Publications by authors named "Ioannis Papastefanou"

28 Publications

  • Page 1 of 1

Competing risks model for prediction of small-for-gestational-age neonates from biophysical markers at 19 to 24 weeks' gestation.

Am J Obstet Gynecol 2021 Apr 24. Epub 2021 Apr 24.

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

Background: Antenatal identification of women at high risk to deliver small-for-gestational-age neonates may improve the management of the condition. The traditional but ineffective methods for small-for-gestational-age screening are the use of risk scoring systems based on maternal demographic characteristics and medical history and the measurement of the symphysial-fundal height. Another approach is to use logistic regression models that have higher performance and provide patient-specific risks for different prespecified cutoffs of birthweight percentile and gestational age at delivery. However, such models have led to an arbitrary dichotomization of the condition; different models for different small-for-gestational-age definitions are required and adding new biomarkers or examining other cutoffs requires refitting of the whole model. An alternative approach for the prediction of small-for-gestational-age neonates is to consider small for gestational age as a spectrum disorder whose severity is continuously reflected in both the gestational age at delivery and z score in birthweight for gestational age.

Objective: This study aimed to develop a new competing risks model for the prediction of small-for-gestational-age neonates based on a combination of maternal demographic characteristics and medical history with sonographic estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure at 19 to 24 weeks' gestation.

Study Design: This was a prospective observational study of 96,678 women with singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks' gestation, which included recording of estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure. The competing risks model for small for gestational age is based on a previous joint distribution of gestational age at delivery and birthweight z score, according to maternal demographic characteristics and medical history. The likelihoods of the estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure were fitted conditionally to both gestational age at delivery and birthweight z score and modified the previous distribution, according to the Bayes theorem, to obtain an individualized posterior distribution for gestational age at delivery and birthweight z score and therefore patient-specific risks for any desired cutoffs for birthweight z score and gestational age at delivery. The model was internally validated by randomly dividing the data into a training data set, to obtain the parameters of the model, and a test data set, to evaluate the model. The discrimination and calibration of the model were also examined.

Results: The estimated fetal weight was described using a regression model with an interaction term between gestational age at delivery and birthweight z score. Folded plane regression models were fitted for uterine artery pulsatility index and mean arterial pressure. The prediction of small for gestational age by maternal factors was improved by adding biomarkers for increasing degree of prematurity, higher severity of smallness, and coexistence of preeclampsia. Screening by maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure, predicted 41%, 56%, and 70% of small-for-gestational-age neonates with birthweights of <10th percentile delivered at ≥37, <37, and <32 weeks' gestation, at a 10% false-positive rate. The respective rates for a birthweight of <3rd percentile were 47%, 65%, and 77%. The rates in the presence of preeclampsia were 41%, 72%, and 91% for small-for-gestational-age neonates with birthweights of <10th percentile and 50%, 75%, and 92% for small-for-gestational-age neonates with birthweights of <3rd percentile. Overall, the model was well calibrated. The detection rates and calibration indices were similar in the training and test data sets, demonstrating the internal validity of the model.

Conclusion: The performance of screening for small-for-gestational-age neonates by a competing risks model that combines maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure was superior to that of screening by maternal characteristics and medical history alone.
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http://dx.doi.org/10.1016/j.ajog.2021.04.247DOI Listing
April 2021

Fetally-injected drugs for immobilization and analgesia do not modify fetal brain development in a rabbit model.

Prenat Diagn 2021 Apr 23. Epub 2021 Apr 23.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven, Belgium.

Objective: During fetal surgery, fetuses receive medication (atropine-fentanyl-curare) to prevent fetal pain, movement and bradycardia. Although essential there has been no detailed review of potential side effects. Herein we aimed to assess the effects of this medication cocktail on fetal brain development in a rabbit model.

Methods: Pregnant does underwent laparotomy at 28 days of gestation. Two pups of each horn were randomized to an ultrasound guided injection with medication (atropine-cisatracurium-fentanyl, as clinically used) or saline (sham). The third pup was used as control. At term, does were delivered by cesarean. Outcome measures were neonatal biometry, neuromotoric functioning and neuro-histology (neuron density, synaptic density and proliferation).

Results: Maternal vital parameters remained stable during surgery. Fetal heart rates did not differ before and after injection, and were comparable for the three groups. At birth, neonatal body weights and brain-to-body weight ratios were also comparable. Both motor and sensory neurobehavioral scores were comparable. There were no differences in neuron density or proliferation. Sham pups, had a lower synaptic density in the hippocampus as compared to the medication group, however there was no difference in the other brain areas.

Conclusion: In the rabbit model, fetal medication does not appear to lead to short-term neurocognitive effects.
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http://dx.doi.org/10.1002/pd.5954DOI Listing
April 2021

Incidence and patterns of abnormal corpus callosum in fetuses with isolated spina bifida aperta.

Prenat Diagn 2021 Mar 30. Epub 2021 Mar 30.

Department of Development and Regeneration, Cluster Woman and Child, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: To determine the incidence and characterise corpus callosum (CC) abnormalities in fetuses with spina bifida aperta (SBA) between 18 and 26 weeks of gestation.

Methods: This was a retrospective study on fetuses with isolated SBA and who were assessed for fetal surgery. Digitally stored ultrasound images of the brain were reviewed for the presence/absence of the CC, and the length and diameter of its constituent parts (rostrum, genu, body and splenium). We used regression analysis to determine the relationship between CC abnormalities and gestational age, head circumference, ventricle size, lesion level and lesion type.

