Publications by authors named "Ranjit Akolekar"

99 Publications

Kielland's rotational forceps delivery: comparison of maternal and neonatal outcomes with pregnancies delivering by non-rotational forceps.

J Obstet Gynaecol 2021 May 25:1-6. Epub 2021 May 25.

Department of Obstetrics, Medway NHS Foundation Trust, Gillingham, UK.

We compared complications in pregnancies that had Kielland's rotational forceps delivery (KRFD) with non-rotational forceps delivery (NRFD). Maternal outcomes included post-partum haemorrhage (PPH) and obstetric anal sphincter injury (OASIS); neonatal outcomes included admission to neonatal intensive care unit (NICU), 5-minute Apgar scores <7, hypoxic ischaemic encephalopathy (HIE), jaundice, shoulder dystocia and birth trauma. The study population included 491 (2.1%) requiring KRFD, 1,257 (5.3%) requiring NRFD and 22,111 (93.0%) that had SVD. In pregnancies with NRFD compared to KRFD, there was higher incidence of OASIS (8.5% vs. 4.7%;  = .006) and a non-significant increased trend for PPH (15.0% vs. 12.4%;  = .173). There was no significant difference in rates of admission to NICU ( = .628), 5-minute Apgar score <7 ( = .375), HIE ( = .532), jaundice ( = .809), severe shoulder dystocia ( = .507) or birth trauma ( = .514). Our study demonstrates that KRFD has lower rates of maternal complications compared to NRFD whilst the rates of neonatal complications are similar.IMPACT STATEMENT Kielland's rotational forceps is used for achieving vaginal delivery in pregnancies with failure to progress in second stage of labour secondary to fetal malposition. The use of Kielland's forceps has significantly declined in the last few decades due to concerns about an increased risk of maternal and neonatal complications, despite the absence of any major studies demonstrating this increased risk. There are some studies which compare the risks in pregnancies delivering by Kiellands forceps with rotational ventouse deliveries but there is limited evidence comparing the risks of rotational with non-rotational forceps deliveries. Our study compares the major maternal and neonatal complications in a large cohort of pregnancies undergoing rotational vs. non-rotational forceps deliveries. The results of our study demonstrate that maternal and neonatal complications in pregnancies delivering by Kielland's rotational forceps undertaken by appropriately trained obstetricians are either lower or similar to those delivering by non-rotational forceps. Consideration should be given to ensure that there is appropriate training provided to obstetricians to acquire skills in using Kielland's forceps.
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http://dx.doi.org/10.1080/01443615.2021.1907557DOI Listing
May 2021

Reference Ranges for Pulsed-Wave Doppler of the Fetal Cardiac Inflow and Outflow Tracts from 13 to 36 Weeks' Gestation.

J Am Soc Echocardiogr 2021 May 3. Epub 2021 May 3.

Medway Fetal and Maternal Medicine Centre, Medway Maritime Hospital, Gillingham, United Kingdom; Institute of Medical Sciences, Canterbury Christ Church University, Chatham, United Kingdom.

Background: Doppler assessment of ventricular filling and outflow tract velocities is an integral part of fetal echocardiography, to assess diastolic function, systolic function, and outflow tract obstruction. There is a paucity of prospective data from a large sample of normal fetuses in the published literature. The authors report reference ranges for pulsed-wave Doppler flow of the mitral valve, tricuspid valve, aortic valve, and pulmonary valve, as well as heart rate, in a large number of fetuses prospectively examined at a single tertiary fetal cardiology center.

Methods: The study population comprised 7,885 fetuses at 13 to 36 weeks' gestation with no detectable abnormalities from pregnancies resulting in normal live births. Prospective pulsed-wave Doppler blood flow measurements were taken of the mitral, tricuspid, aortic, and pulmonary valves. The fetal heart rate was recorded at the time of each assessment. Regression analysis, with polynomial terms to assess for linear and nonlinear contributors, was used to establish the relationship between each measurement and gestational age.

Results: The measurement for each cardiac Doppler measurement was expressed as a Z score (difference between observed and expected values divided by the fitted SD corrected for gestational age) and percentile. Analysis included calculation of gestation-specific SDs. Regression equations are provided for the cardiac inflow and outflow tracts.

Conclusions: This study establishes reference ranges for fetal cardiac Doppler measurements and heart rate between 13 to 36 weeks' gestation that may be useful in clinical practice.
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http://dx.doi.org/10.1016/j.echo.2021.04.017DOI Listing
May 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

Kielland's rotational forceps delivery: A comparison of maternal and neonatal outcomes with rotational ventouse or second stage caesarean section deliveries.

Eur J Obstet Gynecol Reprod Biol 2020 Nov 27;254:175-180. Epub 2020 Aug 27.

Department of Obstetrics, Medway NHS Foundation Trust, Gillingham, Kent, United Kingdom; Fetal Medicine Unit, Medway NHS Foundation Trust, Gillingham, Kent, United Kingdom; Institute of Medical Sciences, Canterbury Christ Church University, Kent, United Kingdom; Medway Innovation Institute, Gillingham, Kent, United Kingdom. Electronic address:

Objectives: The objective of our study was to derive accurate estimates of risks of maternal and neonatal complications associated with Kielland's rotational forceps delivery (KRFD) compared to rotational ventouse delivery (RVD) or 2nd stage caesarean section (CS).

Methods: This was a retrospective cohort study undertaken at a large tertiary maternity and neonatal unit in the United Kingdom between January 2010 and June 2018. Pregnancies with fetal demise, major fetal defects, those lost to follow-up, those delivering by elective or emergency CS in the first stage of labour and non-rotational instrumental deliveries were excluded. The study population included singleton pregnancies delivering by Kielland's forceps, rotational ventouse, 2nd stage CS or spontaneous unassisted cephalic vaginal delivery; the latter forming the control group. The maternal outcomes examined included post-partum haemorrhage (PPH) and obstetric anal sphincter injury (OASIS). The neonatal outcomes included admission to neonatal intensive care unit (NICU), 5-minute Apgar scores <7, hypoxic ischaemic encephalopathy (HIE), jaundice, shoulder dystocia and birth trauma. Absolute risks with 95 % confidence intervals (CI) were calculated in the study groups. Univariate and multivariate logistic regression analysis was carried out to estimate crude and adjusted odds ratio (OR) with 95 % CI.

