Maternal prepregnancy weight as an independent risk factor for congenital heart defects: systematic review and meta-analysis stratified by cardiac defect subtypes and severity.

OBJECTIVES: To assess and quantify the association between pre-pregnancy maternal overweight and obesity, and the risk of congenital heart defects (CHDs) in offspring. METHODS: This systematic review and meta-analysis included searches of PubMed, Medline, Web of science, and Scopus up to April 20th, 2023. Risk estimates were abstracted or calculated for rising body mass index categories (overweight, obesity, moderate and severe obesity) compared to normal weight (reference). Fixed-effects or random-effects models were used to combine individual study risk estimates based on the degree of heterogeneity. Sensitivity analyses were conducted to weight pooled estimates for relevant moderators, particularly diabetes prior and during pregnancy. Subgroup analyses for specific congenital heart defects were conducted if there were at least two studies with accessible data. The findings were presented in two ways: as groups of defects, categorized using severity and topographic-functional criteria, and as individual defects. The certainty of the evidence for each effect estimate was evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: Twenty studies for a total of 4,861,693 patients and 86,136 CHDs cases were included. The risk for CHDs progressively increases from moderate to severe obesity (pooled odds ratio (OR), respectively: 1.15, 95% confidence interval (CI), 1.11-1.20, and 1.39, 95% CI, 1.27-1.53). Sensitivity analysis indicated that this effect persists independently of maternal diabetes status before or during pregnancy. In subgroup analysis, obesity was associated with up to a 1.5-fold increase in the risk of severe CHDs (pooled OR, 1.48; 95% CI, 1.03-2.13). Specifically, severe obesity was found to be associated with an even higher risk, increasing up to 1.8 times for specific CHDs including tetralogy of Fallot (pooled OR, 1.72; 95% CI, 1.38-2.16), pulmonary valve stenosis (pooled OR, 1.79; 95% CI, 1.39-2.30), and atrial septal defects (pooled OR, 1.71; 95% CI, 1.48-1.97). CONCLUSIONS: Maternal weight emerged as a crucial modifiable risk factor for preventing CHDs, particularly the severe forms. Future research is needed to investigate whether weight management prior to pregnancy might serve as a preventive measure against CHDs. Additionally, for pregnant women with obesity, fetal echocardiography ought to be a routine diagnostic procedure. This article is protected by copyright. All rights reserved.

Prenatal diagnosis and postnatal outcome of Type-III vasa previa: systematic review of literature.

OBJECTIVE: Type-III vasa previa (VP) is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. Early diagnosis of Type-III VP is important but technically challenging. The objective of this study was to gather the current available evidence on the perinatal diagnosis and outcome of Type-III VP. METHODS: A systematic review of the literature on the perinatal diagnosis of atypical Type-III VP was carried out in PubMed, MEDLINE and EMBASE accordingto PRISMA guidelines from inception to March 2023. Data extraction and tabulation were performed by two operators and checked by a third senior author. The quality of the included studies was evaluated using the National Institutes of Health tool for the quality assessment of case-series studies. Our local ultrasound database was searched for previously unreported recent cases. Characteristics of prenatally and postnatally diagnosed Type-III VP, including clinical features and perinatal outcomes, were summarized using descriptive statistics. RESULTS: Eighteen cases of Type-III VP were included, of which 16 were diagnosed prenatally (14 cases were retrieved from 10 publications and two were unpublished cases from our center) and two were diagnosed postnatally (retrieved from two publications). All prenatal cases were diagnosed on transvaginal ultrasound at a mean gestational age of 29 weeks (median, 31 weeks; range, 19-38 weeks). Conception was achieved with in-vitro fertilization in 4/16 (25.0%) cases. There were no prenatal symptoms in 15/18 (83.3%) cases, while in two (11.1%) cases there was vaginal bleeding and in one (5.6%) preterm labor occurred. In 15/18 (83.3%) cases, at least one placental abnormality was observed, including low-lying insertion (9/17), succenturiate or accessory lobe (1/17), velamentous cord insertion (3/18) and marginal insertion (9/18). All prenatally diagnosed cases were liveborn and were delivered by Cesarean section before rupture of membranes at a median gestational age of 35 weeks (range, 32-38 weeks) without neonatal complications. Emergency Cesarean section was performed in 2/16 (12.5%) cases with a prenatal diagnosis and 1/2 (50.0%) cases with a postnatal diagnosis (P = 0.179). Among those with data available, an Apgar score of ≤ 7 was observed in the prenatally vs postnatally diagnosed group in 5/13 vs 1/1 cases, respectively, at the 1-min evaluation and 3/13 vs 1/1 cases, respectively, at the 5-min evaluation. CONCLUSIONS: The prenatal diagnosis of Type-III VP is challenging, with few cases reported in the literature; however, it is crucial for minimizing the risk of adverse outcome by enabling early-term elective Cesarean delivery prior to rupture of membranes. Given that clinical manifestations and risk factors are non-specific, and that Type-III VP cannot be excluded when there is a normal cord insertion or a singular placental mass, systematic screening by transvaginal ultrasound in the general pregnant population is recommended, particularly in those with a low-lying or morphologically abnormal placenta and those who conceived using assisted reproductive technology. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal diagnosis and postnatal outcome of fetal congenital knee dislocation: systematic review of literature.

