5-Methyl-tetrahydrofolate in prevention of recurrent preeclampsia

Objective: To evaluate the efficacy of 5-methyl-tetrahydrofolate (5-MTHF) supplementation in prevention of recurrent preeclampsia.Methods: Retrospective cohort of women who received daily oral 5-MTHF 15 mg supplementation as prophylactic treatment since first trimester for recurrent preeclampsia were compared with women who did not. All asymptomatic singleton gestations with prior preeclampsia (in the previous pregnancy) were included. Women with chronic hypertension were excluded. The primary outcome was the incidence of preeclampsia.Results: Three hundred and three singleton gestation met the inclusion criteria: 157 received 5-MTHF, while 146 did not (control group). Women who received 5-MTHF had a significantly lower incidence of recurrent overall preeclampsia (21.7% versus 39.7%; odds ratio (OR) 0.57, 95% confidence interval (CI) 0.25, 0.69), severe preeclampsia (3.2% versus 8.9%; OR 0.44, 95% CI 0.12-0.97) and early-onset preeclampsia (1.9% versus 7.5%; OR 0.34, 95% CI 0.07-0.87) compared to control. The intervention group delivered about 10 d after the control and had higher birth weight.Conclusion: This retrospective study showed that women with prior preeclampsia who received daily oral 5-MTHF 15 mg supplementation had a significantly lower incidence of overall preeclampsia, severe preeclampsia and early-onset preeclampsia. Randomized controlled trials are needed to confirm our findings

Scientific basis for standardization of fetal head measurements by ultrasound: a reproducibility study.

OBJECTIVE: To compare the standard methods for ultrasound measurement of fetal head circumference (HC) and biparietal diameter (BPD) (outer-to-outer (BPDoo) vs outer-to-inner (BPDoi) caliper placement), and compare acquisition of these measurements in transthalamic (TT) vs transventricular (TV) planes. METHODS: This study utilized ultrasound images acquired from women participating in the Oxford arm of the INTERGROWTH-21(st) Project. In the first phase of the study, BPDoo and BPDoi were measured on stored images. In the second phase, real-time measurements of BPD, occipitofrontal diameter (OFD) and HC in TT and TV planes were obtained by pairs of sonographers. Reproducibility of measurements made by the same (intraobserver) and by different (interobserver) sonographers, as well as the reproducibility of caliper placement and measurements obtained in different planes, was assessed using Bland-Altman plots. RESULTS: In Phase I, we analyzed ultrasound images of 108 singleton fetuses. The mean intraobserver and interobserver differences were < 2% (1.34 mm) and the 95% limits of agreement were < 5% (3 mm) for both BPDoo and BPDoi. Neither method for measuring BPD showed consistently better reproducibility. In Phase II, we analyzed ultrasound images of 100 different singleton fetuses. The mean intraobserver and interobserver differences were < 1% (2.26 mm) and the 95% limits of agreement were < 8% (14.45 mm) for all fetal head measurements obtained in TV and TT planes. Neither plane for measuring fetal head showed consistently better reproducibility. Measurement of HC using the ellipse facility was as reproducible as HC calculated from BPD and OFD. OFD by itself was the least reproducible of all fetal head measurements. CONCLUSIONS: Measurements of BPDoi and BPDoo are equally reproducible; however, we believe BPDoo should be used in clinical practice as it allows fetal HC to be measured and compared with neonatal HC. For all head measurements, TV and TT planes provide equally reproducible values at any gestational age, and HC values are similar in both planes. Fetal head measurement in the TT plane is preferable as international standards in this plane are available; however, measurements in the TV plane can be plotted on the same standards. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd

A Systematic Review of Methodology Used in Studies Aimed at Creating Charts of Fetal Brain Structures.

