Unisex and Sex-Specific Prescriptive Fetal Growth Charts for Improved Detection of Small-for-Gestational-Age Babies in a Low-Risk Population: a post hoc analyses of a cluster randomized study.

Introduction Our aim was to develop and evaluate the performance of population-based sex-specific and unisex prescriptive fetal abdominal circumference growth charts in predicting small-for-gestational-age (SGA) birthweight, severe SGA (sSGA) birthweight and severe adverse perinatal outcomes (SAPO) in a low-risk population. Methods This is a post hoc analysis of the Dutch nationwide cluster-randomised IRIS study, encompassing ultrasound data of 7,704 low-risk women. IRIS prescriptive unisex and IRIS sex-specific abdominal circumference (AC) fetal growth charts were derived using quantile regression. As comparison we used the descriptive unisex Verburg chart, which is commonly applied in the Netherlands. Diagnostic parameters were calculated based on the 34-36 weeks ultrasound. Results Sensitivity rates for predicting SGA and sSGA birthweights were more than twofold higher based on the IRIS prescriptive sex-specific (respectively SGA 43%; sSGA 59%) and unisex (SGA 39%; sSGA55%) charts, compared to the Verburg chart (SGA16%; sSGA23% both p < 0.01). Specificity rates were highest for Verburg (SGA 99%; sSGA98%) and lowest for IRIS sex-specific (SGA 94%; sSGA 92%). Results for predicting SGA with SAPO were similar for the prescriptive charts (44%), and again higher than the Verburg chart (20%). The IRIS sex-specific chart identified significantly more males as SGA and sSGA (resp. 42%; 60%, p<0.001) than the IRIS unisex chart (resp. 35%; 53% p < 0.01). Conclusion Our study demonstrates improved performance of both the IRIS sex-specific and unisex prescriptive fetal growth compared to the Verburg descriptive chart, doubling detection rates of SGA, sSGA and SGA with SAPO. Additionally, the sex-specific chart outperformed the unisex chart in detecting SGA and sSGA. Our findings suggest potential benefits of using prescriptive AC fetal growth charts in low-risk populations and emphasize the importance of considering customizing fetal growth charts for sex. Nevertheless, the increased sensitivity of these charts should be weighed against the decrease in specificity.

YouTube as a Source of Patient Information on External Cephalic Version: Cross-Sectional Study.

BACKGROUND: With the global increase of cesarean deliveries, breech presentation is the third indication for elective cesarean delivery. Implementation of external cephalic version (ECV), in which the position of the baby is manipulated externally to prevent breech presentation at term, remains suboptimal. Increasing knowledge for caretakers and patients is beneficial in the uptake of ECV implementation. In recent decades, the internet has become the most important source of information for both patients and health care professionals. However, the use and availability of the internet also bring about concerns since the information is often not regulated or reviewed. Information needs to be understandable, correct, and easily obtainable for the patient. Owing to its global reach, YouTube has great potential to both hinder and support spreading medical information and can therefore be used as a tool for shared decision-making. OBJECTIVE: The objective of this study was to investigate the available information on YouTube about ECV and assess the quality and usefulness of the information in the videos. METHODS: A YouTube search was performed with five search terms and the first 35 results were selected for analysis. A quality assessment scale was developed to quantify the accuracy of medical information of each video. The main outcome measure was the usefulness score, dividing the videos into useful, slightly useful, and not useful categories. The source of upload was divided into five subcategories and two broad categories of medical or nonmedical. Secondary outcomes included audience engagement, misinformation, and encouraging or discouraging ECV. RESULTS: Among the 70 videos, only 14% (n=10) were defined as useful. Every useful video was uploaded by educational channels or health care professionals and 80% (8/10) were derived from a medical source. Over half of the not useful videos were uploaded by birth attendants and vloggers. Videos uploaded by birth attendants scored the highest on audience engagement. The presence of misinformation was low across all groups. Two-thirds of the vloggers encouraged ECV to their viewers. CONCLUSIONS: A minor percentage of videos about ECV on YouTube are considered useful. Vloggers often encourage their audience to opt for ECV. Videos with higher audience engagement had a lower usefulness score compared to videos with lower audience engagement. Sources from medically accurate videos should cooperate with sources with high audience engagement to contribute to the uptake of ECV by creating more awareness and a positive attitude of the procedure, thereby lowering the chance for a cesarean delivery due to breech presentation at term.