Results: Nearly three-quarters of fetuses with isolated SBA had an abnormal CC (71.7%, 76/106). Partial agenesis was most common in the splenium (18.9%, 20/106) and the rostrum (13.2%, 14/106). The most common abnormal pattern was of a short CC with normal diameter throughout. Of note, 20.8% (22/106) had a hypoplastic genu and 28.3% (30/106) had a thick body part. Larger lateral ventricle size was associated with partial agenesis of the CC (odds ratio [OR]: 0.14, p < 0.001) and inversely associated with a shorter CC (OR: 2.60, p < 0.01).

Conclusion: An abnormal CC is common in fetuses with isolated SBA who are referred for fetal surgery.
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http://dx.doi.org/10.1002/pd.5945DOI Listing
March 2021

Placental volume at 11 to 14 gestational weeks in pregnancies complicated with fetal growth restriction and preeclampsia.

Prenat Diagn 2018 11 26;38(12):928-935. Epub 2018 Sep 26.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, Athens Medical School, National and Kapodistrian University of Athens, 'Attikon' University Hospital, Athens, Greece.

Objective: The study aims to evaluate the predictive value of first trimester placental volume in pregnancies destined to develop fetal growth restriction (FGR) and preeclampsia (PE).

Methods: Prospective observational study including placentas from 34 FGR, 12 PE, 15 GH (gestational hypertension) pregnancies, and 265 controls. Placental volume (PV) was obtained using VOCAL technique, and a z score was calculated (z-PV). The association of PV with other first trimester variables and maternal characteristics was assessed with Spearman's correlation.

Results: PV increased exponentially with crown-rump length (CRL) and was unrelated to maternal factors (weight, age, parity, and smoking status) as well as first trimester uterine artery Doppler, free β-hCG, nuchal translucency, or fetal heart rate. However, PV was positively associated with maternal height, CRL, PAPP-A, and birth weight. z-PV was a strong predictor for FGR with abnormal fetal Dopplers (AUC = 0.9472, P < 0.001). z-PV provided moderate prediction of FGR with normal fetal Dopplers (AUC = 0.8396, P < 0.001), PE (AUC = 0.8312, P < 0.001), and GH (AUC = 0.7640, P < 0.001). The addition of maternal weight, PAPP-A, β-hCG, and uterine artery Doppler improved our models.

Conclusion: At 11 to 14 weeks, PV is an independent predictor of pregnancy complications related to placental insufficiency, and the predictive ability is greater for FGR pregnancies with abnormal fetal Dopplers.
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http://dx.doi.org/10.1002/pd.5356DOI Listing
November 2018

Quality assessment of the detailed anomaly ultrasound scan.

J Matern Fetal Neonatal Med 2019 Feb 17;32(4):666-670. Epub 2017 Oct 17.

c Department of Mathematics and Statistics , Agricultural University of Athens , Athens , Greece.

Objectives: The objective of this study is to assess the quality of the views in the detailed anomaly ultrasound scan and examine the parameters that influence it.

Methods: Prospective study on singleton pregnancies examined at 20-24 weeks. Detailed views of all fetal organs were classified by the examiner as optimal/suboptimal. The duration of the examination was observed. Maternal characteristics, Fat Index (FI) (distance between the skin and the surface of the uterus), and fetal position were recorded.

Results: The study population consisted of 940 singleton pregnancies. Optimal visualization of all fetal structures was achieved in 66% of cases. Significant predictors were BMI, FI, and fetal position. None of the women with BMI ≥ 44 and none of the women with FI ≥ 60 mm had optimal visualization of all fetal structures. Median duration of the examination was 23 min. In 75% of cases, it was completed in the first attempt. Maternal weight, FI, and fetal position were the significant independent predictors of total examination time.

Conclusions: Optimal visualization of the fetal anatomy is restricted by maternal parameters and fetal position. The main limitation is accumulation of abdominal fat, usually but not always related to maternal obesity. The FI may be recorded as a measure of technical difficulty. The anomaly scan should be allocated at least 30 min scanning time.
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http://dx.doi.org/10.1080/14767058.2017.1388366DOI Listing
February 2019

Cervical length at 11-40 weeks: unconditional and conditional longitudinal reference ranges.

Acta Obstet Gynecol Scand 2016 Dec 3;95(12):1376-1382. Epub 2016 Nov 3.

Fetal Medicine Unit, Leto Maternity Hospital, Athens, Greece.

Introduction: Our aim was to establish unconditional and conditional longitudinal reference ranges for cervical length throughout pregnancy.

Material And Methods: Prospective longitudinal study. In singleton pregnancies repeated cervical length measurements were carried out by transvaginal ultrasound throughout gestation. Multilevel modeling was applied to establish cervical length reference ranges from 11 to 40 weeks.

Results: In all, 4397 women contributed to 13 765 cervical length measurements. A linear mixed effects random intercept-random slope model was fitted to the data. Mean cervical length had a negative non-linear polynomial association with gestational age. Unconditional ranges were developed. Terms that allow the construction of personalized cervical length charts conditional to a previous measurement were calculated.

Conclusions: We constructed longitudinal reference charts for cervical length in singleton pregnancies. Cervical length should be adjusted according to specific gestational-age-dependent ranges. Individualization of cervical assessment is feasible by the application of charts conditional to previous measurements.
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http://dx.doi.org/10.1111/aogs.13025DOI Listing
December 2016

Second-Trimester Sonographic Diagnosis of Polymicrogyria.

J Ultrasound Med 2016 Oct;35(10):2296-9

Department of Fetal Medicine, Lito Maternity Hospital, Athens, Greece, Fetal Medicine Unit, Emvryomitriki Athens, Greece, Fetal Medicine Unit, Third Department of Obstetrics and Gynecology, University of Athens, Attikon University Hospital, Athens, Greece.

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http://dx.doi.org/10.7863/ultra.15.11074DOI Listing
October 2016

Prediction of Preterm Delivery by Late Cervical Length Measurement after 24 Weeks.

