Longitudinal assessment of spiral artery and intravillous arteriole blood flow and adverse pregnancy outcome.

OBJECTIVE: Superb microvascular imaging (SMI) has been shown to improve visualization of small vessels by suppressing global motions while preserving low-flow components, such as the microvessels in the placenta. We sought to determine if SMI-aided visualization of flow velocity waveforms in the spiral arteries (SA) and intravillous fetal arterioles (IVA) could predict fetal growth restriction (FGR), gestational hypertension (GH) and/or pre-eclampsia (PE). METHODS: This was a prospective longitudinal study of singleton pregnancies without fetal anomaly, receiving prenatal care in one of two medical centers over a 5-year period. Using SMI-aided color Doppler, SA and IVA flow velocity was measured at three timepoints: 11 + 0 to 14 + 0, 18 + 0 to 22 + 6 and 28 + 0 to 34 + 6 weeks of gestation. SA and IVA flow velocity waveforms were reported as resistance indices (RI). RI values were analyzed using multilevel modeling; individual regression curves were estimated and combined to obtain the reference intervals for SA-RI and IVA-RI in uncomplicated pregnancies. The primary clinical outcome was FGR and secondary outcomes were PE and GH. FGR was defined as estimated fetal weight < 10th percentile. Student's t-test was used to compare deviation from expected RI between normal and complicated pregnancies. RESULTS: Among 540 pregnancies included in the analysis, 18 (3.3%) had FGR, 31 (5.7%) PE and 61 (11.3%) GH. In uncomplicated pregnancies, the SA-RI decreased progressively with advancing gestation, whereas the IVA-RI increased with gestational age. In the third trimester, the mean SA-RI and IVA-RI values were significantly higher in the FGR group compared with pregnancies that did not develop FGR, while the mean SA-RI was significantly higher in PE compared with non-PE pregnancies. There was no significant difference in mean SA-RI or IVA-RI between pregnancies with vs those without GH at any gestational age. When all three adverse outcomes were combined, SA-RI was significantly higher in pregnancies with these outcomes when compared to uncomplicated pregnancies in the third trimester (mean ± SD, 0.29 ± 0.12 vs 0.26 ± 0.12; P = 0.02). In screening for FGR using SA-RI, the areas under the receiver-operating-characteristics curves (AUC) were 0.68, 0.73 and 0.73 in the first, second and third trimesters, respectively. The respective AUCs for IVA-RI were 0.72, 0.72 and 0.73 for each trimester. CONCLUSIONS: SA-RI and IVA-RI, measured using SMI technology, were significantly higher in pregnancies at risk for FGR in late gestation. Larger studies are needed to determine if SA and IVA flow are reliable predictors of adverse pregnancy outcome. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Frequency and prediction of persistent urinary tract dilation in third trimester and postnatal urinary tract dilation in infants following diagnosis in second trimester.