Correction: Perinatal mortality rate and adverse perinatal outcomes presumably attributable to placental dysfunction in (near) term gestation: A nationwide 5-year cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0285096.].

Preconception lipid profile and the subsequent risk of pregnancy disorders characterized by uteroplacental dysfunction in a multi-ethnic population: the linked HELIUS-PERINED study.

BACKGROUND: Unfavorable lipid profile is associated with pregnancy disorders characterized by uteroplacental dysfunction, including hypertensive disorders of pregnancy, preterm birth and fetal growth restriction. None of current tools used to predict the risk of pregnancy complications include lipid levels. OBJECTIVE(S): In this study, we examined the association of preconception lipid profile with pregnancy disorders characterized by uteroplacental dysfunction in a multi-ethnic population, aiming to improve the identification of women at high risk for uteroplacental dysfunction using current prediction models. STUDY DESIGN: We conducted a linkage study combining lipid profile collected in the multi-ethnic HELIUS study (Amsterdam, 2011-2015), linked with national perinatal registry data on pregnancy complications after inclusion until 2019. We included 1177 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan origin. Associations were studied using Poisson regression. The discriminative ability was assessed for different pregnancy complications of significantly associated lipid parameters when added to commonly used prediction tools for preeclampsia. RESULTS: Preconception triglyceride level was associated with prevalence of hypertensive disorders of pregnancy (e^triglyceride level (mmol/L) adjusted prevalence ratio 1.07, 95% CI 1.00 to 1.14). Age-adjusted prevalence of hypertensive disorders of pregnancy was also higher among women with high LDL-C level, high TC/HDL-C or ≥4 adverse lipid parameters, but most of these findings were not statistically significant when adjusted for demographic, lifestyle and medical characteristics. Addition of triglyceride level and other lipid parameters to the NICE guideline criteria and to the EXPECT prediction tool did not improve discriminative ability for hypertensive disorders of pregnancy, preterm birth or fetal growth restriction. CONCLUSION(S): Lipid profile did not aid in the identification of women at high risk for pregnancy disorders characterized by uteroplacental dysfunction. Further studies are needed to improve preconception prediction models for hypertensive disorders of pregnancy and other pregnancy disorders characterized by uteroplacental dysfunction using biomarkers or other easily available measurements.

Oxidative stress biomarkers for fetal growth restriction in umbilical cord blood: A scoping review.

Fetal growth restriction and underlying placental insufficiency are associated with increased oxidative stress. Current diagnostics fail to identify all growth restricted fetuses and newborns, due to focus on small size. This scoping review aims to summarize the available evidence on usefulness of cord blood oxidative stress biomarkers for identification of growth restricted newborns in need of monitoring and support because of associated health risks. MEDLINE and EMBASE were searched from inception to May 2024. Studies were included if oxidative stress biomarkers were measured in cord blood collected immediately after delivery in newborns suspected to be growth restricted. Biomarkers were categorized based on the origin and/or biological function and their interrelationships. Oxidative stress was determined for each individual biomarker and category. Literature search identified 78 studies on 39 different biomarkers, with a total of 2707 newborns with suspected growth restriction, and 4568 controls. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells were most consistently associated with suspected growth restriction. Reactive oxygen species/reactive nitrogen species, factors in their production, antioxidant enzymes, non-enzymatic antioxidants, and products of oxidative stress were not consistently associated. This review collates the evidence of associations between cord blood oxidative stress biomarkers and growth restriction. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells could potentially be candidates for developing a cord blood diagnostic tool for future clinical use.

Doppler ultrasound of umbilical and middle cerebral artery in third trimester small-for-gestational age fetuses to decide on timing of delivery for suspected fetal growth restriction: A cohort with nested RCT (DRIGITAT).