Fetal Diagn Ther 2015 15;38(3):200-4. Epub 2015 Sep 15.

Fetal Medicine Unit, Leto Maternity Hospital, Athens, Greece.

Objective: To examine the value of the cervical length (CL) measurement at 24-30 gestational weeks in the prediction of spontaneous preterm delivery (SPD) between 30 and 34 weeks (SPD34) and between 34 and 37 weeks (SPD37).

Methods: We performed a prospective cross-sectional study. CL was measured once by transvaginal ultrasound examination between 24 and 30 weeks.

Results: The study sample consisted of 1,180 low-risk singleton pregnancies. 10 women (0.85%) had a SPD34 and 60 (5.08%) had a SPD37. CL was shorter (p < 0.001) in the women who had a SPD34 (median 11 mm) compared to the women who delivered after 34 weeks (median 31 mm). CL was shorter (p < 0.001) in the women who had a SPD37 (median 22 mm) compared to the women who delivered after 37 weeks (median 31 mm). CL predicted SPD34 (OR = 0.837, R² = 0.2768, AUC = 0.9406, p < 0.001) and SPD37 (OR = 0.907, R² = 0.1085, AUC = 0.7584, p < 0.001). The model achieved a sensitivity of 70.0 and 38.3% for 10% false-positive rate for SPD34 and SPD37, respectively.

Conclusions: CL after 24 weeks is significantly shorter in women destined to have a SPD. In low-risk singleton pregnancies CL performs very well in predicting SPD34 and adequately in predicting SPD37.
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http://dx.doi.org/10.1159/000381144DOI Listing
September 2016

Maternal serum osteocalcin at 11-14 weeks of gestation in gestational diabetes mellitus.

Eur J Clin Invest 2015 Oct 24;45(10):1025-31. Epub 2015 Aug 24.

1st Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece.

Background: Recent studies support that osteocalcin (OC), apart from its skeletal role, is implicated in glucose homoeostasis. Aims of this study were to examine the first-trimester maternal serum concentrations of OC in pregnancies that developed gestational diabetes mellitus (GDM) and to create a first-trimester prediction model for GDM.

Design: Case-control study in a prospective cohort of pregnant women. Maternal serum levels of OC were measured in 40 cases that developed GDM and 94 unaffected controls. First-trimester biophysical parameters, biochemical indices, maternal-pregnancy characteristics, and OC concentrations were assessed in relation to GDM occurrence.

Results: In the GDM group, first-trimester OC serum levels were increased compared to the control group (mean = 8·81 ng/mL, SD = 2·59 vs. mean = 7·34 ng/ml, SD = 3·04, P = 0·0058). Osteocalcin was independent of first-trimester biophysical and biochemical indices. Osteocalcin alone (OR = 1·21, CI: 1·02-1·43, P = 0·023) was a significant predictor of GDM [Model R(2) = 0·04, area under the curve (AUC) = 0·61, CI: 0·55-0·72, P < 0·001]. The combination of maternal and pregnancy characteristics with OC resulted in an improved prediction model for GDM (Model R(2) = 0·21, AUC = 0·80, CI: 0·71-0·88, P < 0·001). The combined model yields a sensitivity of 72·2% for 25% false-positive rate.

Conclusions: First-trimester maternal serum levels of OC are increased in GDM pregnancies. Osteocalcin combined with maternal and pregnancy characteristics provides an effective screening for GDM at 11-14 weeks.
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http://dx.doi.org/10.1111/eci.12500DOI Listing
October 2015

Towards detecting open spina bifida in the first trimester: the examination of the posterior brain.

Fetal Diagn Ther 2015 18;37(4):294-300. Epub 2015 Feb 18.

1st Department of Obstetrics and Gynecology, Alexandra Maternity Hospital, Athens, Greece.

Introduction: Our aim was to examine the value of indirect signs of open spina bifida in the mid-sagittal view of the posterior brain at the 11-13 weeks' ultrasound examination and to summarize the current evidence for the first-trimester diagnosis of spina bifida.

Methods: This was a prospective study in routine obstetric population. The presence of four almost parallel lines (four-line view) in the posterior brain was recorded. Biparietal diameter (BPD), intracranial translucency (IT) and cisterna magna (CM) were measured. The ratio of IT to CM (R ratio) was calculated.

Results: 2,491 pregnancies were examined prospectively. Updated reference ranges for IT and CM were constructed. There were 3 cases with open spina bifida, and the four-line view was abnormal in 2 of them. The abnormal fetuses had smaller BPD as well as pronounced reduction in the CM and increase in the R ratio.

Discussion: Examination of the posterior brain was feasible in all fetuses in the setting of the routine 11-13 weeks' ultrasound examination. Indirect signs of spina bifida are visible in the mid-sagittal view of the posterior brain, and the assessment of these structures can be a reliable tool in the early identification of this abnormality.
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http://dx.doi.org/10.1159/000365920DOI Listing
February 2016

First trimester cervical length is associated with mid-trimester loss.

J Matern Fetal Neonatal Med 2016 8;29(1):51-4. Epub 2014 Dec 8.

a Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology , Athens Medical School, National and Kapodistrian University of Athens, 'Attikon' University Hospital , Athens , Greece .

Objective: To study the value of the cervical length (CL) measurement at 11-14 weeks in predicting second trimester miscarriage occurring at 16-24 weeks.

Methods: Prospective study in routine obstetric population using transvaginal ultrasound examination to measure the length of the endocervical canal at 11-14 weeks.

Results: The study group consisted of 2836 singleton pregnancies. Eleven (0.0038%) women miscarried between 16 and 24 weeks whereas 2825 delivered after 34 weeks. CL was significantly shorter (Mann-Whitney U test, p = 0.001), in women that had a second trimester miscarriage in comparison to those who delivered after 34 weeks (median CL 28 mm versus 32 mm, respectively). First trimester CL was predictive of a late miscarriage (OR = 0.7093304, R(2 )= 0.1211, AUC = 0.7838, p < 0.001). The detection rate was 63.64% for 20% screen positive rate.