OBJECTIVE: To determine the frequency, associated characteristics and prognostic value of the current risk stratification system for prenatal urinary tract dilation (UTD) for predicting persistent UTD in the third trimester and subsequent postnatal UTD in the infant, following diagnosis in the second trimester. METHODS: This was a single-institution retrospective cohort study of singleton pregnancies diagnosed with unilateral or bilateral UTD in the second trimester (before 28 weeks' gestation) with follow-up in the third trimester (at or after 28 weeks) between January 2017 and May 2019. In all cases, the prenatal diagnosis and stratification to low-risk (Grade A1) or increased-risk (Grade A2-3) UTD was made using the 2014 UTD consensus classification system. The primary outcomes included persistent prenatal UTD in the third trimester and postnatal UTD up to 6 months of age. We performed multivariable analysis to assess whether patient and second- and third-trimester sonographic characteristics (such as UTD laterality, other renal abnormality (calyceal dilation, abnormal parenchymal appearance, abnormal ureter or bladder) and anteroposterior renal pelvic diameter (AP-RPD)) were associated with the study outcomes. We assessed the predictive value of the current risk stratification system (Grade A1 vs Grade A2-3) in the second and third trimesters for persistent prenatal UTD and postnatal UTD using the area under the receiver-operating-characteristics curve (AUC). RESULTS: Of 26 620 second-trimester ultrasound assessments in the study period, 347 patients were diagnosed with UTD in the second trimester and had third-trimester follow-up, of whom 150/347 (43% (95% CI, 38-49%)) had persistent UTD in the third trimester. Among the 282/347 (81%) patients with postnatal follow-up available, the frequency of postnatal UTD was 49/282 (17% (95% CI, 13-22%)), and among the subset with persistent UTD in the third trimester, the frequency of postnatal UTD was 46/102 (45% (95% CI, 35-55%)). The most frequent postnatal diagnosis was transient UTD (76%), followed by duplicated collecting system (10%). Of infants originally diagnosed with UTD in the second trimester, 2% (7/347) required surgery; stated differently, of the 49 infants with postnatal UTD, 14% (7/49) required surgery. At second-trimester diagnosis, sonographic predictors of both persistent prenatal UTD and postnatal UTD included the presence of other renal abnormality and UTD Grade A2-3. At third-trimester follow-up, predictors of postnatal UTD were larger mean AP-RPD and UTD Grade A2-3, while all cases had other renal abnormality. Second-trimester diagnosis of UTD Grade A2-3 had satisfactory discrimination for predicting persistent prenatal UTD (AUC, 0.64 (95% CI, 0.58-0.70)) and postnatal UTD (AUC, 0.72 (95% CI, 0.63-0.81)), as did third-trimester UTD Grade A2-3 for predicting postnatal UTD (AUC, 0.66 (95% CI, 0.56-0.76)). CONCLUSIONS: The majority of cases of prenatal UTD did not result in postnatal UTD, and of those that did, very few required surgery. Follow-up third-trimester assessment after a second-trimester diagnosis of UTD is warranted. The current risk stratification system by UTD grade, based on the 2014 UTD consensus classification, can be used to predict postnatal UTD with fair accuracy. Further research is needed to determine whether the predictive performance of this system can be improved by incorporating additional risk factors. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Reference ranges for fetal brain structures using magnetic resonance imaging: systematic review.

OBJECTIVE: To evaluate the methodology of studies reporting reference ranges for fetal brain structures on magnetic resonance imaging (MRI). METHODS: MEDLINE, EMBASE, CINAHL and the Web of Science databases were searched electronically up to 31 December 2020 to identify studies investigating biometry and growth of the fetal brain and reporting reference ranges for brain structures using MRI. The primary aim was to evaluate the methodology of these studies. A list of 26 quality criteria divided into three domains, including 'study design', 'statistical and reporting methods' and 'specific aspects relevant to MRI', was developed and applied to evaluate the methodological appropriateness of each of the included studies. The overall quality score of a study, ranging between 0 and 26, was defined as the sum of scores awarded for each quality criterion and expressed as a percentage (the lower the percentage, the higher the risk of bias). RESULTS: Fifteen studies were included in this systematic review. The overall mean quality score of the studies evaluated was 48.7%. When focusing on each domain, the mean quality score was 42.0% for 'study design', 59.4% for 'statistical and reporting methods' and 33.3% for 'specific aspects relevant to MRI'. For the 'study design' domain, sample size calculation and consecutive enrolment of women were the items found to be at the highest risk of bias. For the 'statistical and reporting methods' domain, the presence of regression equations for mean and SD for each measurement, the number of measurements taken for each variable and the presence of postnatal assessment information were the items found to be at the highest risk of bias. For the 'specific aspects relevant to MRI' domain, whole fetal brain assessment was not performed in any of the included studies and was therefore considered to be the item at the highest risk of bias. CONCLUSIONS: Most of the previously published studies reporting fetal brain reference ranges on MRI are highly heterogeneous and have low-to-moderate quality in terms of methodology, which is similar to the findings reported for ultrasound studies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Outcome-based comparison of SMFM and ISUOG definitions of fetal growth restriction.