OBJECTIVE: To assess the association of the umbilicocerebral ratio (UCR) with adverse perinatal outcome in late preterm small-for-gestational age (SGA) fetuses and to investigate the effect on perinatal outcomes of immediate delivery. DESIGN: Multicentre cohort study with nested randomised controlled trial (RCT). SETTING: Nineteen secondary and tertiary care centres. POPULATION: Singleton SGA pregnancies (estimated fetal weight [EFW] or fetal abdominal circumference [FAC] <10th centile) from 32 to 36+6 weeks. METHODS: Women were classified: (1) RCT-eligible: abnormal UCR twice consecutive and EFW below the 3rd centile at/or below 35 weeks or below the 10th centile at 36 weeks; (2) abnormal UCR once or intermittent; (3) never abnormal UCR. Consenting RCT-eligible patients were randomised for immediate delivery from 34 weeks or expectant management until 37 weeks. MAIN OUTCOME MEASURES: A composite adverse perinatal outcome (CAPO), defined as perinatal death, birth asphyxia or major neonatal morbidity. RESULTS: The cohort consisted of 690 women. The study was halted prematurely for low RCT-inclusion rates (n = 40). In the RCT-eligible group, gestational age at delivery, birthweight and birthweight multiple of the median (MoM) (0.66, 95% confidence interval [CI] 0.59-0.72) were significantly lower and the CAPO (n = 50, 44%, p < 0.05) was more frequent. Among patients randomised for immediate delivery there was a near-significant lower birthweight (p = 0.05) and higher CAPO (p = 0.07). EFW MoM, pre-eclampsia, gestational hypertension and Doppler classification were independently associated with the CAPO (area under the curve 0.71, 95% CI 0.67-0.76). CONCLUSIONS: Perinatal risk was effectively identified by low EFW MoM and UCR. Early delivery of SGA fetuses with an abnormal UCR at 34-36 weeks should only be performed in the context of clinical trials.

Practice variation in timing of antenatal corticosteroid administration in early-onset fetal growth restriction: A secondary analysis of the Dutch STRIDER study.

INTRODUCTION: In early-onset fetal growth restriction the fetus fails to thrive in utero due to unmet fetal metabolic demands. This condition is linked to perinatal mortality and severe neonatal morbidity. Maternal administration of corticosteroids in high-risk pregnancies for preterm birth at a gestational age between 24 and 34 weeks has been shown to reduce perinatal mortality and morbidity. Practice variation exists in the timing of the administration of corticosteroids based on umbilical artery monitoring findings in early-onset fetal growth restriction. The aim of this study was to examine differences in neonatal outcomes when comparing different corticosteroid timing strategies. MATERIAL AND METHODS: This was a post-hoc analysis of the Dutch STRIDER trial. We examined neonatal outcomes when comparing institutional strategies of early (umbilical artery pulsatility index >95th centile) and late (umbilical artery shows absent or reversed end-diastolic flow) administration of corticosteroids. The primary outcomes were neonatal mortality and a composite of neonatal mortality and neonatal morbidity, defined as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis or retinopathy of prematurity. We also analyzed predictors for adverse neonatal outcomes, including gestational age at delivery, birthweight, maternal hypertensive disorders, and time interval between corticosteroids and birth. RESULTS: A total of 120 patients matched our inclusion criteria. In 69 (57.5%) the early strategy was applied and in 51 (42.5%) patients the late strategy. Median gestational age at delivery was 28 4/7 (± 3, 3/7) weeks. Median birthweight was 708 (± 304) g. Composite primary outcome was found in 57 (47.5%) neonates. No significant differences were observed in the primary outcome between the two strategies (neonatal mortality adjusted odds ratio [OR] 1.22, 95% CI 0.44-3.38; composite primary outcome adjusted OR 1.05, 95% CI 0.42-2.64). Only gestational age at delivery was a significant predictor for improved neonatal outcome (adjusted OR 0.91, 95% CI 0.86-0.96). CONCLUSIONS: No significant differences in neonatal outcomes were observed when comparing early and late strategy of antenatal corticosteroid administration on neonatal outcomes in pregnancies complicated by early-onset fetal growth restriction. We found no apparent risk contribution of interval between corticosteroid administration and delivery in multivariate analysis. Gestational age at delivery was found to be an important predictor of neonatal outcome.