Conclusions: First trimester endocervix is significantly shorter in women destined to miscarry between 16 and 24 weeks. In low risk singleton pregnancies, first trimester CL can be useful in predicting second trimester miscarriage.
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http://dx.doi.org/10.3109/14767058.2014.986449DOI Listing
September 2016

Elevated placental growth factor concentrations at 11-14 weeks of gestation to predict gestational diabetes mellitus.

Metabolism 2014 Nov 5;63(11):1419-25. Epub 2014 Aug 5.

First Department of Pediatrics, University of Athens Medical School, Athens, Aghia Sophia Children's Hospital, Athens, Greece.

Objective: To examine maternal serum concentrations of placental growth factor (PlGF) at 11-14 gestational weeks in pregnancies that developed gestational diabetes mellitus (GDM) and to create first trimester prediction models for GDM.

Methods: Case control study including 40 GDM cases and 94 controls. PlGF, biophysical and biochemical markers and maternal-pregnancy characteristics were analyzed.

Results: Log10 transformed PlGF (log10 PlGF) was not related to maternal factors. Log10 PlGF was increased (p=0.008) in the GDM group compared to the control group. Log10 PlGF was associated with fasting glucose levels (p=0.04) in the oral glucose tolerance test. Log10 PlGF had a strong relation with birth weight adjusted for gestational age in the control but not in the GDM group. Maternal weight and maternal age were the only predictors of GDM among the maternal factors [area under the curve (AUC)=0.73, p<0.001]. Log10 PlGF alone was a significant predictor of GDM (AUC=0.63, p<0.001). Combination of maternal weight, maternal age and log10 PlGF resulted in an improved prediction (DR=71.4%, for 25% FPR, AUC=0.78, Model R(2)=0.17, p<0.001).

Conclusion: At 11-14weeks in pregnancies that develop GDM, the maternal serum levels of PlGF are increased. Measurement of serum PlGF at 11-14weeks improves the performance of early screening for GDM provided by maternal factors alone.
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http://dx.doi.org/10.1016/j.metabol.2014.07.016DOI Listing
November 2014

Predicting fetal growth deviation in parous women: combining the birth weight of the previous pregnancy and third trimester ultrasound scan.

J Perinat Med 2015 Jul;43(4):485-92

Aim: To investigate the value of the birth weight of the previous pregnancy (BW1) alone and combined with the third trimester ultrasonographically estimated fetal weight (EFW) and Doppler studies in the prediction of small (SGA) and large for gestational age (LGA) neonates in the index pregnancy (BW2).

Method: Some 1298 parous women with uncomplicated singleton pregnancies who had a third trimester ultrasound scan were considered as samples in this retrospective cohort study. Maternal and pregnancy characteristics, BW1, EFW, umbilical artery, and middle cerebral artery pulsatility indices were investigated as predictors of SGA and LGA.

Results: BW1, maternal weight, mode of conception, and smoking status were associated with BW2 (R2=0.39) with BW1 being the strongest predictor (R2=0.37). The addition of EFW conferred significant improvement (R2=0.63), whereas the addition of the Doppler indices did not. The sensitivity of BW1 alone in the prediction of SGA was 75% for 25% screen positive rate and increased to 92% with the addition of EFW. The equivalent figures for LGA were 68% and 93%, respectively.

Conclusions: BW1 used as a continuous variable is predictive of growth deviations in the index pregnancy. Incorporating EFW enhanced the sensitivity for the detection of both conditions.
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http://dx.doi.org/10.1515/jpm-2013-0308DOI Listing
July 2015

Screening for birth weight deviations by second and third trimester ultrasound scan.

Prenat Diagn 2014 Aug 25;34(8):759-64. Epub 2014 Apr 25.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, 'Attikon' University Hospital, Athens, Greece.

Objective: The aim of this article was to predict small for gestational age (SGA, at or less than the fifth birth weight percentile) and large for gestational age (LGA, at or greater than the 95th birth weight percentile) fetuses by using maternal and fetal parameters from the second and third trimester ultrasound examinations.

Method: This article is a retrospective cohort study on 1979 singleton pregnancies that had a routine 20 to 24 weeks anomaly and a 30 to 34 weeks growth ultrasound scans. SGA delivered before 30 gestational weeks were excluded.

Results: Second trimester estimated fetal weight (EFW2 ), uterine arteries pulsatility index (PI), and maternal pregnancy characteristics were predictive for SGA (SGA second trimester model: R(2)  = 0.225, area under the curve [AUC] = 0.815) and LGA (LGA second trimester model: R(2)  = 0.203, AUC = 0.793). Third trimester EFW (EFW3 ), EFW2 , uterine arteries PI2 , umbilical PI, and maternal pregnancy characteristics improved the prediction of SGA (SGA combined model: R(2)  = 0.423, AUC = 0.896) and LGA (LGA combined model: R(2)  = 0.383, AUC = 0.882). Contingent screening with risk stratification by the second trimester model performed equally well for SGA (AUC = 0.882) and LGA (AUC = 0.861) as the combined models.

Conclusion: Second trimester model performs well in the prediction of SGA and LGA. The addition of third trimester scan offers substantial improvement. Contingency screening is feasible with similar effectiveness.
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http://dx.doi.org/10.1002/pd.4361DOI Listing
August 2014

Reproducibility study of fetal 3-D volumetry in the first trimester: effect of fetal size and rotational angle of VOCAL software.

Ultrasound Med Biol 2014 May 10;40(5):877-83. Epub 2014 Jan 10.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, Attikon University Hospital, Athens, Greece.