OBJECTIVES: Congenital knee dislocation (CKD) is a rare condition, affecting 1 in 100 000 newborns. Its prenatal diagnosis is challenging and not well described in the literature, especially when it appears isolated and not as part of a complex malformation or syndromic pattern. The purpose of this study was to provide a comprehensive review of the available literature on the prenatal diagnosis and postnatal outcome of CKD and to summarize the current evidence on this topic. METHODS: A systematic review of the literature on the prenatal diagnosis of CKD was performed in PubMed, Scopus and EMBASE. A predefined combination of specific keywords was used, focusing on intrauterine manifestations, diagnostic methods, prenatal behavior, postnatal treatment and neonatal outcome as well as long-term outcome in terms of ambulation, motion and joint stability. The quality of studies was assessed using the National Institutes of Health tool for quality assessment of case series. A summary of results was carried out providing proportions and rates of diagnostic and prognostic features associated with this rare condition. RESULTS: In total, 20 cases were retrieved for analysis, of which 19 were obtained from the identified eligible studies (n = 16) and one was an unpublished case from our center. The median gestational age at prenatal diagnosis, which was made using ultrasound in most cases, was 20 weeks (range, 14-38 weeks). Bilaterality was observed in 11/20 (55%) cases. The condition was isolated in 7/20 (35%) cases and associated with other anomalies in 13/20 (65%) cases. An association was observed with oligohydramnios (4/20 (20%)), and an invasive procedure was performed in 13/20 (65%) cases, including 11 cases with an invasive procedure performed for diagnostic purposes. Genetic testing was normal in all isolated cases for which information was available (4/7), while a genetic syndrome was present in 10/13 (77%) non-isolated cases (Larsen, Noonan, Grebe, Desbuquois or Escobar syndrome). There were seven terminations of pregnancy, of which six were performed in cases with associated anomalies and one in an isolated case, 11 cases of postnatal survival, one case of intrauterine death and one of neonatal death. The fetal and neonatal deaths occurred in cases with associated anomalies or abnormal genetic findings. Postnatal treatment was mostly conservative, with only two reports (18% of the 11 surviving neonates) of surgical intervention, both in cases with associated anomalies. Postnatal follow-up was up to 1 year in most cases, and motor outlook appeared normal in all isolated cases. CONCLUSIONS: CKD is a rare fetal anomaly with a prenatal diagnosis achievable from the early second trimester, for which a favorable outcome can be expected when no associated anomalies are present. Prenatal diagnosis should include detailed ultrasound assessment and amniocentesis for extensive genetic studies, particularly in non-isolated cases. Early postnatal treatment achieves success in most cases without surgical intervention and leads to a normal motor outlook. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Effect of mode of delivery on perinatal outcome in severe preterm birth: systematic review and meta-analysis.

OBJECTIVE: To review the evidence on the effect of mode of delivery on perinatal outcome of fetuses born before 32 weeks' gestation. METHODS: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), the ClinicalTrials.gov registry and gray literature sources were searched, starting from the year 2000 to reflect contemporary practice in perinatal care. Non-randomized or randomized studies that included singleton fetuses without chromosomal abnormality or major congenital defect delivered vaginally or via Cesarean section were eligible for inclusion in the analysis. Primary outcomes were neonatal death, defined as death in the first 28 days of age, and survival to discharge. Secondary outcomes were other adverse perinatal events. The ROBINS-I tool was used to assess the risk of bias. The overall quality of evidence for the outcomes was assessed according to GRADE. Summary odds ratios (ORs) with 95% CIs were calculated, and random-effects models were used for data synthesis. Subgroup analysis was performed for delivery before 28 weeks, delivery between 28 and 32 weeks and according to fetal presentation at delivery. RESULTS: A total of 27 retrospective studies (22 887 neonates) were included in the systematic review and meta-analysis, all of which reported on singleton pregnancies. Among cases born before 28 weeks, vaginal delivery significantly increased the risk of neonatal death of fetuses with any type of presentation (n = 1496) (OR 1.87 (95% CI, 1.05-3.35); I2 = 65%, very low quality of evidence) and of fetuses with breech presentation (n = 733) (OR 3.55 (95% CI, 2.42-5.21); I2 = 21%, moderate quality of evidence). The odds of survival to discharge were significantly decreased among fetuses with breech presentation delivered before 28 weeks (n = 646) (OR 0.36 (95% CI, 0.24-0.54); I2 = 21%, low quality of evidence). Among breech fetuses born between 28 and 32 weeks, vaginal delivery increased the odds of perinatal death (intrapartum and neonatal) (n = 1581) (OR 3.06 (95% CI, 1.47-6.35); I2 = 0%, high quality of evidence). In non-cephalic fetuses born between 24 and 32 weeks, vaginal delivery decreased the odds of survival to discharge (n = 1030) (OR 0.28 (95% CI, 0.19-0.40); I2 = 0%, moderate quality of evidence). No significant effect on mortality of mode of delivery was observed in cephalic fetuses at any gestational age. CONCLUSIONS: This systematic review and meta-analysis suggests that vaginal delivery in severe preterm birth is associated with an increased risk of neonatal and perinatal death in breech fetuses, while no significant association was observed for cephalic fetuses. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Reference ranges of uterine artery pulsatility index from first to third trimester based on serial Doppler measurements: longitudinal cohort study.