Antenatal cardiotocography in dutch primary midwife-led care: Maternal and perinatal outcomes and serious adverse events. A prospective observational cohort study.

PROBLEM: It is yet unknown whether shifting antenatal cardiotocography (aCTG) from obstetrician-led to midwife-led care leads to a safe reduction in referrals. BACKGROUND: ACTG is used to assess fetal well-being. In the Netherlands, the procedure has until now been performed as part of obstetrician-led care. Developments in E-health facilitates the performance of aCTG outside the hospital in midwife-led care, hereby increasing continuity of care. AIM: To evaluate 1) process outcomes of implementing aCTG for specific indications in primary midwife-led care; 2) maternal and perinatal outcomes of pregnant women receiving aCTG in midwife-led care; 3) serious adverse events (with outcomes, causes, avoidability, and potential prevention strategies) that have occurred during the innovation project 'aCTG in midwife-led care'. METHODS: Prospective observational cohort study and a case series study of serious adverse events. FINDINGS: A total of 1584 pregnant women with a specific aCTG indication were included in this cohort study for whom 1795 aCTGs were performed in midwife-led care. 1591 aCTGs(89.7%) were classified as reassuring. Referral to obstetrician-led care occurred for 234 women(13.0%) after an aCTG in midwife-led care of whom 202(86%) were referred back. Severe neonatal morbidity occurred in 27 neonates (1.7%). In the 5736 aCTGs included in the case series study, one case with a serious neonatal outcome was assessed as a serious adverse event attributable to human factors. DISCUSSION: ACTGs performed in midwife-led care increased continuity of care. In this innovation project, maternal and perinatal outcomes were in the expected range for women in midwife-led care.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Gestational age and socio-demographic factors associated with school performance at the age of 12 years, a population-based study.

BACKGROUND: Gestational age is positively associated with cognitive development, but socio-demographic factors also influence school performance. Previous studies suggested possible interaction, putting children with low socio-economic status (SES) at increased risk of the negative effects of prematurity. OBJECTIVES: To investigate the association between gestational age in weeks, socio-demographic characteristics, and school performance at the age of 12 years among children in regular primary education. METHODS: Population-based cohort study among liveborn singletons (N = 860,332) born in the Netherlands in 1999-2006 at 25-42 weeks' gestation, with school performance from 2011 to 2019. Regression analyses were conducted investigating the association of gestational age and sociodemographic factors with school performance and possible interaction. RESULTS: School performance increased with gestational age up to 40 weeks. This pattern was evident across socio-demographic strata. Children born at 25 weeks had -0.57 SD (95% confidence interval -0.79, -0.35) lower school performance z-scores and lower secondary school level compared to 40 weeks. Low maternal education, low maternal age, and non-European origin were strongly associated with lower school performance. Being born third or later and low socioeconomic status (SES) were also associated with lower school performance, but differences were smaller than among other factors. When born preterm, children from mothers with low education level, low or high age, low SES or children born third or later were at higher risk for lower school performance compared to children of mothers with intermediate education level, aged 25-29 years, with intermediate SES or first borns (evidence of interaction). CONCLUSIONS: Higher gestational age is associated with better school performance at the age of 12 years along the entire spectrum of gestational age, beyond the cut-off of preterm birth and across socio-demographic differences. Children in socially or economically disadvantaged situations might be more vulnerable to the negative impact of preterm birth. Other important factors in school performance are maternal education, maternal age, ethnicity, birth order and SES. Results should be interpreted with caution due to differential loss to follow-up.

Testing the applicability and additional value of a consultation round after the consensus meeting in the development of two core outcome sets.