Intra- and inter-observer reproducibility of fetal volume measurement by 3-D ultrasound scan (using VOCAL [Virtual Organ Computer-Aided Analysis] software) in 27 fetuses at 7 to 13 wk was studied. For intra-observer variability, the mean difference (MD) and 95% limits of agreement (95% LOA) at 12°, 18° and 30° were MD(12) = 0.097, 95% LOA(12) = -0.87 to +1.06; MD(18) = 0.07, 95% LOA(18) = -1.31 to +1.45; and MD(30) = -0.07, 95% LOA(30) = -1.55 to +1.41. The standard deviation of the differences (SD(DIF)) increased with crown-rump length at 12° (p = 0.0016), 18° (p = 0.0011) and 30° (p = 0.02). For inter-observer variability, MD(12) = 0.15, 95% LOA(12) = -1.65 to +1.95; MD(18) = 0.042, 95% LOA(18) = -1.79 to +1.87; and MD(30) = 0.19, 95% LOA(30) = -1.24 to +1.62. SDDIF increased with crown-rump length at 18° (p = 0.0084) and 30° (p = 0.0073). The accuracy of fetal volume measurement was not influenced by rotational angle or fetal size. Precision deteriorated for wider rotational angles and larger fetuses.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2013.11.012DOI Listing
May 2014

Fetal volume at 11-14 gestational weeks: reference ranges and association with first trimester biochemical and biophysical markers.

J Perinat Med 2014 Jan;42(1):107-12

Aims: To establish reference ranges for fetal volume (FV) measured by three-dimensional ultrasound (3D-US) at 11-14 weeks of gestation and to examine the possible association of FV with maternal/pregnancy characteristics and biochemical parameters.

Methods: Prospective observational study on 240 fetuses at 11-14 weeks. FV was measured by 3D-US using Virtual Organ Computer-Aided Analysis. Pearson correlation coefficient (cc) and regression analysis were used.

Results: FV increased exponentially with crown rump length and was unrelated to maternal weight (cc=-0.137, P=0.071), age (cc=0.009, P=0.899), parity (0.76), smoking status (t-test, P=0.149) and mode of conception (t-test, P=0.8). Z-scores (z) of FV was not associated with z-mean uterine artery pulsatility index (cc=-0.026, P=0.733), log10 multiples of the median (MoM) free beta human chorionic gonadotrophin (cc=0.002, P=0.982), delta value (d) of nuchal translucency (cc=0.072, P=0.331) and d-fetal heart rate (cc=0.009, P=0.902), z-FV was significantly positively correlated with log10 MoM pregnancy associated plasma protein-A (PAPP-A; regression coefficient=1.420976, R2=0.0957, P<0.0001).

Conclusions: FV is strongly related to PAPP-A even after adjustment for crown rump length with a mechanism unrelated to placental perfusion. FV is independent of the vast majority of first trimester parameters; hence, it is a promising marker of early fetal growth.
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http://dx.doi.org/10.1515/jpm-2013-0158DOI Listing
January 2014

Specific formulas improve the estimation of fetal weight by ultrasound scan.

J Matern Fetal Neonatal Med 2014 May 19;27(7):737-42. Epub 2013 Sep 19.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, Attikon University Hospital , Athens , Greece and.

Objective: To develop and evaluate local, sex specific, small for gestational age (SGA) specific, large for gestational age (LGA) specific and combined (biometry, sex and Doppler indices) formulas for ultrasound estimated fetal weight (EFW).

Method: Low-risk singleton pregnancies that delivered within 7 days from ultrasound examination were assessed. A formula-generating group (1407 pregnancies) and a validation group (469 pregnancies) were created. Fractional regression analysis was used to develop the formulas. Systematic error, random error, fraction within the 10% of actual birth weight and Bland-Altman analysis were used.

Results: The local formula and the Hadlock formula with local co-efficients performed better than the Hadlock formula. The SGA-specific formula, the LGA-specific formula and the combined formula had the lower systematic error (MSE: +0.0022291, -0.4226888, +0.8386222, respectively) and the narrower 95% LOA (-292.8 to +292.23, -485.6 to +461.5, -425.7 to +450.46, respectively). The SGA- and the LGA-specific formulas had higher fraction within the 10% of actual birth weight (81.5% and 84%, respectively).

Conclusions: Local formulas improve the EFW calculation. The combined formula can further optimize the accuracy and precision. Application of specific formulas for the small and the large fetus had the most pronounced effect in improving fetal weight estimation.
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http://dx.doi.org/10.3109/14767058.2013.837877DOI Listing
May 2014

Performance of the ultrasound examination in the early and late third trimester for the prediction of birth weight deviations.

Prenat Diagn 2013 Oct 27;33(10):915-20. Epub 2013 Jun 27.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, 'Attikon' University Hospital, Athens, Greece; Fetal Medicine Unit, Leto Maternity Hospital, Athens, Greece.

Objectives: This study aimed to define the optimal gestational age in the third trimester, early (30-33 weeks + 6 days) versus late (34-37 weeks), for performing an ultrasound examination for fetal biometry to predict birth weight deviations: small for gestational age (SGA ≤ 5th centile) and large for gestational age (LGA ≥ 95th centile) neonates.

Methods: We used an observational cross-sectional study in uncomplicated singleton pregnancies that had a third trimester ultrasound for fetal biometry and umbilical and middle cerebral fetal Doppler studies. Estimated fetal weight and fetal Doppler parameters were the examined variables for the prediction of SGA and LGA.