OBJECTIVE: To provide gestational-age (GA)-specific reference ranges for mean uterine artery (UtA) pulsatility index (PI) based on longitudinal data assessment throughout pregnancy. METHODS: This was a prospective longitudinal cohort study of singleton low-risk pregnancies with adequate health and nutritional status at the time of enrolment and without fetal anomaly, receiving prenatal care between January 2018 and July 2021 at the Maternal Fetal Medicine Unit of IRCCS San Raffaele Scientific Institute, Milan, Italy. Women were recruited at ≤ 12 + 6 weeks' gestation and underwent serial standardized ultrasound monitoring, including UtA-PI measurement, by experienced certified operators until delivery. Association of UtA-PI with GA was modeled with fractional polynomial regression. Equations for mean ± SD of the estimated curves were calculated, as well as GA-specific reference charts of centiles for UtA-PI from 10 + 0 to 39 + 0 gestational weeks. RESULTS: We included 476 healthy, low-risk pregnant women and a total of 2045 ultrasound scans (median, 4 (range, 3-9) per patient) were available for analysis. Mean UtA-PI was 1.84 ± 0.55, 1.07 ± 0.38 and 0.78 ± 0.23 in the first, second and third trimesters of pregnancy, respectively. Goodness-of-fit assessment revealed that second-degree smoothing was the most accurate fractional polynomial for describing the course of UtA-PI throughout gestation; therefore, it was modeled in a multilevel framework for the construction of UtA-PI curves. We observed a rapid and substantial decrease in mean UtA-PI before 16 weeks, with subsequent smoother decrement of the slope and more stable values from 20 until 39 weeks. The 3rd , 5th , 10th , 25th , 50th , 75th , 90th , 95th and 97th centiles according to GA for UtA-PI are provided, as well as equations to allow calculation of any value as a centile. CONCLUSIONS: UtA-PI shows a progressive non-linear decrease throughout pregnancy. The new reference ranges for GA-specific mean UtA-PI constructed using rigorous methodology may have a better performance compared with previous models for screening for placenta-associated diseases in the early stages of pregnancy and for evaluating the potential risk for pregnancy-induced hypertension and/or small-for-gestational age later in pregnancy. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Greater estimated fetal weight and birth weight in IVF/ICSI pregnancy after frozen-thawed vs fresh blastocyst transfer: prospective cohort study with novel unified modeling methodology.