Ultrasound-based assessment of the fetal nervous system is routinely recommended at the time of the mid-trimester anatomy scan or at different gestations based on clinical indications. This review evaluates the methodological quality of studies aimed at creating charts for fetal brain structures obtained by ultrasound, as poor methodology could explain substantial variability in percentiles reported. Electronic databases (MEDLINE, EMBASE, Cochrane Library, and Web of Science) were searched from January 1970 to January 2021 to select studies on singleton fetuses, where the main aim was to construct charts on one or more clinically relevant structures obtained in the axial plane: parieto-occipital fissure, Sylvian fissure, anterior ventricle, posterior ventricle, transcerebellar diameter, and cisterna magna. Studies were scored against 29 predefined methodological quality criteria to identify the risk of bias. In total, 42 studies met the inclusion criteria, providing data for 45,626 fetuses. Substantial heterogeneity was identified in the methodological quality of included studies, and this may explain the high variability in centiles reported. In 80% of the studies, a high risk of bias was found in more than 50% of the domains scored. In conclusion, charts to be used in clinical practice and research should have an optimal study design in order to minimise the risk of bias and to allow comparison between different studies. We propose to use charts from studies with the highest methodological quality

Management of late-onset fetal growth restriction: pragmatic approach

OBJECTIVES: International guidelines recommend delivery from 37 weeks in small for gestational age (SGA) fetuses mostly because of stillbirth concerns. Differentiating SGA from late-onset fetal growth restriction (FGR) is challenged by the limited prospective evidence to guide management. We prospectively assessed a novel protocol that used ultrasound criteria to classify women with suspected late FGR into two groups: low-risk with expectant management until the expected date of delivery and high-risk with delivery soon after 37 weeks. Furthermore, we compared the outcome of this prospective cohort with a historical cohort of women similarly presenting with suspected late FGR, to evaluate the impact of implementation of the new protocol. METHODS: This was a prospective study in women with a singleton non-anomalous fetus at ≥32 weeks with any of the following inclusion criteria: estimated fetal weight (EFW) ≤10th centile, ≥50 centiles decrease of the abdominal circumference (AC) from previous scans, umbilical artery Doppler pulsatility index >95th centile or cerebroplacental ratio <5th centile. Women were stratified into low- or high-risk late FGR. Women in the low-risk group were delivered by 41 weeks unless meeting high-risk criteria for delivery later on, whereas women in the high-risk group (PAPP-A <0.4MoM, EFW <3rd centile, or EFW ≥3rd and ≤10th centile with AC drop or abnormal Dopplers) were delivered at 37 weeks. The primary outcome was adverse neonatal outcome including hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, Apgar score <7 at 1 minute, hospital readmission and any of the severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, Apgar score <7 at 5 minutes, metabolic acidosis, sepsis, cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according with the new protocol were compared with a historical cohort where management was guided by individual clinician's expertise. RESULTS: Over 18 months (2018-2019), 321 women were included. Adverse neonatal outcome was significantly less common in low- (n=156) compared with high-risk fetus (n=165): 45 vs 57%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.022. There was no significant difference in adverse maternal outcome (18% vs 24%; aOR, 0.7; 95% CI, 0.4-1.2; P=0.142) and severe adverse neonatal outcome (3.8% vs 8.5%; aOR: 0.5; 95% CI, 0.2-1.3; P=0.153) between low and high-risk group. Compared to women delivered prior to the implementation of the new protocol and classified retrospectively into low- and high-risk late FGR (n=323), there was a lower adverse neonatal outcome (45% vs 58%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.026) in the low-risk late FGR clinic group. CONCLUSIONS: Appropriate risk classification to define management in low- and high-risk FGR groups was associated with reduced adverse neonatal outcome in the low-risk group. In clinical practice a policy of expectantly managing women with late-onset low-risk FGR pregnancies at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence based conservative management protocol of late FGR on perinatal morbidity, mortality and long-term neurodevelopment

International standards for fetal brain structures based on serial ultrasound measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.