Results: Three thousand six hundred ninety women had an early examination, and 2288 women had a late one. For a screen-positive rate of 10%, estimated fetal weight achieved 58% and 53.4% sensitivity for the prediction of SGA [area under the curve (AUC) = 0.8578, p < 0.001] and LGA (AUC = 0.8547, p < 0.001), respectively, by the early examination. Accordingly, the sensitivities significantly increased to 75.2% and 63.2% for the prediction of SGA (AUC = 0.9074, p < 0.001) and LGA (AUC = 0.8782, p < 0.001), respectively, by the late examination. The inclusion of the Doppler indices did not improve the predictive models.

Conclusions: A late third trimester ultrasound was superior in the prediction of SGA and LGA, and this improvement was more pronounced for the prediction of SGA.
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http://dx.doi.org/10.1002/pd.4161DOI Listing
October 2013

Assessment of the posterior brain at 11-14 weeks for the prediction of open neural tube defects.

Prenat Diagn 2012 Dec 4;32(12):1143-6. Epub 2012 Oct 4.

Department of Obstetrics and Gynecology, Rhodos General Hospital, Rhodes, Greece.

Objective: To evaluate the routine midsagittal view of the posterior brain at the 11-13 weeks' ultrasound examination, for predicting open neural tube defects.

Methods: Posterior brain was examined midsagittally for normality of the four-line view (upper and lower border of the brain stem, the choroid plexus of the fourth ventricle and the occipital bone). Intracranial translucency and cisterna magna (CM) were measured.

Results: The posterior brain was assessed in 1330 cases. The four-line view was normal in all but one case. In the two cases of open spina bifida contained in the study population, intracranial translucency was within normal range. The CM and the four-line view were normal in the first case, whereas in the second case, the four-line view was abnormal, and CM was obliterated and impossible to measure. No other cases of abnormal four-line view were observed in the study population.

Conclusion: Obliteration of the CM appears to be the most consistent early sign of open neural tube defects. Attention should focus on either measuring the cisterna magna or simply observing the presence of four lines in the midsagittal view of the posterior brain. However, these early signs of brain herniation are not present in all abnormal cases.
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http://dx.doi.org/10.1002/pd.3973DOI Listing
December 2012

Reproducibility study of crown-rump length and biparietal diameter measurements in the first trimester.

Prenat Diagn 2012 Dec 3;32(12):1158-65. Epub 2012 Oct 3.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, Attikon' University Hospital, Athens, Greece.

Objective: This study aims to investigate the intra-observer and inter-observer variability of crown-rump length (CRL) and biparietal diameter (BPD) measurements in the first trimester.

Methods: A prospective observational study on 592 fetuses between 8 and 14 gestational weeks was conducted. Intra-class correlation coefficients (ICCs) were computed, and Bland-Altman analysis was carried out.

Results: The ICCs (95% confidence interval) and the 95% limits of agreement, expressed as a percentage of the average, for CRL's intra-observer and inter-observer variability were 0.979 (0.974-0.982, p < 0.001), +8.53% to -8.376%, and 0.968 (0.952-0.978, p < 0.001), +9.06% to -7.69%, respectively. The corresponding figures for BPD were 0.981 (0.977-0.984, p < 0.001), +7.41% to -7.51%, and 0.968 (0.952-0.978, p < 0.001), +6.65% to -7.25%. After conversion in days, the ICCs and 95% limits of agreement for CRL's intra-observer and inter-observer variability were 0.983 (0.980-0.986, p < 0.001), +2.88% to -2.84%, and 0.971 (0.957-0.980, p < 0.001), 2.83% to -2.60%, respectively. The corresponding figures for BPD were 0.982 (0.979-0.986, p < 0.001), +3.36% to -3.40%, and 0.968 (0.953-0.978, p < 0.001), +3.06% to -3.38%. CRL's standard deviation of the differences increased with gestation for intra-observer (r = 0.289, p < 0.001) and inter-observer (r = 0.197, p = 0.023) variability.

Conclusion: The BPD and CRL are highly reproducible measurements. CRL's measurement error increased with the magnitude of CRL, whereas BPD's reproducibility was not affected by gestational age.
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http://dx.doi.org/10.1002/pd.3976DOI Listing
December 2012

Third trimester ultrasound for the prediction of the large for gestational age fetus in low-risk population and evaluation of contingency strategies.

Prenat Diagn 2012 Sep 25;32(9):846-53. Epub 2012 Jun 25.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, Attikon University Hospital, Athens, Greece.

Objective: Evaluation of the effectiveness of third trimester fetal biometry and Doppler studies in predicting the birth of a large for gestational age neonate (LGA ≥ 95(th) centile). Assessment of the value of integrated models (combining maternal characteristics, first trimester parameters, third trimester fetal biometry) and the usefulness of contingency strategies.

Method: Observational cross-sectional study on 2308 uncomplicated singleton pregnancies examined at 11 to 14 weeks and at 30 to 34 weeks.

Results: Ultrasound estimated fetal weight (EFW, area under the curve (AUC) = 0.83) was the best single predictor of LGA. Maternal weight, delta nuchal translucency and EFW were independent predictors for the integrated model, but the latter was not statistically better (AUC = 0.84) than using EFW alone. The detection rates for LGA were 72.5% and 73.7% for a 25% screen positive rate, by EFW and the third trimester integrated model respectively. A contingency strategy of rescanning 50% of the population in the third trimester according to the risk estimation by a first trimester prediction model results in detection rate of 64.7% for LGA for the same 25% screen positive rate (AUC = 0.78).

Conclusions: Third trimester ultrasound is an effective screening modality for identifying fetal macrosomia. A contingency strategy utilizing first trimester parameters can reduce the need for unnecessary examinations.
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http://dx.doi.org/10.1002/pd.3918DOI Listing
September 2012

Evaluation of a two-step ultrasound examination protocol for the detection of major fetal structural defects.

J Matern Fetal Neonatal Med 2012 Sep 9;25(9):1814-7. Epub 2012 Mar 9.

