Performance of federated learning-based models in the Dutch TAVI population was comparable to central strategies and outperformed local strategies.

Background: Federated learning (FL) is a technique for learning prediction models without sharing records between hospitals. Compared to centralized training approaches, the adoption of FL could negatively impact model performance. Aim: This study aimed to evaluate four types of multicenter model development strategies for predicting 30-day mortality for patients undergoing transcatheter aortic valve implantation (TAVI): (1) central, learning one model from a centralized dataset of all hospitals; (2) local, learning one model per hospital; (3) federated averaging (FedAvg), averaging of local model coefficients; and (4) ensemble, aggregating local model predictions. Methods: Data from all 16 Dutch TAVI hospitals from 2013 to 2021 in the Netherlands Heart Registration (NHR) were used. All approaches were internally validated. For the central and federated approaches, external geographic validation was also performed. Predictive performance in terms of discrimination [the area under the ROC curve (AUC-ROC, hereafter referred to as AUC)] and calibration (intercept and slope, and calibration graph) was measured. Results: The dataset comprised 16,661 TAVI records with a 30-day mortality rate of 3.4%. In internal validation the AUCs of central, local, FedAvg, and ensemble models were 0.68, 0.65, 0.67, and 0.67, respectively. The central and local models were miscalibrated by slope, while the FedAvg and ensemble models were miscalibrated by intercept. During external geographic validation, central, FedAvg, and ensemble all achieved a mean AUC of 0.68. Miscalibration was observed for the central, FedAvg, and ensemble models in 44%, 44%, and 38% of the hospitals, respectively. Conclusion: Compared to centralized training approaches, FL techniques such as FedAvg and ensemble demonstrated comparable AUC and calibration. The use of FL techniques should be considered a viable option for clinical prediction model development.

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.

Trends in preterm birth in the Netherlands in 2011-2019: A population-based study among singletons and multiples.

INTRODUCTION: Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Rates of PTB in the Netherlands are declining, possibly due to the implementation of preventive strategies. In this study we assessed the overall trend in PTB rates in the Netherlands in recent years, and in more detail in specific subgroups to investigate potential groups that require scrutiny in the near future. MATERIAL AND METHODS: Based on the national perinatal registry, we included all pregnancies without severe congenital abnormalities resulting in a birth from 24 to 42 completed weeks of gestation between 2011 and 2019 in the Netherlands. We assessed PTB rates in two different clinical subtypes (spontaneous vs. iatrogenic) and in five gestational age subgroups: 24-27+6 weeks (extreme), 28-31+6 weeks (very), 32-33+6 weeks (moderate, 34-36+6 weeks [late] and, in general, 24-36+6 weeks [overall PTB]). Trend analysis was performed using the Cochran Armitage test. We also compared PTB rates in different subgroups in the first 2 years compared to the last 2 years. Singleton and multiple gestations were analyzed separately. RESULTS: We included 1 447 689 singleton and 23 250 multiple pregnancies in our study. In singletons, we observed a significant decline in PTB from 5.5% to 5.0% (p < 0.0001), mainly due to a decrease in iatrogenic PTBs. When focusing on different gestational age subgroups, there was a decrease in all iatrogenic PTB and in moderate to late spontaneous PTB. However, in spontaneous extreme and very PTB there was an significant increase. When assessing overall PTB risk in different subgroups, the decline was only visible in women with age ≥25 years, nulliparous and primiparous women, women with a medium or high socioeconomic status and hypertensive women. In multiples, the rate of PTB remained fairly stable, from 52.3% in 2011 to 54.1% in 2019 (p = 0.57). CONCLUSIONS: In the Netherlands, between 2011 and 2019, PTB decreased, mainly due to a reduction in late PTB, and more in iatrogenic than in spontaneous PTB. Focus for the near future should be on specific subgroups in which the decline was not visible, such as women with a low socioeconomic status or a young age.