OBJECTIVES: Test applicability and additional value of a consultation round after the consensus meeting in the development of core outcome sets (COSs). STUDY DESIGN AND SETTING: In two COS procedures (Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints (COSGROVE) and Definition and Core Outcomes on Hyperemesis Gravida (DCOHG)) that followed the Core Outcome Measures in Effectiveness Trials methodology, the first round of convergence to consensus among stakeholder groups in an online Delphi procedure was followed by a face-to-face consensus meeting during which a COS was formulated. We subsequently presented the COS to the online panel in a consultation round to confirm that the online panel agreed with the choices made at the consensus meeting, defined as 80% agreement. PARTICIPANTS: In the COSGROVE Study, there were eight stakeholder groups, and 83 out of 107 participants completed the consultation round. In the DCOHG Study, there were four stakeholder groups, and 96 out of 125 completed the consultation round. INTERVENTIONS: Adding a consultation round after completing a modified Delphi method with a consensus meeting. RESULTS: There was a level of agreement of 81% and 84%, respectively, in the consultation round of both procedures. This was above the preset level of agreement. The consultation round yielded additional suggestions to refine COS formulation in one of the studies. CONCLUSION: Our study shows that in two procedures, the online expert panel agreed with the participants of the consensus meeting in these procedures, lending validity to existing COS methodology. Future studies could evaluate whether bringing back the COS for confirmation after the consensus meeting could potentially increase the uptake of the final COS.

Perinatal mortality rate and adverse perinatal outcomes presumably attributable to placental dysfunction in (near) term gestation: A nationwide 5-year cohort study.

INTRODUCTION: Placental dysfunction can lead to perinatal hypoxic events including stillbirth. Unless there is overt severe fetal growth restriction, placental dysfunction is frequently not identified in (near) term pregnancy, particularly because fetal size is not necessarily small. This study aimed to evaluate, among (near) term births, the burden of hypoxia-related adverse perinatal outcomes reflected in an association with birth weight centiles as a proxy for placental function. MATERIAL AND METHOD: A nationwide 5-year cohort of the Dutch national birth registry (PeriNed) including 684,938 singleton pregnancies between 36+0 and 41+6 weeks of gestation. Diabetes, congenital anomalies, chromosomal abnormalities and non-cephalic presentations at delivery were excluded. The main outcome was antenatal mortality rate according to birthweight centiles and gestational age. Secondary outcomes included perinatal hypoxia-related outcomes, including perinatal death and neonatal morbidity, analyzed according to birthweight centiles. RESULTS: Between 2015 and 2019, 1,074 perinatal deaths (0.16%) occurred in the study population (n = 684,938), of which 727 (0.10%) antenatally. Of all antenatal- and perinatal deaths, 29.4% and 27.9% occurred in birthweights below the 10th centile. The incidence of perinatal hypoxia-related outcomes was highest in fetuses with lowest birthweight centiles (18.0%), falling gradually up to the 50th and 90th centile where the lowest rates of hypoxia-related outcomes (5.4%) were observed. CONCLUSION: Perinatal hypoxia-related events have the highest incidence in the lowest birthweight centiles but are identifiable throughout the entire spectrum. In fact, the majority of the adverse outcome burden in absolute numbers occurs in the group with a birthweight above the 10th centile. We hypothesize that in most cases these events are attributable to reduced placental function. Additional diagnostic modalities that indicate placental dysfunction at (near) term gestation throughout all birth weight centiles are eagerly wanted.

Real-world experience of adding placental histopathology studies into perinatal clinical trials.

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding.

OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

Home telemonitoring versus hospital care in complicated pregnancies in the Netherlands: a randomised, controlled non-inferiority trial (HoTeL).