OBJECTIVE: To create prescriptive growth standards for five fetal brain structures, measured by ultrasound, from healthy, well-nourished women, at low risk of impaired fetal growth and poor perinatal outcomes, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. METHODS: This was a complementary analysis of a large, population-based, multicentre, longitudinal study. We measured, in planes reconstructed from 3-dimensional (3D) ultrasound volumes of the fetal head at different time points in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle (AV), atrium of the posterior ventricle (PV) and cisterna magna (CM). The sample analysed was randomly selected from the overall FGLS population, ensuring an equal distribution amongst the eight diverse participating sites and of 3D ultrasound volumes across pregnancy (range: 15 - 36 weeks' gestation). Fractional polynomials were used to the construct standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. RESULTS: From the entire FGLS cohort of 4321 women, 451 (10.4%) were randomly selected. After exclusions, 3D ultrasound volumes from 442 fetuses born without congenital malformations were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures showed increasing size with gestation and increasing variability for the POF, SF, PV and CM. The 3rd , 5th , 50th , 95th and 97th smoothed centile are presented. The 5th centile of POF and SF were 2.8 and 4.3 at 22 weeks and 4.2 and 9.4mm at 32 weeks respectively. The 95th centile of PV and CM were 8.5 and 7.4 at 22 weeks and 8.5 and 9.4mm at 32 weeks respectively. CONCLUSIONS: We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcomes. We recommend these as international standards for the assessment of measurements obtained by ultrasound from fetal brain structures

Which is best for fetal head biometry: the transthalamic or transventricular plane?

Objectives: There is ongoing disagreement in the literature as to whether fetal head biometry should be measured in the transthalamic (TT) or the transventricular (TV) plane; and whether HC should be measured using an ellipse or by measuring BPD / OFD. In this study we assess both these factors. Methods: 100 fetuses were prospectively scanned between 16 and 40 weeks as part of the INTERGROWTH-21ST project at the University of Oxford. The biparietal diameter (BPD), occipitofrontal diameter (OFD) and head circumference (HC) were obtained for the TT and the TV plane. The biometry was re-measured by replacing callipers. Differences were expressed as a percentage of the fetal measurements to account for gestational age effects. Bland-Altman plots test were performed. Results: The mean systematic bias between observers was \u3c 1% (Table 1). All measurements were repeatable to within 16% in 95% of cases. Neither TV nor TT plane was consistently more reproducible than the other. Overall, around half the variability was due to calliper replacement. The measurement of HC using an ellipse was the most reproducible. Conclusions: The variability introduced by measuring in the two different planes (TT vs. TV) appears lower than the variability between sonographers. The HC by using the ellipse facility should be preferred to calculating from BPD and OFD

Reproducibility of fetal brain measurements using 3D ultrasound

Objectives: To establish the inter- and intra-operator reproducibility of key fetal brain structures throughout gestation using 3D ultrasound. Methods: 3D volumes of the fetal head between 15 and 40 weeks of gestation were acquired prospectively using a standardized protocol as part of the INTERGROWTH-21st Project. For this reproducibility study a random sample of 90 volumes was used. The following measurements were taken: width of the posterior lateral ventricle in the transventricular plane; depth of the parieto-occipital fissure and Sylvian fissure in the transthalamic plane; and width of the cisterna magna and transcerebellar diameter in the transcerebellar plane. Operators worked in pairs. The first extracted the three planes of interest and took all measurements twice; this was repeated by the second operator. The effect of caliper replacement was also assessed. Mean differences and limits of agreement (LOA) were calculated using Bland-Altman plots. Results: As there was a significant change with gestation in the transcerebellar diameter measurements, differences were expressed in percentage terms; the mean difference (95% LOA) was \u3c1% (±12%). All other structures were compared in mm, and their mean differences (95% LOA) were ≤ 0.2mm (±2.8mm) (table 1). The greatest proportion of variability was due to caliper replacement. Conclusions: Measurement of brain structures using standardized 3D fetal head volumes is highly reproducible. Caliper placement accounts for most of the observed variation among operators

Association between lymphadenopathy after toxoplasmosis seroconversion in pregnancy and risk of congenital infection