Financial contribution as reason to opt out of non-invasive prenatal testing.

OBJECTIVE: First trimester non-invasive prenatal testing (NIPT) provides pregnant women with a reliable, non-invasive method to screen for fetal aneuploidies. In the Netherlands, there is a nationwide prenatal screening program in which pregnant women and their partners are counseled about their options around 10 weeks of pregnancy. The first trimester and second trimester scan are fully reimbursed but the NIPT has an own financial contribution of €175 per participant, irrespective of type of insurance. The arguments for this own contribution are fear of uncritical use of NIPT or routinization. NIPT has a relatively stable uptake of 51%, against over 95% for second trimester anomaly scan. We aimed to explore the effect of this financial contribution on the decision to opt out of NIPT. STUDY DESIGN: We performed a survey among 350 pregnant women undergoing a second trimester anomaly scan in our center, Amsterdam UMC, between January 2021 and April 2022. All pregnant women who declined NIPT in the first trimester, were asked to participate and answered 11-13 questions about the decision-making process, the reasons to opt out and the financial contribution. RESULTS: Information about NIPT was desired in 92% of women and 96% felt sufficiently informed. Most women took the decision not to perform NIPT with their partner and did not experience difficulties in taking this decision. The most important reason to decline NIPT was: "Every child is welcome" (69%). "The test was too expensive" was answered in 12% and was significantly correlated with lower maternal age. Additionally, one in five women (19%) said they would have done NIPT if it had been for free, which was significantly higher in younger women. CONCLUSIONS: The own financial contribution plays a role in the decision-making to decline NIPT and partly explains the low uptake in the Netherlands. This suggests that there is no equal access to fetal aneuploidy screening. To overcome this inequality, this own contribution should be abandoned. We speculate that this will have a positive effect on the uptake, which will increase to at least 70% and potentially 94%.

Cancer risk in children, adolescents, and young adults conceived by ART in 1983-2011.

STUDY QUESTION: Do children, adolescents, and young adults born after ART, including IVF, ICSI and frozen-thawed embryo transfer (FET), have an increased risk of cancer compared with children born to subfertile couples not conceived by ART and children from the general population? SUMMARY ANSWER: After a median follow-up of 18 years, the overall cancer risk was not increased in children conceived by ART, but a slight risk increase was observed in children conceived after ICSI. WHAT IS KNOWN ALREADY: There is growing evidence that ART procedures could perturb epigenetic processes during the pre-implantation period and influence long-term health. Recent studies showed (non-)significantly increased cancer risks after ICSI and FET, but not after IVF. STUDY DESIGN SIZE DURATION: A nationwide historical cohort study with prospective follow-up was carried out, including all live-born offspring from women treated with ART between 1983 and 2011 and subfertile women not treated with ART in one of the 13 Dutch IVF clinics and two fertility centers. PARTICIPANTS/MATERIALS SETTING METHODS: Children were identified through the mothers' records in the Personal Records Database. Information on the conception method of each child was collected through the mother's medical record. In total, the cohort comprises 89 249 live-born children of subfertile couples, of whom 51 417 were conceived using ART and 37 832 were not (i.e. conceived naturally, through ovulation induction, or after IUI). Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry for the period 1989-2019. Cancer risk in children conceived using ART was compared with risk in children born to subfertile couples but not conceived by ART (hazard ratio (HR)) and children from the general population (standardized incidence ratios (SIRs)). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 358 cancers were observed after a median follow-up of 18 years. Overall cancer risk was not increased in children conceived using ART, when compared with the general population (SIR = 0.96, 95% CI = 0.81-1.12) or with children from subfertile couples not conceived by ART (HR = 1.06, 95% CI = 0.84-1.33). Compared with children from subfertile couples not conceived by ART, the use of IVF or FET was not associated with increased cancer risk, but ICSI was associated with a slight risk increase (HR = 1.58, 95% CI = 1.08-2.31). Risk of cancer after ART did not increase at older ages (≥18 years, HR = 1.26, 95% CI = 0.88-1.81) compared to cancer risk in children not conceived by ART. LIMITATIONS REASONS FOR CAUTION: The observed increased risk among children conceived using ICSI must be interpreted with caution owing to the small number of cases. WIDER IMPLICATIONS OF THE FINDINGS: After a median follow-up of 18 years, children conceived using ART do not have an increased overall cancer risk. Many large studies with prolonged follow-up are needed to investigate cancer risk in (young) adults conceived by different types of ART. In addition, international pooling of studies is recommended to provide sufficient power to study risk of specific cancer sites after ART. STUDY FUNDING/COMPETING INTERESTS: This work was supported by The Dutch Cancer Society (NKI 2006-3631) that funded the OMEGA-women's cohort, Children Cancer Free (KIKA; 147) that funded the OMEGA-I-II offspring cohort. The OMEGA-III offspring cohort was supported by a Postdoc Stipend of Amsterdam Reproduction & Development, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD088393. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