Results: The study population of 23,786 pregnancies included: 491 (2.1 %) requiring KRFD, 344 (1.4 %) requiring RVD, 840 (3.5 %) that had a 2nd stage CS and 22,111 (93.0 %) spontaneous cephalic vaginal deliveries. With regard to maternal adverse outcomes, in pregnancies that had a KRFD compared to RVD, there was no significant difference in the incidence of OASIS (p = 0.599) or PPH (p = 0.982). In contrast, the risk of PPH was significantly higher in those delivering by a 2nd stage CS compared to KRFD (27.5 % vs. 12.4 %; p < 0.0001). With regard to neonatal adverse outcomes, in those delivering by KRFD compared to RVD and 2nd stage CS, there was no significant difference in the incidence of admission to NICU (p = 0.912; p = 0.746, respectively), 5-minute Apgar score<7 (p = 0.335; p = 0.150, respectively), jaundice (p = 0.810; p = 0.332, respectively), mild shoulder dystocia (p = 0.077), severe shoulder dystocia (p = 0.603) or birth trauma (p = 0.265; p = 0.323, respectively). The risk of maternal composite adverse outcome was highest after 2nd stage CS (OR 7.68; 95 %CI: 6.52-9.04) and lowest after KRFD (OR 3.82; 95 %CI: 2.98-4.91). The risk of composite neonatal adverse outcome was higher in those delivering by RVD (OR 2.87; 95 %CI: 2.10-3.91), compared to KRFD (OR 2.23; 95 %CI: 1.67-2.97) or 2nd stage CS (OR 2.02; 95 %CI: 1.60-2.54).

Conclusion: Our study demonstrates that KRFD is a safer management option when compared to RVD or 2nd stage CS for the management of persistent fetal malposition in labour.
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http://dx.doi.org/10.1016/j.ejogrb.2020.08.026DOI Listing
November 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

Metformin use in obese mothers is associated with improved cardiovascular profile in the offspring.

Am J Obstet Gynecol 2020 08 1;223(2):246.e1-246.e10. Epub 2020 Feb 1.

Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK; School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK. Electronic address:

Background: Maternal obesity increases the risk for pregnancy complications and adverse neonatal outcome and has been associated with long-lasting adverse effects in the offspring, including increased body fat mass, insulin resistance, and increased risk for premature cardiovascular disease. Lifestyle interventions in pregnancy have produced no or modest effects in the reduction of adverse pregnancy outcomes in obese mothers. The Metformin in Obese Pregnant Women trial was associated with reduced adverse pregnancy outcomes and had no effect on birthweight. However, the long-term implications of metformin on the health of offspring remain unknown.

Objective: The purpose of this study was to assess whether prenatal exposure to metformin can improve the cardiovascular profile and body composition in the offspring of obese mothers.

Study Design: In 151 children from the Metformin in Obese Pregnant Women trial, body composition, peripheral blood pressure, and arterial pulse wave velocity were measured. Central hemodynamics (central blood pressure and augmentation index) were estimated with the use of an oscillometric device. Left ventricular cardiac function and structure were assessed by echocardiography.

Results: Children were 3.9±1.0 years old, and 77 of them had been exposed to metformin prenatally. There was no significant difference in peripheral blood pressure, arterial stiffness, and body composition apart from gluteal and tricep circumferences, which were lower in the metformin group (P<.05). The metformin group, compared with the placebo group, had lower central hemodynamics (mean adjusted decrease, -0.707 mm Hg for aortic systolic blood pressure, -1.65 mm Hg for aortic pulse pressure, and -2.68% for augmentation index; P<.05 for all) and lower left ventricular diastolic function (adjusted difference in left atrial area, -0.525 cm, in isovolumic relaxation time, -0.324 msec, and in pulmonary venous systolic wave, 2.97 cm/s; P<.05 for all). There were no significant differences in metabolic profile between the groups.

Conclusion: Children of obese mothers who were exposed prenatally to metformin, compared with those who were exposed to placebo, had lower central hemodynamic and cardiac diastolic indices. These results suggest that the administration of metformin in obese pregnant women potentially may have a beneficial cardiovascular effect for their offspring.
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http://dx.doi.org/10.1016/j.ajog.2020.01.054DOI Listing
August 2020

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

Social Brain Functional Maturation in Newborn Infants With and Without a Family History of Autism Spectrum Disorder.

JAMA Netw Open 2019 04 5;2(4):e191868. Epub 2019 Apr 5.

Institute of Psychiatry, Psychology & Neuroscience, Department of Forensic and Neurodevelopmental Sciences, King's College London, Denmark Hill, London, United Kingdom.

Importance: What is inherited or acquired in neurodevelopmental conditions such as autism spectrum disorder (ASD) is not a fixed outcome, but instead is a vulnerability to a spectrum of traits, especially social difficulties. Identifying the biological mechanisms associated with vulnerability requires looking as early in life as possible, before the brain is shaped by postnatal mechanisms and/or the experiences of living with these traits. Animal studies suggest that susceptibility to neurodevelopmental disorders arises when genetic and/or environmental risks for these conditions alter patterns of synchronous brain activity in the perinatal period, but this has never been examined in human neonates.

Objective: To assess whether alternation of functional maturation of social brain circuits is associated with a family history of ASD in newborns.

