The role of the PLGF in the management of pregnancies complicated with fetal microsomia.

PURPOSE: To explore the contribution of maternal and fetal parameters in predicting the time interval between diagnosis and development of adverse events leading to delivery in singleton pregnancies complicated with fetal microsomia. METHODS: Prospective study on singleton pregnancies referred to a tertiary center because of suspicion of fetal smallness in the third trimester. The study cohort included cases with fetal abdominal circumference (AC) ≤ 10th centile or estimated fetal weight ≤ 10th centile or umbilical artery pulsatitlity index ≥ 90th centile. Development of pre-eclampsia, fetal demise, and fetal deterioration diagnosed by fetal Doppler studies or fetal heart rate monitoring and leading to delivery were considered as adverse events. Maternal demographics, obstetric history, blood pressure, serum PLGF, and fetal Doppler studies were explored as predictors of the time interval between the first visit to the clinic and the diagnosis of complications. RESULTS: In 59 women, the median incubation period from presentation to the clinic to an adverse event was 6, 2 weeks, whereas half of the pregnancies (52.5%) did not develop any adverse event. PLGF was the strongest predictor of adverse events. Both PLGF in raw values and PLGF MOM had equally good predictive ability (AUC 0.82 and 0.78 respectively). Optimal cut-off points were 177.7 pg/ml for PLGF raw values (sensitivity 83% and specificity 66.7%) and 0.277 MoM (sensitivity 76% and specificity 86.7%). On multiple Cox regression analysis, maternal systolic blood pressure, PLGF, fetal increased umbilical artery PI, and reduced CP ratio were independently associated with adverse events. Half of the pregnancies with low PLGF and only one in ten with high PLGF were delivered within two weeks after the initial visit. CONCLUSION: Half of the pregnancies carrying a small fetus in the third trimester will not develop maternal or fetal complications. PLGF is a strong predictor of adverse events that can be used to customize antenatal care.

The role of the PLGF in the prediction of the outcome in pregnancies with a small for gestational age fetus.

PURPOSE: To explore the value of measuring maternal serum PLGF in the prediction of the outcome of small for gestational age fetuses (SGA). METHODS: Singleton pregnancies referred with suspicion of SGA in the third trimester were included if they had: no indication for nor signs of imminent delivery, fetal abdominal circumference (AC) at or below the 10th centile and/or estimated fetal weight (EFW) at or below the 10th centile and/or umbilical artery pulsatility index (Umb-PI) at or above the 90th centile for gestation. Women with pre-eclampsia at presentation were excluded. Maternal blood was drawn at the first (index) visit and analyzed retrospectively. RESULTS: Fifty-one fetuses were examined. Multiple regression analysis showed that family history of microsomia, index EFW and PLGF were significant predictors of the birthweight centile; index femur length centile and PLGF were significant predictors of pre-eclampsia; PLGF and index systolic blood pressure were significant predictors of iatrogenic preterm delivery < 37 weeks, whereas PLGF and index EFW were significant predictors of birthweight ≤ 5th centile and admission to the neonatal intensive care unit. For all outcomes, the addition of maternal-fetal parameters did not improve the prediction compared to PLGF alone. Using a cutoff of 0.3 MoM for PLGF would identify 94.1% of the pregnancies with iatrogenic preterm delivery and/or intra-uterine death and all of the cases that developed pre-eclampsia, for a screen positive rate of 54.9%. Women with PLGF ≤ 0.3 MoM had a poor fetal/maternal outcome (iatrogenic preterm delivery, pre-eclampsia, intra-uterine death) in 61.5% of cases. CONCLUSION: In pregnancies complicated by SGA, PLGF identifies a very high-risk group that may benefit from intense surveillance.

The Incidence of the Agenesis of Fetal Ductus Venosus at the 11-13 Weeks' Ultrasound Examination.

OBJECTIVE: The objective is to examine the incidence of agenesis of fetal ductus venosus (DV) at the routine ultrasound examination at 11-13 weeks. MATERIALS AND METHODS: This is a retrospective study on women presenting for screening for chromosomal abnormalities. The fetal DV was routinely examined by color Doppler in the sagittal view. RESULTS: Out of 8,304 fetuses examined, there were 13 cases of DV agenesis (0.15%). The umbilical vein drainage was intra-hepatic in two-thirds of the cases, and all resulted in normal live births. In the remaining one-third of cases, the umbilical vein drained to the inferior vena cava and all had a poor outcome because of aneuploidies, cardiac defects, and Noonan syndrome. CONCLUSION: Fetal DV agenesis occurs in about one in 650 fetuses and the majority of cases have a benign course and a favorable outcome. Failure to identify the DV should prompt a detailed ultrasound examination, identification of the drainage site of the umbilical vein, and genetic testing.

Screening vs. no screening for preterm delivery in low-risk singleton pregnancies: comparison by propensity score analysis.