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.

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.

Decrease in perinatal mortality after closure of obstetric services in a community hospital in Amsterdam, the Netherlands. A retrospective cohort study.

OBJECTIVE: To assess differences in adverse maternal and neonatal outcomes before and after closure of a secondary obstetric care unit of a community hospital in an urban district. STUDY DESIGN: Retrospective cohort study using aggregated data from National Perinatal Registry of the Netherlands (PERINED) in the very urban region of Amsterdam, consisting of data of five secondary and two tertiary hospitals. We assessed maternal and neonatal outcomes in singleton hospital births between 24+0 weeks of gestational age (GA) up to 42+6 weeks. Data of 78.613 births were stratified in two groups: before closure (years 2012-2015) and after closure (2016-2019). RESULTS: Perinatal mortality decreased significantly from 0.84 % to 0.63 % (p = 0.0009). The adjusted odds ratio (aOR) of the closure on perinatal mortality was 0.73 (95 % CI 0.62-0.87). Both antepartum death (0.46 % vs 0.36 %, p = 0.02) and early neonatal death (0.38 % vs 0.28 %, p = 0.015) declined after closure of the hospital. The number of preterm births decreased significantly (8.7 % vs 8.1 %, p=<0.007) as well as number of neonates with congenital abnormalities (3.2 % vs2.2 %, p=<0.0001). APGAR < 7 after 5 min increased (2.3 % vs 2.5 %, p = 0.04). There was no significant difference in SGA or NICU admission. Postpartum hemorrhage increased significantly from 7.7 % to 8.2 % (p=<0.003). Perinatal mortality from 32 weeks onwards was not significantly different after closure 0.29 % to 0.27 %. CONCLUSIONS: After closure of an obstetric unit in a community hospital in Amsterdam, there was a significant decrease in perinatal, intrapartum and early neonatal mortality in neonates born from 24+0 onwards. The mortality decrease coincides with a reduction of preterm deliveries. The increasing trend in asphyxia and postpartum hemorrhage is of concern.. Centralization of care and increasing birth volume per hospital may lead to improvement of quality of care. A broad integrated, multidisciplinary maternity healthcare system linked with the social domain can achieve health gains in maternity care for all women.

Does induction of labor at 41 weeks (early, mid or late) improve birth outcomes in low-risk pregnancy? A nationwide propensity score-matched study.