Design, Setting, And Participants: In this cohort study of 36 neonates with and without a family history of ASD, neonates underwent magnetic resonance imaging at St Thomas Hospital in London, England, using a dedicated neonatal brain imaging system between June 23, 2015, and August 1, 2018. Neonates with a first-degree relative with ASD (R+) and therefore vulnerable to autistic traits and neonates without a family history (R-) were recruited for the study. Synchronous neural activity in brain regions linked to social function was compared.

Main Outcomes And Measures: Regions responsible for social function were selected with reference to a published meta-analysis and the level of synchronous activity within each region was used as a measure of local functional connectivity in a regional homogeneity analysis. Group differences, controlling for sex, age at birth, age at scan, and group × age interactions, were examined.

Results: The final data set consisted of 18 R+ infants (13 male; median [range] postmenstrual age at scan, 42.93 [40.00-44.86] weeks) and 18 R- infants (13 male; median [range] postmenstrual age at scan, 42.50 [39.29-44.58] weeks). Neonates who were R+ had significantly higher levels of synchronous activity in the right posterior fusiform (t = 2.48; P = .04) and left parietal cortices (t = 3.96; P = .04). In addition, there was a significant group × age interaction within the anterior segment of the left insula (t = 3.03; P = .04) and cingulate cortices (right anterior: t = 3.00; P = .03; left anterior: t = 2.81; P = .03; right posterior: t = 2.77; P = .03; left posterior: t = 2.55; P = .03). In R+ infants, levels of synchronous activity decreased over 39 to 45 weeks' postmenstrual age, whereas synchronous activity levels increased in R- infants over the same period.

Conclusions And Relevance: Synchronous activity is required during maturation of functionally connected networks. This study found that in newborn humans, having a first-degree relative with ASD was associated with higher levels of local functional connectivity and dysmaturation of interconnected regions responsible for processing higher-order social information.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.1868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450332PMC
April 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

Prediction of small for gestational age neonates: screening by maternal factors, fetal biometry, and biomarkers at 35-37 weeks' gestation.

Am J Obstet Gynecol 2019 05 29;220(5):486.e1-486.e11. Epub 2019 Jan 29.

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

Background: Small for gestational age (SGA) neonates are at increased risk for perinatal mortality and morbidity; however, the risks can be substantially reduced if the condition is identified prenatally, because in such cases close monitoring and appropriate timing of delivery and prompt neonatal care can be undertaken. The traditional approach of identifying pregnancies with SGA fetuses is maternal abdominal palpation and serial measurements of symphysial-fundal height, but the detection rate of this approach is less than 30%. A higher performance of screening for SGA is achieved by sonographic fetal biometry during the third trimester; screening at 30-34 weeks' gestation identifies about 80% of SGA neonates delivering preterm but only 50% of those delivering at term, at a screen-positive rate of 10%. There is some evidence that routine ultrasound examination at 36 weeks' gestation is more effective than that at 32 weeks in predicting birth of SGA neonates.

Objective: To investigate the potential value of maternal characteristics and medical history, sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 35- 36 weeks' gestation in the prediction of delivery of SGA neonates.

Materials And Methods: A dataset of 19,209 singleton pregnancies undergoing screening at 35-36 weeks' gestation was divided into a training set and a validation set. The training dataset was used to develop models from multivariable logistic regression analysis to determine whether the addition of uterine artery pulsatility index (UtA-PI), umbilical artery PI (UA-PI), fetal middle cerebral artery PI (MCA-PI), maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT) would improve the performance of maternal factors and EFW in the prediction of delivery of SGA neonates. The models were then tested in the validation dataset to assess performance of screening.

Results: First, in the training dataset, in the SGA group, compared to those with birthweight in ≥10th percentile, the median multiple of the median (MoM) values of PlGF and MCA-PI were reduced, whereas UtA-PI, UA-PI, and sFLT were increased. Second, multivariable regression analysis demonstrated that in the prediction of SGA in <10th percentile there were significant contributions from maternal factors, EFW Z-score, UtA-PI MoM, MCA-PI MoM, and PlGF MoM. Third, in the validation dataset, prediction of 90% of SGA neonates delivering within 2 weeks of assessment was achieved by a screen-positive rate of 67% (95% confidence interval [CI], 64-70%) in screening by maternal factors, 23% (95% CI, 20-26%) by maternal factors, and EFW and 21% (95% CI, 19-24%) by the addition of biomarkers. Fourth, prediction of 90% of SGA neonates delivering at any stage after assessment was achieved by a screen-positive rate of 66% (95% CI, 65-67%) in screening by maternal factors, 32% (95% CI, 31-33%) by maternal factors and EFW and 30% (95% CI, 29-31%) by the addition of biomarkers.

Conclusion: The addition of biomarkers of impaired placentation only marginally improves the predictive performance for delivery of SGA neonates achieved by maternal factors and fetal biometry at 35-36 weeks' gestation.
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http://dx.doi.org/10.1016/j.ajog.2019.01.227DOI Listing
May 2019

Reference Ranges for the Size of the Fetal Cardiac Outflow Tracts From 13 to 36 Weeks Gestation: A Single-Center Study of Over 7000 Cases.

Circ Cardiovasc Imaging 2018 07;11(7):e007575

Harris Birthright Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital NHS Foundation Trust, London, United Kingdom (T.V.V., R.A., A.S., M.C., L.D.A., K.H.N., V.Z., J.M.S.).

Background: Assessment of the outflow tract views is an integral part of routine fetal cardiac scanning. For some congenital heart defects, notably coarctation of the aorta, pulmonary valve stenosis, and aortic valve stenosis, the size of vessels is important both for diagnosis and prognosis. Existing reference ranges of fetal outflow tracts are derived from a small number of cases.