OBJECTIVE: To compare, using a unified approach, standardized estimated fetal weight (EFW) trajectories from the second trimester to birth and birth-weight (BW) measurements in in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) pregnancies obtained after frozen-thawed vs fresh blastocyst transfer (BT). METHODS: This was a secondary analysis of a prospective longitudinal cohort study performed at the Fetal Medicine and Obstetric Departments of San Raffaele Hospital in Milan, Italy, from January 2016 to December 2020. Eligible for inclusion were singleton viable gestations conceived by autologous IVF/ICSI conception after fresh or frozen-thawed BT that underwent standard fetal biometry assessment at 19-41 weeks and had BW measurements available. All ultrasound assessments were performed by operators blinded to the employment of cryopreservation. Patients with twin gestation, significant pregestational disease, miscarriage, major fetal abnormalities and use of other types of medically assisted reproduction techniques were excluded. EFW and BW Z-scores and their trajectories were analyzed using general linear models (GLM) and logistic regression with a unified modeling methodology based on the Fetal Medicine Foundation fetal and neonatal population weight charts, adjusting for major confounders. Differences between prenatal EFW and postnatal BW centiles in the two groups were assessed and compared using contingency tables, χ2 test and conversion of prenatal to postnatal centiles. RESULTS: A total of 631 IVF/ICSI pregnancies were considered, comprising 263 conceived following fresh BT and 368 after frozen-thawed BT. A total of 1795 EFW observations were available (n = 715 in fresh BT group and n = 1080 in frozen-thawed BT group; median of three observations per patient). EFW and BW < 10th centile were significantly more frequent in the fresh than in the frozen-thawed BT group (P = 0.003 and P < 0.001, respectively). EFW and BW > 90th centile were significantly more frequent in the frozen-thawed vs fresh BT group (P = 0.034 and P = 0.002, respectively). GLM showed significantly decreasing EFW Z-scores with advancing gestational age (GA) in both groups. The effect of GA was assumed to be equal in the two study groups, as no significant interaction effect was found. Smoothed mean EFW Z-scores from 19 weeks of gestation to term and smoothed mean BW Z-scores were both significantly higher in the frozen-thawed compared with the fresh BT group (EFW Z-score, 0.70 ± 1.29 vs 0.28 ± 1.43; P < 0.001; BW Z-score, 0.04 ± 1.08 vs -0.31 ± 1.28; P < 0.001). Mean smoothed EFW Z-score values in the frozen-thawed vs fresh BT groups were 1.01 ± 0.12 vs 0.60 ± 0.08 at 19-27 weeks, 0.36 ± 0.07 vs -0.06 ± 0.04 at 28-35 weeks and -0.66 ± 0.01 vs -0.88 ± 0.02 at 36-41 weeks. Mean smoothed BW Z-score values in the frozen-thawed vs fresh BT groups were -0.80 ± 0.14 vs -1.20 ± 0.10 at 28-35 weeks and 0.22 ± 0.16 vs -0.24 ± 0.14 at 36-41 weeks. Assessment of EFW and BW concordance showed a significantly greater rate of postnatal confirmation of prenatally predicted small-for-gestational age (SGA) < 10th centile in the fresh compared with the frozen-thawed BT group (P < 0.001), whereas the rate of postnatal confirmation of large-for-gestational age (LGA) > 90th centile was significantly higher in the frozen-thawed vs the fresh BT group (P < 0.001). Logistic regression analysis showed that the smoothed rate of EFW < 3rd centile was about 6-fold higher in the fresh vs frozen-thawed BT group (P < 0.001), whereas the smoothed rates of EFW 90th -97th centile and > 97th centile were nearly double in the frozen-thawed compared with the fresh BT group (P < 0.05 and P < 0.001, respectively). CONCLUSIONS: Robust novel unified prenatal-postnatal modeling in IVF/ICSI pregnancies after frozen-thawed or fresh BT from 19 weeks of gestation to birth showed non-divergent growth trajectories, with higher EFW and BW Z-scores in the frozen-thawed vs fresh BT group. The mean EFW Z-scores in both IVF/ICSI groups were greater than those expected for natural conceptions, being highest in the midtrimester and decreasing with advancing gestation in both groups, becoming negative after 32 weeks in the fresh and after 35 weeks in the frozen-thawed BT group. Mean BW Z-scores were negative in both groups, with lower values in preterm fetuses, and increased with advancing gestation, becoming positive at term in the frozen-thawed BT group. IVF/ICSI conceptions from frozen-thawed as compared to fresh BT presented increased rate of LGA and reduced rate of SGA both prenatally and postnatally. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Prospective longitudinal cohort study of uterine arteries Doppler in singleton pregnancies obtained by IVF/ICSI with oocyte donation or natural conception.

STUDY QUESTION: Do uterine arteries Doppler studies show different pulsatility index (UtA-PI) measurements in IVF/ICSI pregnancies with oocyte donation (OD) as compared to natural conceptions? SUMMARY ANSWER: In IVF/ICSI pregnancies with OD, UtA-PI is reduced by an average of about 40% as compared to pregnancies with natural conception. WHAT IS KNOWN ALREADY: OD pregnancies present worse pregnancy outcomes as compared to natural conception, particularly for increased incidence of pre-eclampsia (PE). Recent evidence shows that IVF/ICSI pregnancies with frozen blastocyst transfer also present higher prevalence of PE and 15% lower UtA-PI as compared to pregnancies after fresh blastocyst transfers. STUDY DESIGN, SIZE, DURATION: Prospective, longitudinal matched cohort study performed in the Fetal Medicine and Obstetric Departments of San Raffaele Hospital in Milan, between 2013 and 2018. The analysis is based on 584 Doppler observations collected from 296 women with different method of conception (OD n = 122; natural conception n = 174). PARTICIPANTS/MATERIALS, SETTING, METHODS: IVF/ICSI viable singleton pregnancies with OD and natural conception control pregnancies matched for BMI and smoking, performing repeated UtA-PI measurements at 11-34 weeks. Miscarriages, abnormalities, twins, significant maternal diseases and other types of ARTs were excluded. Log mean left-right UtA-PI was used for analysis with linear mixed model (LMM) and correction for significant confounders. Pregnancy outcome was also analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: Participants after OD were older and more frequently nulliparous (mean age: OD 43.4, 95% CI from 42.3 to 44.6; natural conception 35.1, 95% CI from 34.5 to 35.7; P-value < 0.001; nulliparous: OD 96.6%; natural conception 56.2%; P-value < 0.001). Mean pulsatility index was lower in OD (UtA-PI: natural conception 1.22; 95% CI from 1.11 to 1.28; OD 1.04; 95% CI from 0.96 to 1.12; P-value < 0.001). A significant effect of parity, gestational age (GA) modeled with a cubic polynomial and BMI was described in the LMM. The mean Log UtA-PI was on average 37% lower in OD as compared to natural conception pregnancies at LMM (P-value < 0.001). We also found a significant interaction between longitudinal UtA-PI Doppler and GA. Therefore, at 11 weeks' gestation the Log UtA-PI was 42% lower and, at 34 weeks, the differences reduced to 32%. GA at delivery and birth weight were statistically lower in OD group; however, birthweight centile was not statistically different. Preeclampsia was 11-fold more common in the OD group (0.6% and 6.6%, P-value = 0.003). No other significant difference in pregnancy outcome was shown in the study groups (gestational diabetes mellitus, small or large for GA). LIMITATIONS, REASONS FOR CAUTION: It was not possible to properly match for maternal age and to blind the assessment given the major differences between cohorts; however, we did not find significant within-groups effects related to maternal age. Future research is needed to reassess outcomes and correct them for maternal characteristics (e.g. cardiovascular function). WIDER IMPLICATIONS OF THE FINDINGS: This finding reproduces our previous discovery of lower UtA-PI in frozen as compared to fresh blastocyst transfer. The vast majority of OD is obtained by the use of cryopreservation. We speculate that increased uterine perfusion may be the physiological response to compensate dysfunctions both in the mother and in the placenta. STUDY FUNDING/COMPETING INTEREST(S): This is a non-funded study. The authors do not declare competing interest. TRIAL REGISTRATION NUMBER: N/A.