PURPOSE: To compare the effect of a policy of screening for spontaneous preterm delivery (SPD) by transvaginal cervical length (CL) measurement versus a no screening policy in the prevention of severe prematurity. METHODS: Retrospective study on low-risk singleton pregnancies examined at 20-24 weeks. Two cohorts, one with SPD screening and the other without screening, were matched using propensity analysis to create the study groups. Women with short CL were treated with vaginal progesterone and/or cervical cerclage/pessary. The outcomes examined were SPD < 32 weeks (SPD 32) and SPD between 20 and 32 weeks (SPD 20-32). RESULTS: Screening for SPD was associated with a significant reduction in the rate of SPD at less than 32 weeks (0.3 vs. 0.8%, p = 0.001 in the screened and no screened pregnancies, respectively) and in the rate of SPD 20-32 (0.3 vs. 0.9%, p = 0.005 in the screened and no screened pregnancies, respectively). After adjusting for maternal age, parity, body mass index, smoking and mode of conception, the screening group had significantly lower hazard for SPD 20-32 (HR = 0.36, 95% CI: 0.18-0.75, p = 0.006) and SPD32 (HR = 0.39, 95% CI: 0.19-0.82, p = 0.013). CONCLUSION: Screening for SPD by transvaginal CL measurement in mid-pregnancy may reduce the incidence of severe prematurity in low-risk singleton pregnancies.

Reproducibility of cervical length measurement throughout pregnancy.

OBJECTIVES: To assess the intra- and interobserver variability of cervical length (CL) measurement in the three trimesters of pregnancy. METHODS: Prospective observational study. Transvaginal CL measurement was performed by two operators ignorant of each other's results. Two methods of measurement were assessed: the straight line method (SL = from internal to external cervical os along the endocervical mucosa) and the two-line method (TL = the sum of two lines following the curvature of the endocervical canal). RESULTS: There were 236 sets of CL measurements of which 96 (40.7%), 73 (30.5%), and 67 (28.8%) were performed in the first, second, and third trimesters of pregnancy, respectively. Intra- and interobserver variability was excellent for both methods (ICC 0.90) and was not influenced by gestational age. Mean difference was 1 mm (LOA -4 to -3 mm) for the same examiner and 1 mm as well between examiners (LOA -5 to -7 mm). Mean CL was slightly longer for the 2-L method (33 mm, SD = 5.2) compared to the SL method (31.4 mm, SD = 4.9). There was significantly more bias in the difference between methods the longer the CL measurement was (p <.001). CONCLUSIONS: CL measurement shows excellent intra- and interobserver variability across gestation and the variability of the measurement is not influenced by gestational age or CL length for either method. The TL method produces slightly longer values.

Very short cervix in low-risk asymptomatic singleton pregnancies: Outcome according to treatment and cervical length at diagnosis.

INTRODUCTION: The aim of this study was to explore the outcome of low-risk singleton pregnancies with very short cervical length (CL ≤15 mm) according to method of treatment and CL at diagnosis. MATERIAL AND METHODS: Retrospective study on singleton pregnancies devoid of risk factors for spontaneous preterm delivery identified in the course of universal screening programs by vaginal sonography at 20-24 weeks of gestation to have very short CL ≤ 15 mm. RESULTS: The study group consisted of 233 pregnancies with CL ≤ 15 mm of which 88 had cervical cerclage inserted and the remaining 145 were treated with vaginal progesterone. Mean CL at diagnosis was significantly shorter in the cerclage group (5 mm) compared with the progesterone group (12 mm). Regardless of treatment there was no difference in the rate of spontaneous preterm delivery at <32 weeks of gestation in women with CL ≥ 9 mm at screening (11% and 12% in the cerclage and progesterone groups, respectively). In contrast, in the subgroup with CL ≤ 8 mm cervical cerclage resulted in significantly lower rates of spontaneous preterm delivery at <32 weeks of gestation compared with progesterone treatment (20% and 45%, respectively, P = .009) and the median gestational age at birth was significantly greater (37 weeks vs 36 weeks, respectively, P = .013). CONCLUSIONS: The majority of asymptomatic singleton pregnancies with short CL will remain undelivered until 32 weeks of gestation whether treated with progesterone or cerclage. Women with extreme cervical shortening appear to benefit more from cervical cerclage.

Quality assessment of the detailed anomaly ultrasound scan.

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.

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

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.

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

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.

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

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.

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

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.

Upper limb vascular occlusion in the recipient of a monochorionic twin pair.

Monochorionicity is responsible for an increased rate of severe complications because of unequal splitting of the placental mass and/or an imbalance in the blood flow across placental vascular anastomoses. Vascular limb occlusion is one of the rare complications of monochorionic twins, usually occurring in the lower extremities after intra-uterine death of one twin, antenatal intervention (amnio-reduction or laser therapy) or in the presence of twin anemia-polycythemia syndrome. We report a case of vascular occlusion of the upper extremity in the recipient twin of a monochorionic pair in the absence of those predisposing factors.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.