Methods And Results: The study population comprised 7945 fetuses at 13 to 36 weeks' gestation with no detectable abnormalities from pregnancies resulting in normal live births. Prospective measurements were taken of (1) the aortic and pulmonary valves in diastole at the largest diameter with the valve closed, (2) the distal transverse aortic arch on the 3 vessel and trachea view beyond the trachea at the distal point at its widest systolic diameter, and (3) the arterial duct on the 3 vessel and trachea view at its widest systolic diameter. Regression analysis, with polynomial terms to assess for linear and nonlinear contributors, was used to establish the relationship between each measurement and gestational age. The measurement for each cardiac diameter was expressed as a z score (difference between observed and expected value divided by the fitted SD corrected for gestational age) and percentile. Analysis included calculation of gestation-specific SDs. Regression equations are provided for the cardiac outflow tracts and for the distal transverse aortic arch:arterial duct ratio.

Conclusions: The study established reference ranges for fetal outflow tract measurements at 13 to 36 weeks' gestation that are useful in clinical practice.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.007575DOI Listing
July 2018

Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin.

Obstet Med 2017 Dec 16;10(4):170-173. Epub 2017 Oct 16.

Epsom and St Helier University Hospitals NHS Trust, Surrey, UK.

Objectives: To examine whether the reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is mediated by changes in insulin resistance.

Methods: This was a secondary analysis of obese pregnant women in a randomised trial (MOP trial). Fasting plasma glucose and insulin were measured in 384 of the 400 women who participated in the MOP trial. Homeostasis model assessment of insulin resistance (HOMA-IR) was compared in the metformin and placebo groups and in those that developed preeclampsia versus those that did not develop preeclampsia.

Results: At 28 weeks, median HOMA-IR was significantly lower in the metformin group. Logistic regression analysis demonstrated that there was a significant contribution in the prediction of preeclampsia from maternal history of chronic hypertension and gestational weight gain, but not HOMA-IR either at randomisation ( = 0.514) or at 28 weeks ( = 0.643).

Conclusions: Reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is unlikely to be due to changes in insulin resistance.
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http://dx.doi.org/10.1177/1753495X17725465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714110PMC
December 2017

Risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review of the literature.

Minerva Ginecol 2018 Apr 21;70(2):215-219. Epub 2017 Nov 21.

Unit of Fetal Medicine, Medway Maritime Hospital, Gillingham, UK -

Introduction: The aim of this paper was to estimate the risk of miscarriage after amniocentesis or chorionic villus sampling (CVS) based on a systematic review of the literature.

Evidence Acquisition: A search of Medline, Embase, and The Cochrane Library (2000-2017) was carried out to identify studies reporting complications following CVS or amniocentesis. The inclusion criteria for the systematic review were studies reporting results from large controlled studies (N.≥1000 invasive procedures) and those reporting data for pregnancy loss prior to 24 weeks' gestation. Data for cases that had invasive procedure and controls were inputted in contingency tables and risk of miscarriage was estimated for each study. Summary statistics were calculated after taking into account the weighting for each study included in the systematic review. Procedure-related risk of miscarriage was estimated as a weighted risk difference from the summary statistics for cases and controls.

Evidence Snthesis: The electronic search from the databases yielded 2465 potential citations of which 2431 were excluded, leaving 34 studies for full-text review. The final review included 10 studies for amniocentesis and 6 studies for CVS, which were used to estimate risk of miscarriage in pregnancies that had an invasive procedure and the control pregnancies that did not. The procedure-related risk of miscarriage following amniocentesis was 0.35% (95% confidence interval [CI]: 0.07 to 0.63) and that following CVS was 0.35% (95% CI: -0.31 to 1.00).

Conclusions: The procedure-related risks of miscarriage following amniocentesis and CVS are lower than currently quoted to women.
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http://dx.doi.org/10.23736/S0026-4784.17.04178-8DOI Listing
April 2018

Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history.

Am J Obstet Gynecol 2017 11 4;217(5):585.e1-585.e5. Epub 2017 Aug 4.

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

Background: The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial demonstrated that in women who were at high risk for preterm preeclampsia with delivery at <37 weeks' gestation identified by screening by means of an algorithm that combines maternal factors and biomarkers at 11-13 weeks' gestation, aspirin administration from 11 to 14 until 36 weeks' gestation was associated with a significant reduction in the incidence of preterm preeclampsia (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004).

Objective: We sought to examine whether there are differences in the effect of aspirin on the incidence of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial in subgroups defined according to maternal characteristics and medical and obstetrical history.

Study Design: This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. Subgroup analysis was performed to assess evidence of differences in the effect of aspirin on incidence of preterm preeclampsia in subgroups defined by maternal age (<30 and ≥30 years), body mass index (<25 and ≥25 kg/m), racial origin (Afro-Caribbean, Caucasian and other), method of conception (natural and assisted), cigarette smoking (smoker and non-smoker), family history of preterm preeclampsia (present and absent), obstetrical history (nulliparous, multiparous with previous preterm preeclampsia and multiparous without previous preterm preeclampsia), history of chronic hypertension (present and absent). Interaction tests were performed on the full data set of patients in the intention to treat population and on the data set of patients who took ≥ 90% of the prescribed medication. Results are presented as forest plot with P values for the interaction effects, group sizes, event counts and estimated odds ratios. We examined whether the test of interaction was significant at the 5% level with a Bonferroni adjustment for multiple comparisons.

Results: There was no evidence of heterogeneity in the aspirin effect in subgroups defined according to maternal characteristics and obstetrical history. In participants with chronic hypertension preterm preeclampsia occurred in 10.2% (5/49) in the aspirin group and 8.2% (5/61) in the placebo group (adjusted odds ratio, 1.29; 95% confidence interval, 0.33-5.12). The respective values in those without chronic hypertension were 1.1% (8/749) in the aspirin group and 3.9% (30/761) in the placebo group (adjusted odds ratio, 0.27; 95% confidence interval, 0.12-0.60). In all participants with adherence of ≥90% the adjusted odds ratio in the aspirin group was 0.24 (95% confidence interval, 0.09-0.65); in the subgroup with chronic hypertension it was 2.06 (95% confidence interval, 0.40-10.71); and in those without chronic hypertension it was 0.05 (95% confidence interval, 0.01-0.41). For the complete data set the test of interaction was not significant at the 5% level (P = .055), but in those with adherence ≥90%, after adjustment for multiple comparisons, the interaction was significant at the 5% level (P = .0019).