BACKGROUND: Women with complicated pregnancies often require hospital admission. Telemonitoring at home is a promising alternative that fulfils a worldwide need in obstetric health care. Moreover, the COVID-19 pandemic has accelerated the transformation to digital care. The aim of this study was to evaluate safety, clinical effectiveness, patient satisfaction, and costs of home telemonitoring against hospital care in complicated pregnancies. METHODS: We did a multicentre, randomised, controlled, non-inferiority trial in six hospitals (four general teaching hospitals and two university hospitals) in the Netherlands (located in Utrecht, Amsterdam, and Groningen). Women aged 18 years and older with singleton pregnancies (>26 weeks gestation) requiring monitoring for pre-eclampsia, fetal growth restriction, fetal anomaly, preterm rupture of membranes, reduced fetal movements, or history of fetal death were included in the study. Participants were randomly assigned to either hospital admission or telemonitoring in (1:1), stratified for the six diagnoses for inclusion and the six centres of inclusion, using block randomisation (block sizes of four and six). When assigned to telemonitoring, participants went home with devices for cardiotocography and blood pressure measurements and had daily contact with their care providers after digitally sending their home measurements. When assigned to hospital admission, participants received care as usual on the ward until the postpartum period. The primary outcome was a composite of adverse perinatal outcomes assessed after delivery, including mortality; an Apgar score below 7 after 5 min or an umbilical arterial pH at birth below 7·05; maternal morbidity; admission of the newborn to the neonatal intensive care unit; and rate of caesarean section. The primary outcome was assessed in the intention-to-treat population. The non-inferiority margin for the primary outcome was a 10% absolute increase in composite primary endpoint based on baseline 20% incidence. The study was registered at the Dutch Trial Registration (NL5888) and is now closed to new participants. FINDINGS: From Dec 1, 2016, to Nov 30, 2019, 201 pregnant women were randomly assigned to an intervention procedure. 101 women were allocated to the telemonitoring group and 100 to the hospital admission group. One participant in the telemonitoring group withdrew consent before the intervention was initiated, and 100 participants were analysed for the primary outcome. In the hospital admission group, four participants did not receive the allocated intervention because they did not accept hospital admission. 100 participants in each group were analysed for the primary outcome according to the intention-to-treat principal. No participants were lost to follow-up. The primary outcome occurred in 31 (31%) of 100 participants in the telemonitoring group and in 40 (40%) of 100 participants in the hospital admission group. Adjusted for centre of inclusion, diagnosis, and nulliparity, the risk difference in primary outcome between both groups was 10·3% (95% CI -22·4 to 2·2) lower in the telemonitoring group, below the pre-defined non-inferiority margin of 10% absolute increase. A similar distribution for each of the individual components within the composite primary outcome was seen between groups. Five serious adverse events were reported: one neonatal death in the hospital admission group, in addition to one intra-uterine fetal death, two neonatal deaths, and one case of eclampsia in the telemonitoring group, all unrelated to the study. INTERPRETATION: This non-inferiority trial shows the first evidence that telemonitoring might be as safe as hospital admission for monitoring complicated pregnancies. FUNDING: Stichting Achmea Gezondheidszorg and ICT Healthcare Technology Solutions.

Offspring school performance at age 12 after induction of labor vs non-intervention at term: A linked cohort study.

INTRODUCTION: The incidence of induction of labor, for both medical reasons and as an elective procedure, has been rising and a further increase in induction of labor following the ARRIVE trial may be expected. The effects of induction of labor at term on childhood neurodevelopment, however, are not well studied. We aimed to study the influence of elective induction of labor for each week of gestation separately from 37 to 42 weeks on offspring school performance at 12 years of age after uncomplicated pregnancies. MATERIAL AND METHODS: We performed a population-based study among 226 684 liveborn children from uncomplicated singleton pregnancies, born from 37+0 to 42+0 weeks of gestation in cephalic presentation in 2003-2008 (no hypertensive disorders, diabetes or birthweight ≤p5) in the Netherlands. Children with congenital anomalies, of non-white mothers and born after planned cesarean section were excluded. Birth records were linked with national data on school achievement. We compared, using a fetus-at-risk approach and per week of gestation, school performance score and secondary school level at age 12 in those born after induction of labor to those born after non-intervention, ie spontaneous onset of labor in the same week plus all those born at later gestations. Education scores were standardized to a mean of 0 and a standard deviation of 1 and adjusted in the regression analyses. RESULTS: For each gestational age up to 41 weeks, induction of labor was associated with decreased school performance scores compared with non-intervention (at 37 weeks -0.05 SD, 95% confidence interval [CI] -0.10 to -0.01 SD; adjusted for confounding factors). After induction of labor, fewer children reached higher secondary school level (at 38 weeks 48% vs 54%; adjusted odds ratio [aOR] 0.88, 95% CI 0.82-0.94). CONCLUSIONS: In women with uncomplicated pregnancies at term, consistently, at every week of gestation from 37 to 41 weeks, induction of labor is associated with lower offspring school performance at age 12 and lower secondary school level compared with non-intervention, although residual confounding may remain. These long-term effects of induction of labor should be incorporated in counseling and decision making.