INTRODUCTION: This study aimed to assess whether induction of labor at 41 weeks of gestation improved perinatal outcomes in a low-risk pregnancy compared with expectant management. MATERIAL AND METHODS: Registry-based national cohort study in The Netherlands. The study population comprised 239 971 low-risk singleton pregnancies from 2010 to 2019, with birth occurring from 41+0 to 42+0 weeks. We used propensity score matching to compare induction of labor in three 2-day groups to expectant management, and further conducted separate analyses by parity. The main outcome measures were stillbirth, perinatal mortality, 5-min Apgar <4 and <7, neonatal intensive care unit (NICU) admissions ≥24 h, and emergency cesarean section rate. RESULTS: Compared with expectant management, induction of labor at 41+0 to 41+1 weeks resulted in reduced stillbirths (adjusted odds ratio [aOR] 0.15, 95% confidence interval [CI] 0.05-0.51) in both nulliparous and multiparous women. Induction of labor increased 5-min Apgar score <7 (aOR 1.30, 95% CI 1.09-1.55) and NICU admissions ≥24 h (aOR 2.12, 95% CI 1.53-2.92), particularly in nulliparous women, and increased the cesarean section rate (aOR 1.42, 95% CI 1.34-1.51). At 41+2-41+3 weeks, induction of labor reduced perinatal mortality (aOR 0.13, 95% CI 0.04-0.43) in both nulliparous and multiparous women. The rate of 5-min Apgar score <7 was increased (aOR 1.26, 95% CI 1.06-1.50), reaching significance in multiparous women. The cesarean section rate increased (aOR 1.57, 95% CI 1.48-1.67) in both nulliparous and multiparous women. Induction of labor at 41+4 to 41+5 weeks reduced stillbirths (aOR 0.30, 95% CI 0.10-0.93). Induction of labor increased rates of 5-min Apgar score <4 (aOR 1.61, 95% CI 1.01-2.56) and NICU admissions ≥24 h (aOR 1.52, 95% CI 1.08-2.13) in nulliparous women. Cesarean section rate was increased (aOR 1.47, 95% CI 1.38-1.57) in nulliparous and multiparous women. CONCLUSIONS: At 41+2 to 41+3 weeks, induction of labor reduced perinatal mortality, and in all 2-day groups at 41 weeks, it reduced stillbirths, compared with expectant management. Low 5-min Apgar score (<7 and <4) and NICU admissions ≥24 h occurred more often with induction of labor, especially in nulliparous women. Induction of labor in all 2-day groups coincided with elevated cesarean section rates in nulliparous and multiparous women. These findings pertaining to the choice of induction of labor vs expectant management should be discussed when counseling women at 41 weeks of gestation.

An integrated approach to geographic validation helped scrutinize prediction model performance and its variability.

OBJECTIVES: To illustrate in-depth validation of prediction models developed on multicenter data. METHODS: For each hospital in a multicenter registry, we evaluated predictive performance of a 30-day mortality prediction model for transcatheter aortic valve implantation (TAVI) using the Netherlands heart registration (NHR) dataset. We measured discrimination and calibration per hospital in a leave-center-out analysis (LCOA). Meta-analysis was used to calculate I2 values per performance metric from the LCOA and to compute mean and confidence interval (CI) estimates. Case mix differences between studies were inspected using the framework of Debray et al. for understanding external validation. We also aimed to discover subgroups (SGs) with high model prediction error (PE) and their distribution over the centers. RESULTS: We studied 16 hospitals with 11,599 TAVI patients with an early mortality of 3.7%. The models' area under the curve (AUCs) had a wide range between hospitals from 0.59 to 0.79, and miscalibration occurred in seven hospitals. Mean AUC from meta-analysis was 0.68 (95% CI 0.65-0.70). I2 values were 0%, 74%, and 0% for AUC, calibration intercept and slope, respectively. Between-hospital case-mix differences were substantial, and model transportability was low. One SG was discovered with marked global PE and was associated with poor performance on validation centers. CONCLUSION: The illustrated combination of approaches provides useful insights to inspect multicenter-based prediction models, and it exposes their limitations in transportability and performance variability when applied to different populations.

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.

Cardiovascular mortality in women in their forties after hypertensive disorders of pregnancy in the Netherlands: a national cohort study.

