poor maternal and perinatal outcomes, as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) To create a consensus document that provides guidance for the first‐trimester screening and prevention of preterm PE, and to disseminate and encourage its use. Based on high‐quality evidence, the document outlines current global standards for the first‐trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of pre‐eclampsia in singleton pregnancy.1 It provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To deal with the issue of PE, FIGO recommends the following: Public health focus: There should be greater international attention given to PE and to the links between maternal health and noncommunicable diseases (NCDs) on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early prenatal visits targeted at reproductive‐aged women, particularly in low‐resource countries. Universal screening: All pregnant women should be screened for preterm PE during early pregnancy by the first‐trimester combined test with maternal risk factors and biomarkers as a one‐step procedure. The risk calculator is available free of charge at https://fetalmedicine.org/research/assess/preeclampsia. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure this. The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI). Where it is not possible to measure PLGF and/or UTPI, the baseline screening test should be a combination of maternal risk factors with MAP, and not maternal risk factors alone. If maternal serum pregnancy‐associated plasma protein A (PAPP‐A) is measured for routine first‐trimester screening for fetal aneuploidies, the result can be included for PE risk assessment. Variations to the full combined test would lead to a reduction in the performance screening. A woman is considered high risk when the risk is 1 in 100 or more based on the first‐trimester combined test with maternal risk factors, MAP, PLGF, and UTPI. Contingent screening: Where resources are limited, routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of PLGF and UTPI for a subgroup of the population (selected on the basis of the risk derived from screening by maternal factors and MAP) can be considered. Prophylactic measures: Following first‐trimester screening for preterm PE, women identified at high risk should receive aspirin prophylaxis commencing at 11–14+6 weeks of gestation at a dose of ~150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed. Low‐dose aspirin should not be prescribed to all pregnant women. In women with low calcium intake (<800 mg/d), either calcium replacement (≤1 g elemental calcium/d) or calcium supplementation (1.5–2 g elemental calcium/d) may reduce the burden of both early‐ and late‐onset PE.
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http://dx.doi.org/10.1002/ijgo.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944283PMC
May 2019

The effect of parity on longitudinal maternal hemodynamics.

Am J Obstet Gynecol 2019 09 2;221(3):249.e1-249.e14. Epub 2019 Apr 2.

Fetal Medicine Research Institute, King's College London, London UK. Electronic address:

Background: Parous women have a lower risk for pregnancy complications, such as preeclampsia or delivery of small-for-gestational-age neonates. However, parous women are a heterogeneous group of patients because they contain a low-risk cohort with previously uncomplicated pregnancies and a high-risk cohort with previous pregnancies complicated by preeclampsia and/or small for gestational age. Previous studies examining the effect of parity on maternal hemodynamics, including cardiac output and peripheral vascular resistance, did not distinguish between parous women with and without a history of preeclampsia or small for gestational age and reported contradictory results.

Objective: The objective of the study was to compare maternal hemodynamics in nulliparous women and in parous women with and without previous preeclampsia and/or small for gestational age.

Study Design: This was a prospective, longitudinal study of maternal hemodynamics, assessed by a bioreactance method, measured at 11 to 13, 19 to 24, 30 to 34, and 35 to 37 weeks' gestation in 3 groups of women. Group 1 was composed of parous women without a history of preeclampsia and/or small for gestational age (n = 632), group 2 was composed of nulliparous women (n = 829), and group 3 was composed of parous women with a history of preeclampsia and/or small for gestational age (n = 113). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal characteristics, medical history, and development of preeclampsia or small for gestational age in the current pregnancy.

Results: In groups 1 and 2, cardiac output increased with gestational age to a peak at 32 weeks and peripheral vascular resistance showed a reversed pattern with its nadir at 32 weeks; in group 1, compared with group 2, there was better cardiac adaptation, reflected in higher cardiac output and lower peripheral vascular resistance. In group 3 there was a hyperdynamic profile of higher cardiac output and lower peripheral vascular resistance at the first trimester followed by an earlier sharp decline of cardiac output and increase of peripheral vascular resistance from midgestation. The incidence of preeclampsia and small for gestational age was highest in group 3 and lowest in group 1.

Conclusion: There are parity-specific differences in maternal cardiac adaptation in pregnancy.
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http://dx.doi.org/10.1016/j.ajog.2019.03.027DOI Listing
September 2019

First trimester combined screening in patients with systemic lupus erythematosus: impact of pre-analytical variables on risk assessment.

Clin Rheumatol 2019 May 28;38(5):1251-1255. Epub 2019 Mar 28.

Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, UK.

Background: Prenatal diagnosis of fetal trisomy 21 and other chromosomal abnormalities is based on invasive tests, such as amniocentesis and chorionic villus sampling, which are carried out in women identified through screening as being at high risk for these abnormalities. The most widely used method of screening is the first-trimester combined test which utilizes maternal age, and measurements of fetal nuchal translucency thickness (NT) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (hCG).