Conclusion: The beneficial effect of aspirin in the prevention of preterm preeclampsia may not apply in pregnancies with chronic hypertension. There was no evidence of heterogeneity in the aspirin effect in subgroups defined according to maternal characteristics and obstetrical history.
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http://dx.doi.org/10.1016/j.ajog.2017.07.038DOI Listing
November 2017

Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age.

Fetal Diagn Ther 2018 21;43(4):250-265. Epub 2017 Jul 21.

Hy Laboratories, Rehovot, Israel.

Background: LGALS13 (placental protein 13 [PP13]) promoter DNA polymorphisms was evaluated in predicting preeclampsia (PE), given PP13's effects on hypotension, angiogenesis, and immune tolerance.

Methods: First-trimester plasma samples (49 term and 18 intermediate) of PE cases matched with 196 controls were collected from King's College Hospital, London, repository. Cell-free DNA was extracted and the LGALS13 exons were sequenced after PCR amplification. Expression of LGALS13 promoter reporter constructs was determined in BeWo trophoblast-like cells with luciferase assays. Adjusted odds ratio (OR) was calculated for the A/A genotype combined with maternal risk factors.

Results: The A/A, A/C, and C/C genotypes in the -98 promoter position were in Hardy-Weinberg equilibrium in the control but not in the PE group (p < 0.036). The dominant A/A genotype had higher frequency in the PE group (p < 0.001). The A/C and C/C genotypes protected from PE (p < 0.032). The ORs to develop term and all PE, calculated for the A/A genotype, previous PE, body mass index (BMI) >35, black ethnicity, and maternal age >40 were 15.6 and 11.0, respectively (p < 0.001). In luciferase assays, the "-98A" promoter variant had lower expression than the "-98C" variant in non-differentiated (-13%, p = 0.04) and differentiated (-26%, p < 0.001) BeWo cells. Forskolin-induced differentiation led to a larger expression increase in the "-98C" variant than in the "-98A" variant (4.55-fold vs. 3.85-fold, p < 0.001).

Conclusion: Lower LGALS13 (PP13) expression with the "A" nucleotide in the -98 promoter region position (compared to "C") and high OR calculated for the A/A genotype in the -98A/C promoter region position, history of previous PE, BMI >35, advanced maternal age >40, and black ethnicity could serve to aid in PE prediction in the first trimester.
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http://dx.doi.org/10.1159/000477933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882584PMC
October 2018

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia.

N Engl J Med 2017 08 28;377(7):613-622. Epub 2017 Jun 28.

From King's College Hospital (D.L.R., L.C.P., N.O., A.S., R.A., K.H.N.), Homerton University Hospital (S.C.), North Middlesex University Hospital (D.J.), and University College London Comprehensive Clinical Trials Unit (K.M.), London, University of Exeter, Exeter (D.W.), Medway Maritime Hospital, Gillingham (R.A.), and Southend University Hospital, Westcliff-on-Sea (M.S.) - all in the United Kingdom; Chinese University of Hong Kong, Hong Kong (L.C.P.); Hospital Clínico Universitario Virgen de la Arrixaca, Murcia (C.P.M.), Hospital Universitario San Cecilio, Granada (F.S.M.), and Hospiten Group, Tenerife (W.P.) - all in Spain; Ospedale Maggiore Policlinico, Milan (N.P.); University Hospital Brugmann, Université Libre de Bruxelles, Brussels (J.C.J.); Attikon University Hospital, Athens (G.P.); Rabin Medical Center, Petach Tikva (K.T.-G.), and HyLabs Diagnostics, Rehovot (H.M.) - both in Israel; and University of Iceland, Reykjavik (S.G.).

Background: Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia.

Methods: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle.

Results: A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.

Conclusions: Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013-003778-29 ; Current Controlled Trials number, ISRCTN13633058 .).
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http://dx.doi.org/10.1056/NEJMoa1704559DOI Listing
August 2017

Endoscopic Placental Laser Coagulation in Dichorionic and Monochorionic Triplet Pregnancies.

Fetal Diagn Ther 2016 25;40(3):174-180. Epub 2016 Feb 25.

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

Objective: To report the outcome of monochorionic (MC) and dichorionic (DC) triamniotic (TA) triplet pregnancies treated with endoscopic laser coagulation of the communicating placental vessels for severe feto-fetal transfusion syndrome (FFTS) and selective fetal growth restriction (sFGR).

Methods: Laser surgery was performed at 18 (15-24) weeks' gestation in 11 MCTA and 33 DCTA pregnancies complicated by FFTS and 14 DCTA pregnancies complicated by sFGR. Data from our study and previous reports were pooled using meta-analytic techniques.

Results: Survival of at least one baby and survival among all fetuses was 97.0 and 72.7% in DCTA pregnancies with FFTS, 78.6 and 52.4% in DCTA pregnancies with sFGR and 81.8 and 39.4% in MCTA pregnancies with FFTS. In the combined data from our study and previous reports, the pooled survival rates in 132 DCTA pregnancies with FFTS were 94.4 and 76.1%, and in 29 MCTA pregnancies with FFTS, they were 80.6 and 57.5%.

Conclusions: Survival after laser surgery is higher in DC triplets with FFTS than in those with sFGR and in DC than in MC triplets with FFTS.
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http://dx.doi.org/10.1159/000443792DOI Listing
February 2017

Metabolomic determination of pathogenesis of late-onset preeclampsia.