BACKGROUND: Hypertensive disorders of pregnancy are associated with cardiovascular disease later in life. Given that hypertensive disorders of pregnancy often occur at a relatively young age, there might be an opportunity to use preventive measures to reduce the risk of early cardiovascular disease and mortality. The aim of this study was to assess the risk of cardiovascular mortality in women after a hypertensive disorder of pregnancy. METHODS: In this population-based cohort study, the Netherlands Perinatal Registry (PRN) and the national death registry at the Dutch Central Bureau for Statistics were linked. We analysed women in the Netherlands with a first birth during 1995-2015 to determine the association between cardiovascular mortality and hypertensive disorders of pregnancy (based on recorded diastolic blood pressure or proteinuria, or both). We analysed the association between the highest diastolic blood pressure measured in pregnancy and cardiovascular mortality and constructed survival curves to assess cardiovascular mortality after hypertensive disorders of pregnancy, specifically pre-eclampsia and gestational hypertension. To differentiate between the severity of hypertensive disorders of pregnancy, cardiovascular mortality was assessed in women with a combination of hypertensive disorders of pregnancy with preterm birth (gestational age <37 weeks) and growth restriction (birthweight in the 10th percentile or less). All hazard ratios (HRs)were adjusted for maternal age. FINDINGS: Between Jan 1, 1995, and Dec 31, 2015, the PRN contained 2 462 931 deliveries and 1 625 246 women. In 1 243 890 women data on their first pregnancy were available and were included in this analysis after linkage, with a median follow-up time of 11·2 years (IQR 6·1-16·3). 259 177 (20·8%) women had hypertensive disorders of pregnancy, and of these 45 482 (3·7%) women had pre-eclampsia and 213 695 (17·2%) women had gestational hypertension; 984 713 (79·2%) women did not develop hypertension in their first pregnancy. Compared with women without hypertensive disorders of pregnancy, the risk of death from any cause was higher in women who had hypertensive disorders (HR 1·30 [95% CI 1·23-1·37], p<0·001), pre-eclampsia (1·65 [1·48-1·83]; p<0·0001), and gestational hypertension (1·23 [1·16-1·30]; p<0·0001). Those women with pre-eclampsia had a higher risk of cardiovascular mortality compared with those without any hypertensive disorders of pregnancy (adjusted HR 3·39 [95% CI 2·67-4·29]), as did those with gestational hypertension (2·22 [1·91-2·57]). For women with a history of hypertensive disorders of pregnancy combined with preterm birth (gestational age <37 weeks) and birthweight in the 10th percentile or less, the adjusted HR for cardiovascular mortality was 6·43 (95% CI 4·36-9·47), compared with women without a hypertensive disorder of pregnancy. The highest diastolic blood pressure measured during pregnancy was the strongest risk factor for cardiovascular mortality (for 80-89 mm Hg: adjusted HR 1·47 [95% CI 1·00-2·17]; for 130 mm Hg and higher: 14·70 [7·31-29·52]). INTERPRETATION: Women with a history of hypertensive disorders of pregnancy have a risk of cardiovascular mortality that is 2-3 times higher than that of women with normal blood pressure during pregnancy. The highest measured diastolic blood pressure during pregnancy is an important predictor for cardiovascular mortality later in life; therefore, women who have hypertensive disorders of pregnancy should be given personalised cardiovascular follow-up plans to reduce their risk of cardiovascular mortality. FUNDING: None.

Impact of ethnicity and neighborhood deprivation on preterm birth: How does urban living play a role?