Onset of labor and use of analgesia in women using thromboprophylaxis with 2 doses of low-molecular-weight heparin: insights from the Highlow study.

BACKGROUND: Peripartum management of women using low-molecular-weight heparin (LMWH) varies widely. Minimum time intervals are required between LMWH injection and neuraxial procedure, and they differ by dose. OBJECTIVES: The objective of this study was to describe the onset of labor and use of analgesia in women using LMWH and to compare practices between intermediate-dose and low-dose LMWH. METHODS: In the Highlow study (NCT01828697), 1110 women were randomized to intermediate-dose or low-dose LMWH and were instructed to discontinue LMWH when labor commenced unplanned or 24 hours prior to planned delivery. The required time interval since last injection to receive a neuraxial procedure was ≥24 hours for intermediate-dose LMWH or ≥12 hours for low-dose LMWH. RESULTS: In total, 1018 women had an ongoing pregnancy for ≥24 weeks. Onset of labor was spontaneous in 198 of 509 (39%) women on intermediate-dose LMWH and in 246 of 509 (49%) on low-dose LMWH. With unplanned onset, a neuraxial procedure was performed in 37% on intermediate-dose and in 48% on low-dose LMWH (risk difference -11%, 95% CI -20% to -2%). Based on time interval, 61% on intermediate-dose and 82% on low-dose LMWH were eligible for a neuraxial procedure. With planned onset, 68% on intermediate-dose and 66% on low-dose LMWH received a neuraxial procedure, whereas 81% and 93%, respectively, were eligible for a neuraxial procedure (risk difference -13%, 95% CI -18% to -8%). CONCLUSION: With spontaneous onset of labor, neuraxial procedures were performed less often in women using intermediate-dose LMWH. Irrespective of onset, fewer women on intermediate-dose LMWH than those on low-dose LMWH were eligible for neuraxial procedures based on required time intervals since the last LMWH injection.

Statins in pre-eclampsia or fetal growth restriction: A systematic review and meta-analysis on maternal blood pressure and fetal growth across species.

BACKGROUND: Several human randomised controlled trials (RCTs) are investigating the effects of statins on pre-eclampsia (PE) and fetal growth restriction (FGR). This cross-species meta-analysis summarises the preclinical evidence of statin use for PE and FGR. OBJECTIVES: Evaluate the effects of statins on maternal blood pressure (MBP) and birthweight (BW) in pregnancies complicated by PE or FGR. SEARCH STRATEGY: PubMed and Embase.com were searched on 10 May 2022 using 'statins' and 'pregnancy'. SELECTION CRITERIA: We included RCTs and cohorts with matched control groups as well as animal studies. DATA COLLECTION AND ANALYSIS: The main outcomes were MBP in mmHg and BW in grams. The standardised mean difference (SMD) with a 95% confidence interval (CI) was calculated. Subgroup analyses on species, statin, dose, timing and route of administration were performed if subgroups included at least three studies. MAIN RESULTS: Our data included one human and 12 animal studies. Prenatal administration of statins significantly reduced MBP during pregnancy (SMD  -2.49 mmHg [95% CI -4.26 to -0.71], p = 0.01). There was no significant effect of statins on BW (SMD 0.69 [95% CI -0.65 to 2.03], p = 0.28). Our subgroup analyses showed no effect on MBP of different doses, species or route of administration. CONCLUSIONS: Our cross-species meta-analyses demonstrate that statins only reduce maternal blood pressure in rodent pregnancies complicated by pre-eclampsia or fetal growth restriction and have no effect on birthweight across species. The broad confidence intervals, inconsistent direction of the observed effects across the studies and large risk of bias lead us to conclude that a solid base for further human RCTs is lacking.