Fetal Medicine Unit, Leto Maternity Hospital, Athens, Greece.

Objective: To evaluate a two-step screening protocol of ultrasound examinations (11-14 and 20-24 weeks) for the detection of major fetal structural defects.

Methods: Retrospective study in a private maternity hospital. Women with viable singleton pregnancies having both first trimester scan and anomaly scan at our department and subsequently delivered at our hospital were included. Major fetal structural defects were defined as those requiring medical or surgical treatment or those causing mental handicap.

Results: A total of 3,902 pregnancies included 61 fetuses with structural defects (1.56%). Twenty-six (42.6%) were diagnosed in the first trimester and 29 (47.5%) in the second. Six anomalies were detected in the third trimester or after birth. Overall detection rate of the two-step program was 90.2%.

Conclusions: Detailed examination of fetal anatomy at 11-14 weeks resulted in the early diagnosis of about 40% of major structural defects.
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http://dx.doi.org/10.3109/14767058.2012.664199DOI Listing
September 2012

First trimester fetal ultrasound parameters associated with PAPP-A and fβ-hCG.

J Matern Fetal Neonatal Med 2012 Jul 7;25(7):1029-33. Epub 2011 Nov 7.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, Attikon University Hospital, Athens, Greece.

Objective: To study the association of fβ-hCG and PAPP-A measured at 11-14 weeks of gestation with delta crown-rump-length (dCRL), delta fetal heart rate (dFHR) and delta nuchal translucency (dNT). To calculate adjusted MoM taking into consideration these associations.

Methods: Retrospective cross-sectional study on 5,536 singleton euploid pregnancies participating in a first trimester screening program for chromosomal abnormalities by nuchal translucency and maternal serum biochemistry. Adjusted MoM were calculated for fβ-hCG and PAPP-A and compared to the observed MoM (calculated by the Fetal Medicine Foundation screening algorithm).

Results: fβ-hCG correlates positively with dCRL and negatively with dNT, whereas PAPP-A shows a positive correlation with dNT and a negative one with dCRL and dFHR. After adjustment for the ultrasound parameters, the median MoM values for fβ-hCG and PAPP-A changed from 1.02 and 0.92 observed MoM to 0.98 and 0.99 adjusted MoM respectively. The difference between the observed and adjusted MoM was statistically significant (p < 0.001). Delta CRL increases with gestation and this effect manifests mainly after CRL of 62 mm.

Conclusions: Adjustment for dCRL, dFHR and dNT improves the calculation of MoM for fβ-hCG and PAPP-A. CRL measurement overestimates fetal size at the end of the screening period 11-14 weeks.
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http://dx.doi.org/10.3109/14767058.2011.614656DOI Listing
July 2012

First trimester prediction of small- and large-for-gestation neonates by an integrated model incorporating ultrasound parameters, biochemical indices and maternal characteristics.

Acta Obstet Gynecol Scand 2012 Jan 18;91(1):104-11. Epub 2011 Oct 18.

Fetal Medicine Unit, 3rd Department of Obstetrics and Gynaecology, University of Athens, 'Attikon' University Hospital, Athens, Greece.

Objective: To identify maternal/pregnancy characteristics, first trimester ultrasound parameters and biochemical indices which are significant independent predictors of small-for-gestational age (SGA) and large-for-gestational age (LGA) neonates.

Design: Retrospective cross-sectional study.

Setting: Two fetal Medicine Units.

Population: 4 702 singleton pregnancies presenting for screening for chromosomal abnormalities by nuchal translucency and maternal serum biochemistry at 11-14 weeks.

Methods: Reference ranges for birthweight applied to our population were constructed by the Royston and Wright method. Multiple logistic regression was applied to develop first trimester prediction models for SGA and LGA.

Main Outcome Measures: Birth of SGA or LGA neonate.

Results: Maternal height, parity, smoking, assisted conception, delta crown-rump length, delta nuchal translucency, free beta human chorionic gonadotrophin and pregnancy-associated plasma protein-A were significant independent predictors of SGA. Maternal weight and height, smoking, delta crown-rump length and delta nuchal translucency were significant independent predictors of LGA. Models for SGA (AUC=0.7296, CI: 0.69-0.76, p<0.0001) and LGA (AUC=0.6901, CI: 0.65-0.72, p<0.0001) were derived, applicable to routine obstetric population at low risk for these conditions. For 20% screen positive rate the modeling achieves sensitivities of about 55% for SGA and 48% for LGA neonates.

Conclusion: Prediction for birthweight deviations is feasible using data available at the routine 11-14 weeks' examination. Delta CRL and delta nuchal translucency were significant independent predictors for both SGA and LGA.
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http://dx.doi.org/10.1111/j.1600-0412.2011.01271.xDOI Listing
January 2012

Cervical length changes from the first to second trimester of pregnancy, and prediction of preterm birth by first-trimester sonographic cervical measurement.

J Ultrasound Med 2011 Jul;30(7):997-1002

Third Department of Obstetrics and Gynecology, Attikon University Hospital, Rimini 1, Haidari, 124-62 Athens, Greece.

Objectives: The purpose of this study was to examine the evolution of cervical length from the first to second trimester of pregnancy and the value of first-trimester cervical measurement in the prediction of preterm delivery.

Methods: We conducted a longitudinal prospective study. Cervical length was measured by transvaginal sonography at 11 to 14 weeks (Cx1), 16 to 19 weeks (Cx2), and 20 to 24 weeks (Cx3).