OBJECTIVE: The recent international guidelines by the Society for Maternal-Fetal Medicine (SMFM) and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) differ in their definitions of fetal growth restriction (FGR). Our aim was to compare the performance of the two definitions in predicting neonatal small-for-gestational age (SGA) and composite adverse neonatal outcome (ANO). METHODS: This was a secondary analysis of data from a prospective study of women referred for fetal growth ultrasound examination between 26 + 0 and 36 + 6 weeks' gestation. The SMFM and ISUOG guidelines were used to define pregnancies with FGR. The SMFM definition of FGR is estimated fetal weight (EFW) or abdominal circumference (AC) < 10th percentile. The ISUOG-FGR definition follows the Delphi consensus criteria and includes either EFW or AC < 3rd percentile or EFW or AC < 10th percentile combined with abnormal Doppler findings or a decrease in growth centiles. The primary outcome was the prediction of neonatal SGA, defined as birth weight < 10th percentile, and a composite of ANO, which was defined as one or more of: Grade-III or -IV intraventricular hemorrhage, respiratory distress syndrome, neonatal death, cord blood pH < 7.1, seizures and admission to the neonatal intensive care unit. Test characteristics (sensitivity, specificity, positive predictive value (PPV), negative predictive value and positive (LR+) and negative likelihood ratios) and area under the receiver-operating-characteristics curve were determined. The association between FGR detected by each definition and selected adverse outcomes was assessed using logistic regression analysis. RESULTS: Of the 1054 pregnancies that met the inclusion criteria, 137 (13.0%) and 55 (5.2%) were defined as having FGR by the SMFM and ISUOG definitions, respectively. Composite ANO and SGA neonate each occurred in 139 (13.2%) pregnancies. For the prediction of neonatal SGA, the SMFM-FGR definition had a higher sensitivity (54.7%) than did the ISUOG definition (28.8%). The ISUOG-FGR definition had higher specificity (98.4% vs 93.3%), LR+ (18.0 vs 8.2) and PPV (72.7% vs 55.5%) than did the SMFM definition for the prediction of a SGA neonate. The SMFM- and ISUOG-FGR definitions had similarly poor performance in predicting composite ANO, with sensitivities of 15.1% and 10.1%, respectively. CONCLUSIONS: The SMFM definition of FGR is associated with a higher detection rate for SGA neonates but at the cost of some reduction in specificity. The ISUOG-FGR definition has a higher specificity, LR+ and PPV for the prediction of neonatal SGA. Both definitions of FGR performed poorly in predicting a composite ANO. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Validation of Delphi procedure consensus criteria for defining fetal growth restriction.

OBJECTIVE: Recently, a Delphi procedure was used to establish new criteria for defining fetal growth restriction (FGR). These criteria require clinical validation. We sought to validate the Delphi consensus criteria by comparing their performance with that of our current definition (estimated fetal weight (EFW) < 10th percentile) in predicting adverse neonatal outcome (ANO). METHODS: This was a secondary analysis of data from a prospective cohort study of women referred for fetal growth assessment between 26 and 36 weeks' gestation. The current standard definition of FGR used in our clinical practice is EFW < 10th percentile using Hadlock's fetal growth standard. The Delphi consensus criteria for FGR include either a very small fetus (abdominal circumference (AC) or EFW < 3rd percentile) or a small fetus (AC or EFW < 10th percentile) with additional abnormal Doppler findings or a decrease in AC or EFW by two quartiles or more. The primary outcome was the prediction of a composite of ANO including one or more of: admission to the neonatal intensive care unit, cord pH < 7.1, 5-min Apgar score < 7, respiratory distress syndrome, intraventricular hemorrhage, neonatal seizures or neonatal death. The discriminatory capacities of the two definitions of FGR for composite ANO and delivery of a small-for-gestational-age (SGA) neonate, defined as birth weight < 10th percentile, were compared using area under the receiver-operating-characteristics curve (AUC). The sensitivity, specificity and predictive values of the methods were also compared. RESULTS: Of 1055 pregnancies included in the study, composite ANO occurred in 139 (13.2%). There were only two cases of early FGR (before 32 weeks); therefore, the study focused on late FGR. Our current FGR diagnostic criterion of EFW < 10th percentile was not associated significantly with composite ANO (relative risk (RR), 1.1 (95% CI, 0.6-1.8)), while the Delphi FGR criteria were (RR, 2.0 (95% CI, 1.2-3.3)). Our current definition of FGR showed higher discriminatory ability in the prediction of a SGA neonate (AUC, 0.69 (95% CI, 0.65-0.73)) than did the Delphi definition (AUC, 0.64 (95% CI, 0.60-0.67)) (P = 0.001). The AUCs of both definitions were poor for the prediction of composite ANO, despite slightly improved performance using the Delphi consensus definition of FGR (AUC, 0.53 (95% CI, 0.50-0.55)) compared with that of our current definition (AUC, 0.50 (95% CI, 0.48-0.53)) (P = 0.02). CONCLUSION: The newly postulated criteria for defining FGR based on a Delphi procedure detects fewer cases of neonatal SGA than does our current definition of EFW < 10th percentile, but is associated with a slight improvement in predicting ANO. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Systematic error and cognitive bias in obstetric ultrasound.