External validation of a simple risk score based on the ASPRE trial algorithm for preterm pre-eclampsia considering maternal characteristics in nulliparous pregnant women: a multicentre retrospective cohort study.

OBJECTIVE: To validate the performance of a first-trimester simple risk score based on the ASPRE trial algorithm for pre-eclampsia. DESIGN: Multicentre retrospective cohort analysis. SETTING: Four Italian hospitals. POPULATION: Unselected nulliparous women at 11-13 weeks of gestation from January 2014 through to January 2018. METHODS: Model performance was evaluated based on discrimination and calibration. MAIN OUTCOME MEASURES: Delivery before 37 weeks of gestation with a diagnosis of pre-eclampsia. RESULTS: Based on 73 preterm pre-eclampsia cases and 7546 controls (including 101 cases of late pre-eclampsia), the area under the receiver operating characteristics curve was 0.659 (95% CI 0.579-0.726). The sensitivity was 32.9% (95% CI 22.1-43.7) at a false-positive rate of 8.8%. The positive likelihood ratio was 3.74 (95% CI 2.67-5.23), the positive predictive value was 3.49% (95% CI 2.12-4.86%) and the negative predictive value was 99.3% (95% CI 99.1-99.5%). The sensitivity and positive likelihood ratio were approximately 40% lower than in the original study. The calibration analysis showed a good agreement between observed and expected risks (P = 0.037). Comparison with the Fetal Medicine Foundation (FMF) algorithm yielded a difference in the area under the curve of 0.084 (P = 0.007). CONCLUSIONS: In our Italian population, the simple risk score had a lower performance than expected for the prediction of preterm pre-eclampsia in nulliparous women. The FMF algorithm applied to the same data set resulted in a better prediction. TWEETABLE ABSTRACT: Simple risk score predicts preterm pre-eclampsia in Italy.

Uterine artery Doppler in singleton pregnancies conceived after in-vitro fertilization or intracytoplasmic sperm injection with fresh vs frozen blastocyst transfer: longitudinal cohort study.

OBJECTIVE: Pregnancies conceived by frozen blastocyst transfer (FBT) have higher gestational age and weight at birth as compared to those derived by fresh blastocyst transfer. The aim of this study was to evaluate uterine artery pulsatility index (UtA-PI) in pregnancies conceived by in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) techniques using fresh vs cryopreserved blastocysts. METHODS: This was a prospective longitudinal study of viable singleton IVF/ICSI pregnancies conceived after FBT or fresh blastocyst transfer, that underwent serial ultrasound assessment at San Raffaele Hospital, Milan, Italy at 7-37 gestational weeks. We excluded pregnancies conceived using other assisted reproductive techniques such as egg donation, twin gestation, pregnancy with abnormality and those resulting in miscarriage. Pregnant women underwent ultrasound assessment at 7-10, 11-14, 18-25 and 26-37 weeks' gestation. Mean UtA-PI was measured using Doppler ultrasound according to The Fetal Medicine Foundation criteria. Pregnancy outcomes were recorded. The primary outcome was mean UtA-PI measurement and secondary outcomes were gestational age at birth, birth weight and fetal and maternal complications, including small-for-gestational age (SGA), pre-eclampsia and large-for-gestational age. UtA-PI values were made Gaussian after log10 transformation. Analysis of repeated measures using a multilevel linear mixed model (fixed effects and random effects) was performed. The possible effect of other covariates on UtA-PI Doppler values, including body mass index, SGA and pre-eclampsia, was also evaluated. RESULTS: A total of 367 IVF/ICSI cycles, comprising 164 with fresh blastocyst transfer and 203 with FBT, were included and a total of 625 observations (median, 2.5 (range, 1-4)) were collected and analyzed. The FBT group had on average 14% lower UtA-PI compared with the fresh-blastocyst-transfer group. In pregnancies with SGA fetuses, UtA-PI was 18% higher compared to pregnancies without, irrespective of the study group. Pregnancies that underwent fresh blastocyst transfer had significantly lower birth-weight centile (43.4 ± 23.3 vs 50.0 ± 23.1; P = 0.007) and a higher rate of SGA (7.9% vs 2.0%; P = 0.008) compared to those that underwent FBT. No significant differences were found between the two groups with respect to gestational age at birth and rates of preterm birth, pre-eclampsia, gestational diabetes mellitus and large-for-gestational age. CONCLUSION: UtA-PI and the proportion of SGA are lower in IVF/ICSI pregnancies conceived after FBT as compared to fresh blastocyst transfer. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis.