OBJECTIVE: Women of Black and other non-Western ethnicity and women who live in deprived neighborhoods are at increased risk for preterm birth (PTB). These women may live clustered in certain urban areas. If ethnicity reflects a biological rather than a socioeconomic risk factor, women should have a PTB risk independent of the urban area where they live. In this study we explored the association between urban living and the risk of PTB, combined with knowledge on ethnicity and neighborhood deprivation in these specific urban areas in the Netherlands. STUDY DESIGN: National cohort study of 935,381 women (2014-2019) with a singleton pregnancy resulting in live birth between 24.0 and 42.6 weeks. Antepartum death and severe congenital anomalies were excluded. We performed logistic regression analysis and analyzed the impact of living in one of the four main urban areas on PTB. We adjusted for maternal age, parity and fetal gender. We tested for interaction between ethnicity, neighborhood deprivation index (NDI) and urban living. RESULTS: Mean PTB rate among singleton pregnancies in The Netherlands is 5.1%. There was a strong ethnic difference in PTB risk, with the highest prevalence among South Asian women (7.9%) and African women (6.6%). In the most deprived neighborhoods the PTB risk was 5.7%. We found a significant interaction between ethnicity and urban living, and between NDI and urban living. South Asian and African women living in urban areas had the greatest risk of PTB, between 7.0% and 8.8%. CONCLUSION: Ethnicity remains a fixed biological risk for PTB that cannot be fully explained by socioeconomic status or neighborhood deprivation. Independent of ethnicity and neighborhood deprivation, urban living has a great influence on the risk of preterm birth. Future studies and policies should focus on population-based interventions in those urban areas where South Asian and African ethnic groups live and where the preterm birth risk is the highest.

Cardiovascular risk profile after a complicated pregnancy across ethnic groups: The HELIUS study.

AIMS: Little is known about how pregnancy complications and cardiovascular disease (CVD) risk are associated, specifically among ethnic minorities. In this study we examined this association in women from six ethnic groups, and the potential value of pregnancy complications as eligibility criterion for CVD risk screening. METHODS: We conducted a cross-sectional study combining obstetric history from the Dutch perinatal registry with data on cardiovascular risk up to 15 years after pregnancy from the multi-ethnic HELIUS study. We included 2,466 parous women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin. Associations were studied across ethnicities and predictive value of pregnancy complications for CVD risk factors above traditional eligibility criteria for CVD risk screening was assessed using Poisson regression. RESULTS: History of hypertensive disorders of pregnancy and preterm birth were associated with higher prevalence of chronic hypertension and chronic kidney disease across most groups (prevalence ratio 1.6-1.9). Gestational diabetes mellitus was associated with increased type 2 diabetes mellitus risk, particularly in ethnic minority groups (prevalence ratio 4.5-7.7). Associations did not significantly differ across ethnic groups. The prediction models did not improve substantially after adding pregnancy complications to traditional eligibility criteria for CVD risk screening. CONCLUSION: History of hypertensive disorders of pregnancy, preterm birth and gestational diabetes mellitus is associated with CVD risk factors in parous women, without evidence of a differential association across ethnic groups. However, addition of pregnancy complications to traditional eligibility criteria for CVD risk screening does not substantially improve the prediction of prevalent CVD risk factors.

Women of different ethnic backgrounds who had pregnancy complications (high blood pressure or diabetes during pregnancy, or who delivered their baby too early) have a higher risk of heart disease later in life. Screening for a high risk of heart disease is important, because interventions may help to prevent heart disease. Currently, general practitioners use several criteria to select women for screening, such as heart disease among close relatives or smoking. In our study in women in whom these 'traditional' criteria for screening were measured, the pregnancy complications did not help to find more women with a high risk. Yet, pregnancy complications may be a signal for both patients and healthcare professionals to regularly consider the need for screening. Women who had high blood pressure in pregnancy or delivered their baby too early had up to two times more often chronic hypertension or kidney disease later in life. Women who had diabetes in pregnancy, had up to eight times more type 2 diabetes later in life. Women of South-Asian Surinamese, African Surinamese and Ghanaian origin living in the Netherlands more often had pregnancy complications and cardiovascular risk factors than women with a Dutch background.

Development and validation of a prediction model for early mortality after transcatheter aortic valve implantation (TAVI) based on the Netherlands Heart Registration (NHR): The TAVI-NHR risk model.