J Matern Fetal Neonatal Med 2017 Mar 28;30(6):658-664. Epub 2016 Aug 28.

b Harris Birthright Research Centre for Fetal Medicine , Division of Women's Health, King's College Hospital , London , UK.

Objective: Our primary objective was to apply metabolomic pathway analysis of first trimester maternal serum to provide an insight into the pathogenesis of late-onset preeclampsia (late-PE) and thereby identify plausible therapeutic targets for PE.

Methods: NMR-based metabolomics analysis was performed on 29 cases of late-PE and 55 unaffected controls. In order to achieve sufficient statistical power to perform the pathway analysis, these cases were combined with a group of previously analyzed specimens, 30 late-PE cases and 60 unaffected controls. Specimens from both groups of cases and controls were collected in the same clinical centers during the same time period. In addition, NMR analyses were performed in the same lab and using the same techniques.

Results: We identified abnormalities in branch chain amino acids (valine, leucine and isoleucine) and propanoate, glycolysis, gluconeogenesis and ketone body metabolic pathways. The results suggest insulin resistance and metabolic syndrome, mitochondrial dysfunction and disturbance of energy metabolism, oxidative stress and lipid dysfunction in the pathogenesis of late PE and suggest a potential role for agents that reduce insulin resistance in PE.

Conclusions: Branched chain amino acids are known markers of insulin resistance and strongly predict future diabetes development. The analysis provides independent evidence linking insulin resistance and late-PE and suggests a potentially important therapeutic role for pharmacologic agents that reduce insulin resistance for late-PE.
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http://dx.doi.org/10.1080/14767058.2016.1185411DOI Listing
March 2017

Maternal and pregnancy characteristics affect plasma fibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy.

Am J Obstet Gynecol 2016 10 11;215(4):466.e1-8. Epub 2016 May 11.

Harris Birthright Research Center for Fetal Medicine, King's College Hospital Foundation Trust, London, United Kingdom.

Background: D-dimers have a high negative predictive value for excluding venous thromboembolism outside of pregnancy but the use in pregnancy remains controversial. A higher cut-off value has been proposed in pregnancy due to a continuous increase across gestation. Fibrin monomer complexes have been considered as an alternative diagnostic tool for exclusion of venous thromboembolism in pregnancy due to their different behavior.

Objective: We sought to establish normal values of fibrin monomer complexes and D-dimer as a diagnostic tool for the exclusion of venous thromboembolism in pregnancy and examine the effect of maternal and obstetric factors on these markers.

Study Design: Plasma D-dimer and fibrin monomer complexes were measured by quantitative immunoturbidimetry in 2870 women with singleton pregnancies attending their routine first-trimester hospital visit in a prospective screening study for adverse obstetric outcome. Multiple regression analysis was used to determine maternal characteristics and obstetric factors affecting the plasma concentrations and converting these into multiple of the median values after adjusting for significant maternal and obstetric characteristics.

Results: Plasma fibrin monomer complexes increased with maternal weight and were lower in women with a history of cocaine abuse and chronic hypertension. D-dimers increased with gestational age and maternal weight and were higher in sickle cell carriers and in women of African and South Asian racial origin compared to Caucasians.

Conclusion: Fibrin monomer complexes and D-dimers are affected by maternal and obstetric characteristics rather than only gestational age. The utility of these fibrin-linked markers as a tool for exclusion of venous thromboembolism in pregnancy might be improved by adjusting for patient-specific characteristics.
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http://dx.doi.org/10.1016/j.ajog.2016.05.013DOI Listing
October 2016

Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus.

N Engl J Med 2016 Feb;374(5):434-43

From the Harris Birthright Research Centre for Fetal Medicine, King's College Hospital (A.S., K.H.N., R.A., R.K., A.P.), and the Departments of Endocrinology (J.B., S.H.) and Maternal Medicine (H.S.), Epsom and St. Helier University Hospitals NHS Trust, London, and the Department of Fetal Medicine, Medway Maritime Hospital, Gillingham, Kent (R.A.) - all in the United Kingdom.

Background: Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin.

Methods: In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle.

Results: A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, -0.71 to 0.92] and 0.17 in the placebo group [interquartile range, -0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.

Conclusions: Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. (Funded by the Fetal Medicine Foundation; ClinicalTrials.gov number, NCT01273584; EudraCT number, 2008-005892-83.).
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http://dx.doi.org/10.1056/NEJMoa1509819DOI Listing
February 2016

Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11-13 weeks gestation.

Am J Obstet Gynecol 2016 Jan 19;214(1):103.e1-103.e12. Epub 2015 Aug 19.

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

Background: Preeclampsia affects approximately 3% of all pregnancies and is a major cause of maternal and perinatal morbidity and death. In the last decade, extensive research has been devoted to early screening for preeclampsia with the aim of reducing the prevalence of the disease through pharmacologic intervention in the high-risk group starting from the first trimester of pregnancy.

Objective: The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history (maternal factors) and biomarkers.

Study Design: The data for this study were derived from prospective screening for adverse obstetric outcomes in women who attended for their routine first hospital visit at 11-13 weeks gestation in 2 maternity hospitals in England. We screened 35,948 singleton pregnancies that included 1058 pregnancies (2.9%) that experienced preeclampsia. Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A, and placental growth factor multiple of the median values. Five-fold cross validation was used to assess the performance of screening for preeclampsia that delivered at <37 weeks gestation (preterm-preeclampsia) and ≥37 weeks gestation (term-preeclampsia) by models that combined maternal factors with individual biomarkers and their combination with screening by maternal factors alone.