OBJECTIVE: There is no consensus in current practice guidelines on whether conception by in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) techniques is an indication for performing a fetal echocardiogram. The aim of the study was to assess whether congenital heart defects (CHD) occur more often in pregnancies conceived after IVF/ICSI as compared with those conceived spontaneously. METHODS: A systematic search for studies was conducted of PubMed/MEDLINE, EMBASE and Scopus from inception to September 2017. The search included the following medical subject heading (MeSH) terms alone or in different combinations: 'IVF', 'IVF/ICSI', 'ART pregnancy', 'assisted conception', 'birth defect', 'congenital heart defects' and 'congenital malformation or abnormalities'. Studies comparing neonatal incidence of CHD in pregnancies conceived after IVF/ICSI and those conceived spontaneously were included. Studies reporting on other types of assisted reproductive technology (ART) or lacking information concerning termination of pregnancy were excluded. Chromosomal abnormalities were excluded in all analyzed studies. A meta-analysis of selected cohort studies was conducted to estimate the pooled odds ratio (OR) with 95% CI using a random-effects model. Statistical heterogeneity among the studies was evaluated with the I2 statistic and Q-test. RESULTS: Forty-one studies were identified for review including six case-control and 35 cohort studies. Data of eight selected cohort studies were used for meta-analysis. A total of 25 856 children conceived from IVF/ICSI techniques and 287 995 children conceived spontaneously, involving both singleton and multiple gestations, were included in the analysis. Total CHD events were 337/25 856 (1.30%) and 1952/287 995 (0.68%) in the IVF/ICSI and spontaneous conception groups, respectively. The risk of CHD was significantly increased in the IVF/ICSI group as compared with the spontaneous conception group (pooled OR, 1.45; 95% CI, 1.20-1.76; P = 0.0001; I2 = 44%; P = 0.08). In the subgroup of singleton IVF pregnancies, a significant difference was also obtained (OR, 1.55; 95% CI, 1.21-1.99; P = 0.0005; I2 = 36%; P = 0.18) and also multiple confounding factors adjusted ORs showed statistical significance (pooled OR, 1.29; 95% CI, 1.03-1.60; P = 0.02; I2 = 0%; P = 0.43). CONCLUSION: Fetuses conceived with IVF/ICSI methods are at an increased risk of developing CHD compared with those conceived spontaneously. However, this finding deserves further investigation due to heterogeneity of both ART procedures and cardiac defects. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta-analysis of cohort studies.