Linked Comment: Ultrasound Obstet Gynecol 2019; 53: 454-464.

Maternal and perinatal outcomes after elective induction of labor at 39 weeks in uncomplicated singleton pregnancy: a meta-analysis.

OBJECTIVE: The rate of maternal and perinatal complications increases after 39 weeks' gestation in both unselected and complicated pregnancies. The aim of this study was to synthesize quantitatively the available evidence on the effect of elective induction of labor at 39 weeks on the risk of Cesarean section, and on maternal and perinatal outcomes. METHODS: PubMed, US Registry of Clinical Trials, SCOPUS and CENTRAL databases were searched from inception to August 2018. Additionally, the references of retrieved articles were searched. Eligible studies were randomized controlled trials of singleton uncomplicated pregnancies in which participants were randomized between 39 + 0 and 39 + 6 gestational weeks to either induction of labor or expectant management. The risk of bias of individual studies was assessed using the Cochrane Risk of Bias Tool. The overall quality of evidence was assessed according to the GRADE guideline. Primary outcomes included Cesarean section, maternal death and admission to the neonatal intensive care unit (NICU). Secondary outcomes included operative delivery, Grade-3/4 perineal laceration, postpartum hemorrhage, maternal infection, hypertensive disease of pregnancy, maternal thrombotic events, length of maternal hospital stay, neonatal death, need for neonatal respiratory support, cerebral palsy, length of stay in NICU and length of neonatal hospital stay. Pooled risk ratios (RRs) were calculated using random-effects models. RESULTS: The meta-analysis included five studies (7261 cases). Induction of labor was associated with a decreased risk for Cesarean section (moderate quality of evidence; RR 0.86 (95% CI, 0.78-0.94); I2  = 0.1%), maternal hypertension (moderate quality of evidence; RR 0.65 (95% CI, 0.57-0.75); I2  = 0%) and neonatal respiratory support (moderate quality of evidence; RR 0.73 (95% CI, 0.58-0.95); I2  = 0%). Neonates born after induction weighed, on average, 81 g (95% CI, 63-100 g) less than those born after expectant management. No significant effects were found for the other outcomes with the available data. The main limitation of our analysis was that the majority of data were derived from a single large study. A second limitation arose from the open-label design of the studies, which may theoretically have affected the readiness of the attending clinician to resort to Cesarean section. CONCLUSIONS: Elective induction of labor in uncomplicated singleton pregnancy at 39 weeks' gestation is not associated with maternal or perinatal complications and may reduce the need for Cesarean section, risk of hypertensive disease of pregnancy and need for neonatal respiratory support. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Large-for-gestational age and stillbirth: is there a role for antenatal testing?