The aim of the study was to describe the pregnancy outcome of a large cohort of women with toxoplasmosis seroconversion in pregnancy and to investigate the relation between maternal lymphadenopathy and risk of congenital toxoplasmosis (CT). This was a retrospective study involving women with confirmed toxoplasmosis seroconversion in pregnancy between 2001 and 2017. Women were clinically evaluated for lymphadenopathy and classified as follows: lymphadenopathy absent (L-) or lymphadenopathy present (L+). The mothers were treated and followed-up according to local protocol, and neonates were monitored at least for 1 year in order to diagnose CT. A total of 218 women (one twin pregnancy) were included in the analysis. Pregnancy outcome was as follows: 149 (68%) of children not infected, 62 (28.3%) infected, 4 (1.8%) first trimester termination of pregnancy, 2 (0.9%) first trimester miscarriages, and 3 (1.4%) stillbirths (of which one already counted in the infected cohort). 13.8% of women were L+ , and they were nearly three times more likely to have a child with CT compared to L- women (aOR, 2.90; 95%CI, 1.28–6.58). Moreover, the result was still statistically significant when the analysis was restricted to 81 children whose mothers were clinically examined and received treatment within 5 weeks from estimated time of infection. In conclusion, there is a positive association between L+ status in pregnant women, and risk of CT also confirmed when restricting the analysis to women with early diagnosis of seroconversion and treatment. This data could be very useful in counselling pregnant women with toxoplasmosis seroconversion and lead to direct a more specific therapeutic and diagnostic protocol

Pregnant women's perspectives on severe acute respiratory syndrome coronavirus 2 vaccine

BACKGROUND: Since coronavirus disease 2019 vaccines have been distributed, a debate has raised on whether pregnant women should get the vaccine. No available data exist so far regarding the safety, efficacy, and toxicology of these vaccines when administered during pregnancy. Most of the Obstetrics and Gynecology societies suggested that pregnant could agree to be vaccinated, after a thorough counseling of risks and benefits with their gynecologists, thus leading to an autonomous decision. OBJECTIVE: This study aimed to evaluate the attitude to coronavirus disease 2019 vaccination in pregnant and breastfeeding women in Italy. STUDY DESIGN: A survey was made at the University of Naples Federico II and the Ospedale Cristo Re, Tor Vergata University of Rome, on pregnant and breastfeeding women asking their perspectives on the available vaccines after reading the recommendations issued by our national Obstetrics, Gynecology, and Neonatology societies. The questionnaire included 12 items finalized to evaluate general features of the women and 6 items specifically correlated to their attitudes toward the severe acute respiratory syndrome coronavirus 2 vaccination. Chi-square or Fisher's exact tests were used to compare group differences of categorical variables and Wilcoxon signed rank or Mann-Whitney U test for continuous variables. The study was approved by the institutional review boards of the University of Naples Federico II (ref. no. 409/2020) and the Ospedale Cristo Re, Tor Vergata University of Rome (ref. #Ost4-2020). RESULTS: Most of the included women did not agree to eventually receive severe acute respiratory syndrome coronavirus 2 vaccine during pregnancy (40 [28.2%] vs 102 [71.8%]). Being pregnant was considered a determinant factor to refuse the vaccine prophylaxis (99 [69.7%] vs 43 [30.3%]; chi-square test=24.187; P&lt;.001), even if a very large percentage declared to be generally in favor of vaccines (128 [90.1%] vs 14 [9.9%]; chi-square test=6.091; P=.014) and most of them confirmed they received or would receive other recommended vaccines during pregnancy (75 [52.8%] vs 67 [47.2%]; chi-square test=10.996; P=.001). CONCLUSION: Urgent data are needed on the safety, efficacy, and toxicology of severe acute respiratory syndrome coronavirus 2 vaccines during pregnancy to modify this trend and to help obstetricians during the counseling. Furthermore, pregnant women should be included in future vaccine development trials to not incur again in such uncertainty