OBJECTIVE: Preterm birth (PTB) is more common in pregnancies conceived by in-vitro fertilization (IVF) as compared with those conceived naturally. However, the extent to which this is attributed to spontaneous labor or to iatrogenic indications has not been determined. The aim of this study was to quantify the risk of spontaneous PTB (sPTB) in singleton pregnancies resulting from IVF or intracytoplasmic sperm injection (ICSI) treatment as compared with that in spontaneously conceived pregnancies. METHODS: An electronic search of PubMed/MEDLINE, Scopus and Web of Science to September 2017 and manual search of reference lists identified articles comparing the risk of sPTB in IVF/ICSI vs spontaneously conceived singleton pregnancies. Inclusion criteria were singleton conception with IVF/ICSI, PTB defined as delivery before 37 weeks' gestation and cohort design with clear distinction between spontaneous and indicated PTB. The primary outcome was sPTB < 37 weeks. Relevant secondary outcomes were also analyzed, including sPTB < 34 and < 32 weeks, preterm prelabor rupture of membranes, stillbirth, perinatal mortality, neonatal sepsis, respiratory distress syndrome and gastrointestinal morbidity. A meta-analysis provided the estimation of risk of sPTB in IVF/ICSI pregnancies. RESULTS: In total, 674 records were identified from the search, of which 15 met the inclusion criteria and were included in the meta-analysis. A pooled crude analysis of the primary outcome generated a total sample size of 61 677 births, including 8044 singletons conceived after IVF/ICSI and 53 633 conceived spontaneously. A pooled crude data analysis showed a significant increase in the incidence of sPTB < 37 weeks in singleton IVF/ICSI pregnancies compared with those conceived spontaneously (810/8044 (10.1%) vs 2932/53 633 (5.5%); odds ratio (OR), 1.75; 95% CI, 1.50-2.03; I2 = 39%). A subgroup analysis of studies matching for maternal age and parity confirmed the finding (OR, 1.63; 95% CI, 1.30-2.05; I2 = 33%). A pooled crude analysis of secondary outcomes showed a significant increase in the incidence of sPTB < 34 weeks in pregnancies conceived after IVF/ICSI compared with those conceived spontaneously (37/1012 (3.6%) vs 24/1107 (2.2%); OR, 1.78; 95% CI, 1.03-3.08; I2 = 6%) and did not show any significant difference for any of the other secondary outcomes analyzed. The quality of evidence, rated using the GRADE criteria, was low for the outcome sPTB < 37 weeks and very low for sPTB < 34 weeks. CONCLUSIONS: The risk of sPTB in singleton pregnancies resulting from IVF/ICSI is significantly greater than that in spontaneously conceived singletons. These findings should be interpreted with caution given the low quality of the available evidence. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the hypothesis that fetal abdominal circumference (AC) and uterine artery (UtA) Doppler pulsatility index (PI) could be used to select two homogeneous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without intrauterine growth restriction (IUGR). METHODS: This was a multicenter retrospective study of cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to fetomaternal medicine units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design composite indicators of risk factors for maternal metabolic syndrome and of severity for maternal functional organ damage. RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP cases with appropriate-for-gestational-age (AGA) fetuses (HDP-AGA), diagnosed by normal fetal AC and UtA-PI (n = 205), and a group of HDP cases with IUGR fetuses (HDP-IUGR), diagnosed by fetal AC < 5(th) centile and UtA-PI > 95(th) centile (n = 124). Curves fitted to the birth weights of these two groups were significantly different, but gestational age at admission for HDP (< 34 or ≥ 34 weeks) did not show an independent association with birth weight. When birth weight was expressed as a Z-score with respect to local reference charts, the average corresponded to the 6(th) and 48(th) centiles, respectively. The occurrence of HDP-AGA (as compared with HDP-IUGR) was significantly associated with risk factors for maternal metabolic syndrome (odds ratio, 2.79 (95% CI, 1.57-4.97)), independent of gestational age. The same risk factors yielded non-significant odds ratios for the development of late-onset (vs early-onset) HDP. Women with HDP-IUGR had worse clinical outcomes. CONCLUSIONS: This study provides new information based on simple prenatal bedside examinations that might help to differentiate HDP-IUGR from HDP-AGA fetuses. These groups are associated with different fetal growth patterns and risk factors, independent of gestational age at onset of the disease. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Aberrant right subclavian artery in fetuses with Down syndrome: a systematic review and meta-analysis.

OBJECTIVES: The primary objective was to estimate the prevalence of aberrant right subclavian artery (ARSA) in fetuses with Down syndrome. Secondary objectives were to assess the prevalence of ARSA in euploid fetuses, the feasibility of ultrasound evaluation of the right subclavian artery (RSA) in the first and second trimesters of pregnancy, the performance of ARSA in screening for trisomy 21 and its association with other abnormalities. METHODS: Web-based databases (PubMed, EMBASE and MEDLINE) were searched up to July 2014. The STROBE, PRISMA and QUIPS instruments were used to assess all included studies and for reporting of methodology, results and conclusions. Original studies that reported prenatal ultrasound evaluation of ARSA, assessment of its prevalence in Down-syndrome and euploid fetuses, feasibility of ultrasound evaluation of the RSA in the first and second trimesters of pregnancy and correlation of ARSA with other abnormalities were included, excluding duplications and case reports. Collected data were summarized to estimate prevalence and feasibility. A meta-analysis was performed pooling the study-specific positive and negative likelihood ratios (LR+ and LR-), detection rates and false-positive rates for trisomy 21. RESULTS: Prevalence of ARSA in Down-syndrome fetuses was 23.6% (95% CI, 19.4-27.9%), whereas in euploid fetuses it was 1.02% (95% CI, 0.86-1.10%). Ultrasound evaluation of the RSA course and origin in the first and second trimesters of pregnancy was feasible in 85% and 98% of cases (first and second trimester, respectively) and it was directly related to sonographic experience and fetal crown-rump length and inversely related to maternal body mass index. In more than 20% of fetuses with ARSA there was an association with other abnormalities but ARSA seemed to be an independent marker of trisomy 21. The meta-analysis showed that ARSA is a significant risk factor for Down syndrome (pooled LR+ = 26.93, 95% CI, 19.36-37.47, P for effect < 0.001, P for Q = 0.3, I(2) = 17.3%), whereas normal RSA is a significant protective marker (pooled LR- = 0.71, 95% CI, 0.51-0.99, P for effect = 0.043, P for Q = 0.9, I(2) = 0%). CONCLUSIONS: ARSA appears to be a clinically useful prenatal ultrasound marker of Down syndrome. Additional testing when ARSA is diagnosed should involve evaluation of all risk factors by applying a mathematical model. There is insufficient evidence to recommend fetal karyotyping in cases with isolated ARSA. If the background risk is higher or additional markers are present, full fetal karyotyping is advisable, including analysis for 22q11 microdeletion.