Results: Eight hundred singleton pregnancies were studied. The median cervical lengths were 33 mm for Cx1 and 31 mm for Cx2 and Cx3. Significant independent predictors for cervical length were maternal weight, height, and history of cervical surgery for Cx1, maternal height, history of cervical surgery, and history of preterm delivery for Cx2, and history of cervical surgery, history of first-trimester miscarriage, and history of spontaneous preterm delivery for Cx3. Mean cervical length shortening was 2.36 mm between Cx1 and Cx3. In the subgroups of women with previous cervical surgery and history of previous preterm birth, cervical shortening was significantly more prominent. The median Cx1 was significantly shorter in the women who subsequently delivered preterm; Cx1 predicted preterm delivery before 34 weeks (odds ratio, 0.746; 95% confidence interval, 0.649-0.869) and preterm delivery before 32 weeks (odds ratio, 0.734; 95% confidence interval, 0.637-0.912).

Conclusions: Cervical length in the first trimester depends on maternal characteristics and a history of cervical surgery. The cervix exhibits minimal changes from 11 to 24 weeks for most women, although the shortening is more prominent in women with a history of cervical surgery or preterm delivery. First-trimester cervical length measurement can predict preterm delivery.
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http://dx.doi.org/10.7863/jum.2011.30.7.997DOI Listing
July 2011

Correlation between maternal first trimester plasma leptin levels and birth weight among normotensive and preeclamptic women.

J Matern Fetal Neonatal Med 2010 Dec 16;23(12):1435-43. Epub 2010 Mar 16.

Department of Obstetrics and Gynaecology, Tzaneio General Hospital, Pireaus, Greece.

Objective: To determine the connection between maternal first trimester serum leptin levels and newborn weight.

Methods: The study included 37 preeclamptic women and 53 normotensive women who considered the control group. Maternal blood samples were withdrawn at 13 weeks of gestation for the measurement of leptin concentrations. Birth weights were transformed to z-scores according to maternal and obstetrical features, based on customized centiles. Non-parametric tests, student's t-test, Pearson's correlation, Spearman's correlation and linear regression analysis were performed in our analysis.

Results: Pre-pregnancy body mass index and first trimester maternal plasma leptin levels were significantly higher among women with preeclampsia (p=0.015 and p<0.001, respectively). Birth weight z-score was negatively correlated with leptin levels (r= -0.570, p<0.001), in preeclamptic group and in control group (r= -0.477, p<0.001). The regression modelling demonstrated a significant negative association between birth weight z-scores and leptin for both groups.

Conclusion: Maternal first trimester serum leptin demonstrates a significant negative association with neonatal weight in preeclamptic pregnancies and to a lesser extent in normotensive pregnancies. A possible leptin's involvement in pathophysiological adaptations that define the foetal growth potential can be supported.
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http://dx.doi.org/10.3109/14767051003678283DOI Listing
December 2010

Relation between first trimester maternal serum leptin levels and body mass index in normotensive and pre-eclamptic pregnancies--role of leptin as a marker of pre-eclampsia: a prospective case-control study.

Gynecol Endocrinol 2010 May;26(5):338-43

Department of Obstetrics and Gynaecology. Tzaneio General Hospital, Pireaus, Greece.

Objective: We measured first trimester plasma leptin concentrations in 37 women who subsequently developed pre-eclampsia and 53 normotensive controls to determine the interrelation between leptin and body mass index (BMI) in both groups. We further investigated the association between the risks for pre-eclampsia with maternal leptin levels.

Methods: Bloods samples were collected at 13 weeks. Non-parametric tests, Spearman's correlation, linear regression analysis and multiple logistic regression analysis were applied in our data.

Results: 1 kg/m(2) increase in pre-pregnancy BMI was related to a 2.747 (95% CI: 3.242-2.252) ng/ml rise in leptin concentration among cases and 2.502 (95% CI: 2.873-2.131) ng/ml rise in leptin concentrations among controls. Increased leptin concentration (>or=25.3 ng/ml ) in lean women is associated with a 18.8-fold increased risk of pre-eclampsia (adjusted OR: 18.8, CI: 1.8-194, p = 0.014 ). Leptin treated as a continuous variable is a significant predictor of pre-eclampsia (adjusted OR: 1.08, CI: 1.018-1.133, p = 0.009).

Conclusion: Increased leptin concentration can definitely contribute to the prediction of pre-eclampsia in lean women, but this is not the case in overweight women. Further research in terms of longitudinal case-control studies is required to clarify the predictive value of pre-eclampsia.
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http://dx.doi.org/10.3109/09513590903511463DOI Listing
May 2010

Intracytoplasmic sperm injection--an assisted reproduction technique that should make us cautious about imprinting deregulation.

J Soc Gynecol Investig 2006 Jul;13(5):317-28

Laboratory of Physiology, School of Medicine, Democritus University of Thrace, Dragana, Alexandroupolis, Greece.

Objective: Due to the extensive use of intracytoplasmic sperm injection (ICSI) in assisted reproduction, not only among couples with severe male factor infertility problems, but to a broader scale, a lot of concern has been raised regarding the safety of the method and its implications in epigenetic control and imprinting dysregulation. This review means to provide a comprehensive report of the published scientific data, outline putative associations between ICSI and epigenetic control, and suggest measures to improve the current state of affairs and reach more scientifically consolidated results.

Methods: This review was conducted by studying a broad spectrum of articles dealing with the subject of epigenetic control and its relation with ICSI. We tried to view the two subjects as parallel procedures that occur in the organism and by delineating the molecular and biochemical steps that comprise them make suggestions about putative associations between ICSI and epigenetic control.

Conclusions: No hard evidence presented at the moment can prove or disapprove ICSI's implications in epigenetic control. Nevertheless, we take the view that more comprehensive, long-term, and properly designed studies are imperative to be applied on a large-scale basis. We urge cautiousness, since the welfare of our progeny is what is at stake.
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http://dx.doi.org/10.1016/j.jsgi.2006.04.002DOI Listing
July 2006