BACKGROUND: The currently available mortality prediction models (MPM) have suboptimal performance when predicting early mortality (30-days) following transcatheter aortic valve implantation (TAVI) on various external populations. We developed and validated a new TAVI-MPM based on a large number of predictors with recent data from a national heart registry. METHODS: We included all TAVI-patients treated in the Netherlands between 2013 and 2018, from the Netherlands Heart Registration. We used logistic-regression analysis based on the Akaike Information Criterion for variable selection. We multiply imputed missing values, but excluded variables with >30% missing values. For internal validation, we used ten-fold cross-validation. For temporal (prospective) validation, we used the 2018-data set for testing. We assessed discrimination by the c-statistic, predicted probability accuracy by the Brier score, and calibration by calibration graphs, and calibration-intercept and calibration slope. We compared our new model to the updated ACC-TAVI and IRRMA MPMs on our population. RESULTS: We included 9144 TAVI-patients. The observed early mortality was 4.0%. The final MPM had 10 variables, including: critical-preoperative state, procedure-acuteness, body surface area, serum creatinine, and diabetes-mellitus status. The median c-statistic was 0.69 (interquartile range [IQR] 0.646-0.75). The median Brier score was 0.038 (IQR 0.038-0.040). No signs of miscalibration were observed. The c-statistic's temporal-validation was 0.71 (95% confidence intervals 0.64-0.78). Our model outperformed the updated currently available MPMs ACC-TAVI and IRRMA (p value < 0.05). CONCLUSION: The new TAVI-model used additional variables and showed fair discrimination and good calibration. It outperformed the updated currently available TAVI-models on our population. The model's good calibration benefits preprocedural risk-assessment and patient counseling.

Long-term outcomes following antenatal exposure to low-dose aspirin: study protocol for the 4-year follow-up of the APRIL randomised controlled trial.

INTRODUCTION: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age. METHODS AND ANALYSIS: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design. ETHICS AND DISSEMINATION: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Preterm Birth is Associated with Lower Academic Attainment at Age 12 Years: A Matched Cohort Study by Linkage of Population-Based Datasets.

OBJECTIVE: To compare academic attainment at age 12 years in preterm children born below 30 weeks of gestation with matched term-born peers, using standardized, nationwide and well-validated school tests. STUDY DESIGN: This population-based, national cohort study was performed by linking perinatal data from the nationwide Netherlands Perinatal Registry with educational outcome data from Statistics Netherlands and included 4677 surviving preterm children born at 250/7-296/7 weeks of gestational age and 366 561 controls born at 40 weeks of gestational age in 2000-2007. First, special education participation rate was calculated. Subsequently, all preterm children with academic attainment test data derived at age 12 years were matched to term-born children using year and month of birth, sex, parity, socioeconomic status, and maternal age. Total, language, and mathematics test scores and secondary school level advice were compared between these 2 groups. RESULTS: Children below 30 weeks of gestation had a higher special education participation rate (10.2% vs 2.7%, P < .001) than term-born peers. Preterm children had lower total (-0.37 SD; 95% CI -0.42 to -0.31), language (-0.21 SD; 95% CI -0.27 to -0.15), and mathematics (-0.45 SD; 95%CI -0.51 to -0.38) z scores, and more often a prevocational secondary school level advice (62% vs 46%, P < .001). CONCLUSIONS: A substantial proportion of children born before 30 weeks of gestation need special education at the end of elementary schooling. These children have significant deficits on all measures of academic attainment at age 12 years, especially mathematics, compared with matched term-born peers.

Thyroid Function at Age Fifty After Prenatal Famine Exposure in the Dutch Famine Birth Cohort.