Results: In pregnancies that experienced preeclampsia, the values of uterine artery pulsatility index and mean arterial pressure were increased, and the values of serum pregnancy-associated plasma protein-A and placental growth factor were decreased. For all biomarkers, the deviation from normal was greater for early than late preeclampsia; therefore, the performance of screening was related inversely to the gestational age at which delivery became necessary for maternal and/or fetal indications. Combined screening by maternal factors, uterine artery pulsatility index, mean arterial pressure, and placental growth factor predicted 75% (95% confidence interval, 70-80%) of preterm-preeclampsia and 47% (95% confidence interval, 44-51%) of term-preeclampsia, at a false-positive rate of 10%; inclusion of pregnancy-associated plasma protein-A did not improve the performance of screening. Such detection rates are superior to the respective values of 49% (95% confidence interval, 43-55%) and 38% (34-41%) that were achieved by screening with maternal factors alone.

Conclusion: Combination of maternal factors and biomarkers provides effective first-trimester screening for preterm-preeclampsia.
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http://dx.doi.org/10.1016/j.ajog.2015.08.034DOI Listing
January 2016

Validation of metabolomic models for prediction of early-onset preeclampsia.

Am J Obstet Gynecol 2015 Oct 23;213(4):530.e1-530.e10. Epub 2015 Jun 23.

Department of Obstetrics and Gynecology, King's College Hospital, London, United Kingdom.

Objective: We sought to perform validation studies of previously published and newly derived first-trimester metabolomic algorithms for prediction of early preeclampsia (PE).

Study Design: Nuclear magnetic resonance-based metabolomic analysis was performed on first-trimester serum in 50 women who subsequently developed early PE and in 108 first-trimester controls. Random stratification and allocation was used to divide cases into a discovery group (30 early PE and 65 controls) for generation of the biomarker model(s) and a validation group (20 early PE and 43 controls) to ensure an unbiased assessment of the predictive algorithms. Cross-validation testing on the different algorithms was performed to confirm their robustness before use. Metabolites, demographic features, clinical characteristics, and uterine Doppler pulsatility index data were evaluated. Area under the receiver operator characteristic curve (AUC), 95% confidence interval (CI), sensitivity, and specificity of the biomarker models were derived.

Results: Validation testing found that the metabolite-only model had an AUC of 0.835 (95% CI, 0.769-0.941) with a 75% sensitivity and 74.4% specificity and for the metabolites plus uterine Doppler pulsatility index model it was 0.916 (95% CI, 0.836-0.996), 90%, and 88.4%, respectively. Predictive metabolites included arginine and 2-hydroxybutyrate, which are known to be involved in vascular dilation, and insulin resistance and impaired glucose regulation, respectively.

Conclusion: We found confirmatory evidence that first-trimester metabolomic biomarkers can predict future development of early PE.
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http://dx.doi.org/10.1016/j.ajog.2015.06.044DOI Listing
October 2015

Endoscopic Placental Laser Coagulation in Monochorionic Diamniotic Twins with Type II Selective Fetal Growth Restriction.

Fetal Diagn Ther 2015 15;38(2):86-93. Epub 2015 Apr 15.

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

Objective: To determine predictors of survival in monochorionic diamniotic twins with selective fetal growth restriction type II (sFGR-II), with or without twin-to-twin transfusion syndrome (TTTS), treated by endoscopic placental laser coagulation.

Methods: Laser surgery was performed at 20 (15-27) weeks' gestation in 405 cases of sFGR-II with and 142 without coexisting TTTS. Multivariable logistic regression analysis was performed to determine significant predictors of survival to discharge from hospital.

Results: There was survival of the small twin in 216 (39.5%) and of the large twin in 379 (69.3%) cases. Significant predictors of survival of both the small and larger twin were ductus venosus Doppler findings in the small twin, gestational age at laser and cervical length, but not the presence of TTTS or Doppler findings in the large twin.

Conclusions: In sFGR-II, survival after laser surgery is primarily dependent on the condition of the small twin.
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http://dx.doi.org/10.1159/000374109DOI Listing
May 2016

Competing risks model in screening for preeclampsia by maternal characteristics and medical history.

Am J Obstet Gynecol 2015 Jul 25;213(1):62.e1-62.e10. Epub 2015 Feb 25.

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

Objective: The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history.

Study Design: This was a screening study of 120,492 singleton pregnancies at 11-13 weeks' gestation, including 2704 pregnancies (2.2%) that experienced preeclampsia. A survival-time model for the gestational age at delivery with preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of preeclampsia. A 5-fold cross validation study was conducted to compare the performance of the new model with the National Institute for Health and Clinical Excellence (NICE) guidelines.

Results: In the new model, increased risk for preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of preeclampsia, and conception by in vitro fertilization. The risk for preeclampsia decreases with increasing maternal height and in parous women with no previous preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total preeclampsia and preeclampsia requiring delivery at <37 and <34 weeks' gestation, respectively, which were significantly higher than the respective values of 35%, 40%, and 44% achieved by application of NICE guidelines.

Conclusion: A new model that is based on maternal characteristics and medical history has been developed for the estimation of patient-specific risks for preeclampsia. Such estimation of the a priori risk for preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease.
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http://dx.doi.org/10.1016/j.ajog.2015.02.018DOI Listing
July 2015

First-Trimester Screening for Gestational Diabetes Mellitus Based on Maternal Characteristics and History.

Fetal Diagn Ther 2015 18;38(1):14-21. Epub 2014 Dec 18.

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

Objectives: To develop and validate a prediction model for gestational diabetes mellitus (GDM) at 11-13 weeks' gestation based on maternal characteristics and history and to compare its performance with the method recommended by the National Institute of Health and Care Excellence (NICE) and five other published prediction models.

Methods: A predictive logistic regression model for GDM was developed from 1,827 cases (2.4%) who developed GDM and 73,334 unaffected controls. A 5-fold cross-validation study was performed to validate this model and to compare its performance with those of the NICE guidelines and the previously published models.