Objectives: To assess the influence of SLE on the levels of NT, PAPP-A, and β-hCG and whether any alterations in such levels may increase the rate of false positives and the subsequent number of invasive tests.

Method: This was a prospective first-trimester screening study for trisomies 21, 18, and 13 by a combination of maternal age, fetal nuchal translucency thickness, and serum PAPP-A and β-hCG at King's College Hospital, London, between March 2006 and February 2011. The study population included 47 cases with maternal SLE and 45,493 without SLE. The results of biomarkers in the SLE and non-SLE groups were compared.

Results: In the SLE group, compared to the non-SLE group, there were no significant differences in median maternal age, fetal NT, or serum PAPP-A MoM, but serum free β-hCG MoM was increased (1.402, IQR 0.872-2.290 vs 0.994, IQR 0.676-1.508).

Conclusion: In first trimester screening for trisomies, the measured value of free ß-hCG should be adjusted for maternal SLE to avoid false positive results and overuse of invasive tests.
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http://dx.doi.org/10.1007/s10067-019-04525-1DOI Listing
May 2019

Routine assessment of cerebroplacental ratio at 35-37 weeks' gestation in the prediction of adverse perinatal outcome.

Am J Obstet Gynecol 2019 07 13;221(1):65.e1-65.e18. Epub 2019 Mar 13.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom. Electronic address:

Background: Third-trimester studies in selected high-risk pregnancies have reported that low cerebroplacental ratio, due to high pulsatility index in the umbilical artery, and or decreased pulsatility index in the fetal middle cerebral artery, is associated with increased risk of adverse perinatal outcomes.

Objective: To investigate the predictive performance of screening for adverse perinatal outcome by the cerebroplacental ratio measured routinely at 35-37 weeks' gestation.

Study Design: This was a prospective observational study in 47,211 women with singleton pregnancies undergoing routine ultrasound examination at 35 to 37 weeks' gestation, including measurement of umbilical artery-pulsatility index and middle cerebral artery-pulsatility index. The measured umbilical artery-pulsatility index and middle cerebral artery-pulsatility index and their ratio were converted to multiples of the median after adjustment for gestational age. Multivariable logistic regression analysis was used to determine whether umbilical artery-pulsatility index, middle cerebral artery-pulsatility index, and cerebroplacental ratio improved the prediction of adverse perinatal outcome that was provided by maternal characteristics, medical history, and obstetric factors. The following outcome measures were considered: (1) adverse perinatal outcome consisting of stillbirth, neonatal death, or hypoxic-ischemic encephalopathy grades 2 and 3; (2) presence of surrogate markers of perinatal hypoxia consisting of umbilical arterial or venous cord blood pH ≤7 and ≤7.1, respectively, 5-minute Apgar score <7, or admission to the neonatal intensive care unit for >24 hours; (3) cesarean delivery for presumed fetal compromise in labor; and (4) neonatal birthweight less than the third percentile for gestational age.

Results: First, the incidence of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, and cesarean delivery for presumed fetal compromise in labor was greater in pregnancies with small for gestational age neonates with birthweight <10th percentile compared with appropriate for gestational age neonates; however, 80%-85% of these adverse events occurred in the appropriate for gestational age group. Second, low cerebroplacental ratio <10th percentile was associated with increased risk of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, cesarean delivery for presumed fetal compromise in labor, and birth of neonates with birthweight less than third percentile. However, multivariable regression analysis demonstrated that the prediction of these adverse outcomes by maternal demographic characteristics and medical history was only marginally improved by the addition of cerebroplacental ratio. Third, the performance of low cerebroplacental ratio in the prediction of each adverse outcome was poor, with detection rates of 13%-26% and a false-positive rate of about 10%. Fourth, the detection rates of adverse outcomes were greater in small for gestational age than in appropriate for gestational age babies and in pregnancies delivering within 2 weeks rather than at any stage after assessment; however, such increase in detection rates was accompanied by an increase in the false-positive rate. Fifth, in appropriate for gestational age neonates, the predictive accuracy of cerebroplacental ratio was low, with positive and negative likelihood ratios ranging from 1.21 to 1.82, and 0.92 to 0.98, respectively; although the accuracy was better in small for gestational age neonates, this was also low with positive likelihood ratios of 1.31-2.26 and negative likelihood ratios of 0.69-0.92. Similar values were obtained in fetuses classified as small for gestational age and appropriate for gestational age according to the estimated fetal weight.

Conclusions: In pregnancies undergoing routine antenatal assessment at 35-37 weeks' gestation, measurement of cerebroplacental ratio provides poor prediction of adverse perinatal outcome in both small for gestational age and appropriate for gestational age fetuses.
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http://dx.doi.org/10.1016/j.ajog.2019.03.002DOI Listing
July 2019