The risk of preeclampsia beyond the first pregnancy among women with type 1 diabetes parity and preeclampsia in type 1 diabetes.

AIM: To estimate the incidence of preeclampsia (PE) among nulliparous and multiparous patients with type 1 diabetes and to study predictors of PE. METHODS: We prospectively collected data on all pregnancies of patients with pregestational type 1 diabetes, followed at our Prenatal Medicine Unit between 1993 and 2008. Medical records were prospectively reviewed by two obstetricians for maternal demographics, pregnancy data, maternal and fetal outcomes. Data were analyzed according to the development of PE and parity. RESULTS: We identified and collected data on 291 eligible pregnancies (195 among nulliparae and 96 among multiparae). The incidence of PE was 9.2% (95% CI: 5.6-14.2) among nulliparae and 9.4% (95% CI: 4.4-17.0) among multiparae. Patients who developed PE had higher HbA1c during pregnancy compared to patients who did not (p=0.026 among nulliparae and p=0.032 among multiparae). Chronic hypertension [OR 17.12 (3.22, 91.00)], microalbuminuria at the beginning of the pregnancy [OR 3.77 (1.22, 11.61)], weight gain during pregnancy [OR 1.13 (1.04, 1.23)] and HbA1c in the first trimester [2.81 (1.12, 7.05)], but not parity, were significant predictors of PE. CONCLUSIONS: Among patients with type 1 diabetes the incidence of PE was similar among nulliparae and multiparae, unlikely in the general population where PE is a disease of the first pregnancy. An increased risk of PE should be assumed for both nulliparous and multiparous women with pregestational diabetes.

Transvaginal ultrasound predicts delayed response to chemotherapy and drug resistance in stage I low-risk trophoblastic neoplasia.

OBJECTIVES: Methotrexate (MTX) resistance is defined on the basis of the human chorionic gonadotropin (hCG) curve. The aim of this study was to identify low-risk non-metastatic patients with gestational trophoblastic neoplasia (GTN) who can achieve resolution by continuing MTX treatment despite a transient hCG plateau. METHODS: Before starting chemotherapy, 24 patients with FIGO Stage I GTN underwent transvaginal ultrasonography with power Doppler in order to identify myometrial lesions (areas of increased echogenicity and increased power Doppler signal). Ultrasound response to chemotherapy was defined when myometrial lesions decreased in echogenicity, Doppler signal or size. When ultrasound response occurred, despite chemoresistance defined by hCG values, MTX treatment was continued. RESULTS: MTX was continued in three out of seven chemoresistant patients because ultrasound suggested response to MTX. All three of these patients achieved a complete response, thus nearly halving the MTX-resistance rate. CONCLUSION: Among patients who are candidates for second-line treatment on the basis of hCG, ultrasound may identify those in whom further MTX administration can induce a delayed complete response.

Actual controversies in twin delivery: from the analysis of the case histories to a reasoned protocol.

AIM: Twin pregnancy has to be considered a risk pregnancy. One of its most controversial aspects is delivery. There is no agreement on the following topics: gestational age at term (GA), mode of delivery, use of epidural analgesia or oxytocic acceleration, impact of chorionicity and amnionicity. The aim of this study was to develop a twin delivery management protocol. METHODS: A retrospective study over a cohort population of 481 twin deliveries that occurred in the Department of Obstetrics of the San Raffaele Hospital of Milan (Italy) from 1996 to 2007 was conducted, and the results were compared with those present in literature. RESULTS: Management of twin pregnancies that exceed the 37 week is controversial. There is an inclination towards fixing bichorionic and monochorionic pregnancy terms at 38 and 35 weeks respectively. In our case history, 73.8% of monochorionic and 15% of bichorionic pregnant women delivered after the 35 and 38 week respectively, without repercussions on the neonatal outcome. A longer gestational age appears to decrease the occurrence of lower Apgar scores and neonatal morbidity. This study, which exclusively considered twin pregnant women with both fetuses in cephalic presentation eligible for a vaginal delivery, did not find any significant differences in neonatal outcome among the types of deliveries. Moreover, the authors observed that the average maternal blood loss in cesarean section (CS) is significantly greater than that of vaginal deliveries. CONCLUSIONS: In consideration of its safety for mother and fetuses, vaginal delivery of two cephalic fetuses at 38 and 35 weeks for bichorionic and monochorionic pregnancies respectively may be considered as a valid alternative to elective cesarean section.