Background: Early-life exposures during gestation may permanently alter thyroid physiology and health in adulthood. We investigated whether exposure to the Dutch Famine (1944-1945) in late, mid, or early gestation influences thyroid function (i.e., incidence of thyroid disease, thyroid autoantibodies, thyroid stimulating hormone (TSH), and free thyroxine (FT4) levels) in adulthood. We specifically assessed whether potential effects of famine differed for men and women. Methods: This study includes 910 men and women born as term singletons in the Wilhelmina Gasthuis in Amsterdam, the Netherlands, shortly before, during, or after the Dutch Famine. We evaluated medical histories for previous diagnosis or current treatment for thyroid dysfunction. At age 50 blood samples were drawn from 728 individuals for tests of thyroid function. We studied the prevalence of overt hypo- and hyperthyroidism and thyroid autoimmunity using medical histories, and measurements of TSH, FT4, anti-TPO and anti-TG, comparing participants exposed to famine at different pregnancy trimesters or born before or conceived after the famine. Additionally, we studied associations of TSH and FT4 levels with in utero famine exposure in a subsample of men and women free of thyroid disease that were exposed in late, mid, or early gestation. Results: There were no differences in thyroid dysfunction diagnosis or current treatment between participants at age 50 years who been exposed to famine during different periods of gestation and those born before or conceived after. There was no association between famine exposure and overt hypo- or hyperthyroidism or thyroid autoantibody positivity. Women who had been exposed to famine in mid gestation had slightly lower TSH levels than women who had not been exposed to famine prenatally (b=-0.06; 95%; CI=[-0.11,-0.02]; p<0.01). No differences in TSH levels were observed in men, and no differences in FT4 levels were observed in men or women. Conclusions: There are no differences in adult thyroid disease at age 50 years according to prenatal famine exposure. However, the lower TSH levels in women exposed to famine in the second trimester suggest that there may be sex-specific effects of famine exposure during a critical period of thyroid development on hypothalamic-pituitary-thyroid axis regulation in adulthood.

Deprived neighborhoods and spontaneous preterm birth: A national cohort study.

OBJECTIVE: Spontaneous preterm birth is the leading cause of infant morbidity and mortality in the developed world. Environmental socio-economic factors, such as neighborhood deprivation, are known to negatively affect birth outcomes, including overall preterm birth. However, the role of neighborhood deprivation in spontaneous preterm birth (SPTB) is unclear. The aim of the study is to 1) to determine the effect of neighborhood deprivation on SPTB birth and 2) to investigate the trend in rates of SPTB between 2010 and 2019 for each quintile of neighborhood deprivation. STUDY DESIGN: Based on the national perinatal registry, we included 1,584,225 singleton pregnancies resulting in a birth from 22 to 42 completed weeks of gestation between 2010 and 2019 in the Netherlands. Deprivation scores per neighborhood were derived from the Netherlands Institute of Social Research and were linked to the perinatal registry data, using the woman's home address. The scores were divided into quintiles (Q). Rates of SPTB were calculated, categorized into <37 weeks, <32 weeks and <28 weeks of gestation. We used logistic regression analysis to adjust for maternal age, parity and ethnicity. RESULTS: Compared to the most affluent neighborhoods (Q1), women in all other quintiles had a statistically significant increased risk for SPTB. The largest effect was observed in the most deprived neighborhoods (Q5); adjusted odds ratio 1.16 (95% confidence interval 1.13 - 1.19). From 2010 to 2019, we observed an overall decrease of 0.21% in SPTB < 37 weeks (p < 0.0001). All quintiles showed a decrease in SPTBs < 37 weeks, but only in Q1, Q2 & Q5 this decline in SPTB was statistically significant. CONCLUSIONS: Pregnant women in deprived neighborhoods in the Netherlands are more at risk for spontaneous preterm birth. From 2010 to 2019, the rate of spontaneous preterm birth decreased. Efforts should be made by both governmental and medical professionals to develop intervention programs to reduce spontaneous preterm birth in more deprived neighborhoods.