OBJECTIVE: To investigate the association between large-for-gestational-age (LGA) pregnancy and stillbirth to determine if the LGA fetus may benefit from antenatal testing with non-stress test or biophysical profile. METHODS: This was a retrospective cohort study of singleton pregnancies that were ongoing at 24 weeks' gestation and that had undergone routine second-trimester anatomy ultrasound examination, during the period 1990 to 2009. Pregnancies complicated by fetal anomaly or aneuploidy, those with missing birth weight information and those that were small-for-gestational age were excluded. Appropriate-for-gestational age (AGA) and LGA were defined as birth weight between the 10th and 90th percentiles and > 90th percentile, respectively, according to the Alexander growth standard. The incidence of stillbirth was calculated as the number of stillbirths per 10 000 ongoing pregnancies. Adjusted odds ratios (aOR) with 95% CI for stillbirth in LGA compared with AGA pregnancies were estimated using logistic regression analysis, controlling for pre-existing and gestational diabetes. The incidence and aOR for stillbirth were estimated at 4-week intervals from ≥ 24 to ≥ 40 weeks' gestation. RESULTS: Of 52 749 pregnancies ongoing at 24 weeks, 46 205 (87.6%) were AGA and 6544 (12.4%) were LGA at delivery. The incidence of stillbirth in LGA pregnancies was significantly higher than that in AGA pregnancies from 36 weeks' gestation (26/10 000 vs 7/10 000; aOR, 3.10; 95% CI, 1.68-5.70). When women with diabetes were excluded in stratified analysis, pregnancies complicated by LGA continued to be at increased risk for stillbirth ≥ 36 weeks (18/10 000 vs 7/10 000; OR, 2.63; 95% CI, 1.27-5.43). CONCLUSION: Pregnancies complicated by LGA are at significantly increased risk for stillbirth at or beyond 36 weeks, independent of maternal diabetes status, and may benefit from antenatal testing. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Vasa previa screening strategies: decision and cost-effectiveness analysis.

OBJECTIVE: To perform a decision and cost-effectiveness analysis comparing four screening strategies for the antenatal diagnosis of vasa previa in singleton pregnancies. METHODS: A decision-analytic model was constructed comparing vasa previa screening strategies. Published probabilities and costs were applied to four transvaginal screening scenarios that were carried out at the time of mid-trimester ultrasound: no screening, ultrasound-indicated screening, screening only pregnancies conceived by in-vitro fertilization (IVF) and universal screening. Ultrasound-indicated screening was defined as performing transvaginal ultrasound at the time of the routine anatomy ultrasound scan in response to one of the following sonographic findings associated with an increased risk of vasa previa: low-lying placenta, marginal or velamentous cord insertion or bilobed or succenturiate lobed placenta. The primary outcome was cost per quality-adjusted life year (QALY) in US$. The analysis was performed from a healthcare system perspective with a willingness-to-pay threshold of $100 000 per QALY selected. One-way and multivariate sensitivity analysis (Monte-Carlo simulation) was performed. RESULTS: This decision-analytic model demonstrated that screening pregnancies conceived by IVF was the most cost-effective strategy, with an incremental cost effectiveness ratio (ICER) of $29186.50/QALY. Ultrasound-indicated screening was the second most cost-effective, with an ICER of $56096.77/QALY. These data were robust to all one-way and multivariate sensitivity analyses performed. CONCLUSIONS: Within the baseline assumptions, transvaginal ultrasound screening for vasa previa appears to be most cost-effective when performed among IVF pregnancies. However, both IVF and ultrasound-indicated screening strategies fall within contemporary willingness-to-pay thresholds, suggesting that both strategies may be appropriate to apply in clinical practice. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Weight discordance and perinatal mortality in twin pregnancy: systematic review and meta-analysis.