Results: In the logistic regression model, maternal age, weight, height, racial origin, family history of diabetes, use of ovulation drugs, birth weight, and previous history of GDM were found to be significant predictors of GDM. In screening for GDM in the 5-fold cross-validation study, detection rates (DRs) were higher (p < 0.0001) for the proposed model (DR = 83.2%) than for the NICE guidelines (DR = 77.5%) for a false positive rate of approximately 40% (determined by NICE). The area under the receiver operating characteristic curve of the new model was higher (p < 0.0001) than that of the previous five models (0.823 vs. 0.688-786).

Conclusions: Early effective screening for GDM can be achieved based on maternal characteristics and history.
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http://dx.doi.org/10.1159/000369970DOI Listing
May 2016

Size-based molecular diagnostics using plasma DNA for noninvasive prenatal testing.

Proc Natl Acad Sci U S A 2014 Jun 19;111(23):8583-8. Epub 2014 May 19.

Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China;Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China;

Noninvasive prenatal testing using fetal DNA in maternal plasma is an actively researched area. The current generation of tests using massively parallel sequencing is based on counting plasma DNA sequences originating from different genomic regions. In this study, we explored a different approach that is based on the use of DNA fragment size as a diagnostic parameter. This approach is dependent on the fact that circulating fetal DNA molecules are generally shorter than the corresponding maternal DNA molecules. First, we performed plasma DNA size analysis using paired-end massively parallel sequencing and microchip-based capillary electrophoresis. We demonstrated that the fetal DNA fraction in maternal plasma could be deduced from the overall size distribution of maternal plasma DNA. The fetal DNA fraction is a critical parameter affecting the accuracy of noninvasive prenatal testing using maternal plasma DNA. Second, we showed that fetal chromosomal aneuploidy could be detected by observing an aberrant proportion of short fragments from an aneuploid chromosome in the paired-end sequencing data. Using this approach, we detected fetal trisomy 21 and trisomy 18 with 100% sensitivity (T21: 36/36; T18: 27/27) and 100% specificity (non-T21: 88/88; non-T18: 97/97). For trisomy 13, the sensitivity and specificity were 95.2% (20/21) and 99% (102/103), respectively. For monosomy X, the sensitivity and specificity were both 100% (10/10 and 8/8). Thus, this study establishes the principle of size-based molecular diagnostics using plasma DNA. This approach has potential applications beyond noninvasive prenatal testing to areas such as oncology and transplantation monitoring.
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http://dx.doi.org/10.1073/pnas.1406103111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060699PMC
June 2014

A new direction for prenatal chromosome microarray testing: software-targeting for detection of clinically significant chromosome imbalance without equivocal findings.

PeerJ 2014 22;2:e354. Epub 2014 Apr 22.

Cytogenetics, Guy's & St Thomas' NHS Foundation Trust , London , UK ; King's College , London , UK.

Purpose. To design and validate a prenatal chromosomal microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of copy number variants (CNVs) of unclear prognosis that cause parental anxiety. Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n = 342) were tested by chromosomal microarray and only CNVs of established deletion/duplication syndrome regions and any other CNV >3 Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy. Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 CNVs were detected in 44 of these cases (17.7%). None of these additional CNVs were of clear clinical significance. Conclusion. This prenatal chromosomal microarray strategy detected all CNVs of clear prognostic value and did not miss any CNVs of clear clinical significance. This strategy avoided both the problems associated with interpreting CNVs of uncertain prognosis and the parental anxiety that are a result of such findings.
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http://dx.doi.org/10.7717/peerj.354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006225PMC
May 2014

Replacing the combined test by cell-free DNA testing in screening for trisomies 21, 18 and 13: impact on the diagnosis of other chromosomal abnormalities.

Fetal Diagn Ther 2014 8;35(3):174-84. Epub 2014 Feb 8.

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

Objective: To estimate the proportion of other chromosomal abnormalities that could be missed if combined testing was replaced by cell-free (cf) DNA testing as the method of screening for trisomies 21, 18 and 13.

Methods: The prevalence of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities was examined in pregnancies undergoing first-trimester combined screening and chorionic villus sampling (CVS).

Results: In 1,831 clinically significant chromosomal abnormalities in pregnancies with combined risk for trisomies 21, 18 and 13≥1:100, the contribution of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities at high risk of adverse outcome was 82.9, 8.2, 3.9 and 5.0%, respectively. Combined screening followed by CVS for risk≥1:10 and cfDNA testing for risk 1:11-1:2,500 could detect 97% of trisomy 21 and 98% of trisomies 18 and 13. Additionally, 86% of monosomy X, half of 47,XXY, 47,XYY or 47,XXX, half of other chromosomal abnormalities and one third of triploidies, which are currently detected by combined screening and CVS for risk≥1:100, could be detected.

Conclusions: Screening by cfDNA testing, contingent on results of combined testing, improves detection of trisomies, but misses a few of the other chromosomal abnormalities detected by screening with the combined test.
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http://dx.doi.org/10.1159/000358388DOI Listing
February 2015

Pregnancy Loss Following Amniocentesis or CVS Sampling-Time for a Reassessment of Risk.

J Clin Med 2014 Jul 8;3(3):741-6. Epub 2014 Jul 8.

Medway Maritime Hospital, Gillingham, Kent ME7 5NY, UK.

Risk of procedure-related pregnancy loss is currently widely quoted in the UK as 1% for amniocentesis and 1.5% for chorionic villus sampling. Published data suggest that these risk figures are out of date and inaccurate, and that new guidelines are required for pre-test counseling. It is our opinion that accurate and evidence-based information concerning miscarriage risk is vital when counseling women, as exaggeration of this risk may deter women from testing, or cause unjustified remorse if a miscarriage ensues. It is also essential that health-care economists are aware of the up-to-date evidence on "procedure-related risk" when applying risk-benefit analysis to assess new technology for non-invasive screening.
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http://dx.doi.org/10.3390/jcm3030741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449654PMC
July 2014