OBJECTIVES: The primary aim of this systematic review was to explore the strength of association between birth-weight (BW) discordance and perinatal mortality in twin pregnancy. The secondary aim was to ascertain the contribution of gestational age and growth restriction in predicting mortality in growth-discordant twins. METHODS: MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched. Only studies reporting on the risk of mortality in twin pregnancies affected compared with those not affected by BW discordance were included. The primary outcomes explored were incidence of intrauterine death (IUD), neonatal death (NND) and perinatal death. Outcome was assessed separately for monochorionic (MC) and dichorionic (DC) twin pregnancies. Analyses were stratified according to BW discordance cut-off (≥ 15%, ≥ 20%, ≥ 25% and ≥ 30%) and selected gestational characteristics, including incidence of IUD or NND before and after 34 weeks' gestation, presence of at least one small-for-gestational age (SGA) fetus in the twin pair and both twins being appropriate-for-gestational age. Risk of mortality in the larger vs smaller twin was also assessed. Meta-analyses using individual data random-effects logistic regression and meta-analyses of proportion were used to analyze the data. RESULTS: Twenty-two studies (10 877 twin pregnancies) were included in the analysis. In DC pregnancies, a higher risk of IUD, but not of NND, was observed in twins with BW discordance ≥ 15% (odds ratio (OR) 9.8, 95% CI, 3.9-29.4), ≥ 20% (OR 7.0, 95% CI, 4.15-11.8), ≥ 25% (OR 17.4, 95% CI, 8.3-36.7) and ≥ 30% (OR 22.9, 95% CI, 10.2-51.6) compared with those without weight discordance. For each cut-off of BW discordance explored in DC pregnancies, the smaller twin was at higher risk of mortality compared with the larger one. In MC twin pregnancies, excluding cases affected by twin-twin transfusion syndrome, twins with BW discordance ≥ 20% (OR 2.8, 95% CI, 1.3-5.8) or ≥ 25% (OR 3.2, 95% CI, 1.5-6.7) were at higher risk of IUD, compared with controls. MC pregnancies with ≥ 25% weight discordance were also at increased risk of NND (OR 4.66, 95% CI, 1.8-12.4) compared with those with concordant weight. The risk of IUD was higher when considering discordant pregnancies involving at least one SGA fetus. The overall risk of mortality in MC pregnancies was similar between the smaller and larger twin, except in those with BW discordance ≥ 20%. CONCLUSION: DC and MC twin pregnancies discordant for fetal growth are at higher risk of IUD but not of NND compared with pregnancies with concordant BW. The risk of IUD in BW-discordant DC and MC twins is higher when at least one fetus is SGA. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Loop electrosurgical excision procedure and risk of vaginal infections during pregnancy: an observational study.

OBJECTIVE: To investigate the risk for preterm birth associated with vaginal infections in pregnancies after a loop electrosurgical excision procedure (LEEP), compared with women with no prior LEEP. DESIGN: Multicentre retrospective cohort study. SETTING: USA. POPULATION: Women with LEEP between 1996 and 2006 were compared with two unexposed groups who had cervical biopsy or Pap test, without any other cervical procedure, in the same calendar year. METHODS: The first pregnancy progressing beyond 20 weeks of gestation in women with prior LEEP was compared with pregnancy in women without LEEP. Stratified analysis according to the presence or the absence of vaginal infection during pregnancy was used to investigate whether the risk for preterm birth differed according to the presence or the absence of infection. The interaction between LEEP and vaginal infection was investigated using multivariable logistic regression with interaction terms, as well as the Mantel-Haenszel test for homogeneity. MAIN OUTCOME MEASURES: Spontaneous preterm birth (<37 and <34 weeks of gestation). RESULTS: Of 1727 patients who met the inclusion criteria, 34.4% (n = 598) underwent LEEP prior to an index pregnancy. There was no increased risk for vaginal infections among women with LEEP compared with women without LEEP. Chlamydia infection and LEEP demonstrated significant interaction, suggesting that the presence of chlamydia infection in women with a history of LEEP augments the risk for preterm birth, compared with women with no history of LEEP. CONCLUSIONS: Vaginal infections during pregnancy in women with a history of LEEP may be associated with an increased risk for preterm birth, compared with women with no history of LEEP.

Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial.

OBJECTIVE: To estimate the effect of early administration of aspirin on the prevention of pre-eclampsia in high-risk women. METHODS: This was planned as a randomized, double-blind, placebo-controlled trial of aspirin for women with risk factors for pre-eclampsia. Participants were randomized to start either aspirin (81 mg/day) or placebo at 11 + 0 to 13 + 6 weeks of gestation. The primary outcome was pre-eclampsia and secondary outcomes included gestational hypertension and small-for-gestational age at birth. RESULTS: The trial suffered from slow recruitment, leading to a protocol change to broaden the inclusion criteria (from a minimum score of multiple risk factors to at least one risk factor for pre-eclampsia). The trial was then terminated prematurely due to continuing slow recruitment and a lack of equipoise given a change in national guidelines to administer aspirin to high-risk women. From the 53 women who were randomized, 30 were included in the final analysis. There was no evidence that the primary outcome of pre-eclampsia was prevented by low-dose aspirin (relative risk (RR) 0.88, 95% CI 0.21-3.66). Gestational hypertension was seen in two women, both in the aspirin group. There was no evidence that the occurrence of small-for-gestational age was reduced by aspirin (RR 0.88, 95% CI 0.06-12.72). CONCLUSIONS: Although this study was underpowered to show effectiveness of aspirin compared to placebo due to the premature termination and difficulties encountered, it highlights practical issues to inform future studies.

Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis.

OBJECTIVE: Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in-situ hybridization (FISH), in the setting of prenatally-diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting. METHODS: Articles in PubMed, EMBASE and Web of Science databases from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: 'array comparative genomic hybridization', 'copy number variants' and 'fetal congenital heart defects'. Articles regarding karyotyping or 22q11 deletion only were excluded. RESULTS: Thirteen publications (including 1131 cases of CHD) met the inclusion criteria for the analysis. Meta-analysis indicated an incremental yield of 7.0% (95% CI, 5.3-8.6%) for the detection of CNVs using aCGH, excluding aneuploidy and 22q11 microdeletion cases. Subgroup results showed a 3.4% (95% CI, 0.3-6.6%) incremental yield in isolated CHD cases, and 9.3% (95% CI, 6.6-12%) when extracardiac malformations were present. Overall, an incremental yield of 12% (95% CI, 7.6-16%) was found when 22q11 deletion cases were included. There was an additional yield of 3.4% (95% CI, 2.1-4.6%) for detecting variants of unknown significance (VOUS). CONCLUSIONS: In this review we provide an overview of published data and discuss the benefits and limitations of using aCGH. If karyotyping and 22q11 microdeletion analysis by FISH are normal, using aCGH has additional value, detecting pathogenic CNVs in 7.0% of prenatally diagnosed CHD, with a 3.4% additional yield of detecting VOUS.

Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta-analysis.

OBJECTIVE: To estimate the incremental yield of detecting copy number variants (CNVs) by genomic microarray over karyotyping in fetuses with increased nuchal translucency (NT) diagnosed by first-trimester ultrasound. METHODS: This was a systematic review conducted in accordance with PRISMA criteria. We searched PubMed, Ovid MEDLINE and Web of Science for studies published between January 2009 and January 2015 that described CNVs in fetuses with increased NT, usually defined as ≥ 3.5 mm, and normal karyotype. Search terms included: fetal or prenatal, nuchal translucency or cystic hygroma or ultrasound anomaly, array comparative genomic hybridization or copy number variants, with related search terms. Risk differences were pooled to estimate the overall and stratified microarray incremental yield using RevMan. Quality assessment of included studies was performed using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2) checklist. RESULTS: Seventeen studies met the inclusion criteria for analysis. Meta-analysis indicated an incremental yield of 5.0% (95% CI, 2.0-8.0%) for the detection of CNVs using microarray when pooling results. Stratified analysis of microarray results demonstrated a 4.0% (95% CI, 2.0-7.0%) incremental yield in cases of isolated NT and 7.0% (95% CI, 2.0-12.0%) when other malformations were present. The most common pathogenic CNVs reported were 22q11.2 deletion, 22q11.2 duplication, 10q26.12q26.3 deletion and 12q21q22 deletion. The pooled prevalence for variants of uncertain significance was 1%. CONCLUSION: The use of genomic microarray provides a 5.0% incremental yield of detecting CNVs in fetuses with increased NT and normal karyotype.