Reference Values for Placental Weight and Placental:Fetal Weight Ratio in a Swedish Population.

INTRODUCTION: There is important clinical information from placental weight and its ratio to the fetal weight. The aim with this study was to establish reference values for the placental weight and the placental:fetal weight ratio for gestational weeks 13-43 in a Swedish population. MATERIALS AND METHODS: Cases were retrospectively collected from the database used at the Pathology Department at Karolinska University Hospital and information about the placental weight, fetal weight, and gestational age was retrieved. Conditions, which could affect the placental- or fetal weight were excluded. Thereafter percentile curves were calculated for the placental weight and the placental:fetal weight ratio for gestational weeks. RESULTS: A total of 730 cases were included and percentile curves for the placental weight for gestational week 13-43 and placental:fetal weight ratio for gestational week 18-43 are presented. CONCLUSIONS: Reference values for post fixation placental weight and its ratio to fetal weight for a Swedish population are presented. The reference values are lower than the current reference values used in our institution, and this will be of importance when interpreting findings after placental examination.

Risk of stillbirth after a previous caesarean delivery: A Swedish nationwide cohort study.

OBJECTIVES: To investigate the risk of stillbirth in relation to (1) a previous caesarean delivery (CD) compared with those following a vaginal birth (VB); and (2) vaginal birth after caesarean (VBAC) compared with a repeat CD. DESIGN: Population-based cohort study. SETTING: The Swedish Medical Birth registry. POPULATION: Women with their first and second singletons between 1982 and 2012. METHODS: Multivariable logistic regression models were performed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) of the association between CD in the first pregnancy and stillbirth in the second pregnancy and the association between VBAC and stillbirth. Sub-group analyses were performed by types of CD and timing of stillbirth (antepartum and intrapartum). MAIN OUTCOME MEASURES: Stillbirth (antepartum and intrapartum fetal death). RESULTS: Of the 1 771 700 singleton births from 885 850 women, 117 114 (13.2%) women had a CD in the first pregnancy, and 51 755 had VBAC in the second pregnancy. We found a 37% increased odds of stillbirth (aOR 1.37; 95% CI 1.23-1.52) in women with a previous CD compared with VB. The odds of intrapartum stillbirth were higher in the previous pre-labour CD group (aOR 2.72; 95% CI 1.51-4.91) and in the previous in-labour CD group (aOR 1.35; 95% CI 0.76-2.40), although not statistically significant in the latter case. No increased odds were found for intrapartum stillbirth in women who had VBAC (aOR 0.99; 95% CI 0.48-2.06) compared with women who had a repeat CD. CONCLUSIONS: This study confirms that a CD is associated with an increased risk of subsequent stillbirth, with a greater risk among pre-labour CD. This association is not solely mediated by increases in intrapartum asphyxia, uterine rupture or attempted VBAC. Further research is needed to understand this association, but these findings might help healthcare providers to reach optimal decisions regarding mode of birth, particularly when CD is unnecessary.

Risk of stillbirth and adverse pregnancy outcomes in a third pregnancy when an earlier pregnancy has ended in stillbirth.

INTRODUCTION: Our study evaluated how a history of stillbirth in either of the first two pregnancies affects the risk of having a stillbirth or other adverse pregnancy outcomes in the third subsequent pregnancy. MATERIAL AND METHODS: We used the Swedish Medical Birth Register to define a population-based cohort of women who had at least three singleton births from 1973 to 2012. The exposure of interest was a history of stillbirth in either of the first two pregnancies. The primary outcome was subsequent stillbirth in the third pregnancy. Secondary outcomes included: preterm birth, preeclampsia, placental abruption and small-for-gestational-age infant. Adjusted logistic regression was performed including maternal age, body mass index, smoking, diabetes and hypertension. A sensitivity analysis was performed excluding stillbirths associated with congenital anomalies, pregestational and gestational diabetes, hypertension and preterm stillbirths. RESULTS: The study contained data on 1 316 175 births, including 8911 stillbirths. Compared with women who had two live births, the highest odds of stillbirth in the third pregnancy were observed in women who had two stillbirths (adjusted odds ratio [aOR] 11.40, 95% confidence interval [95% CI] 2.75-47.70), followed by those who had stillbirth in the second birth (live birth-stillbirth) (aOR 3.59, 95% CI 2.58-4.98), but the odds were still elevated in those whose first birth ended in stillbirth (stillbirth-live birth) (aOR 2.35, 1.68, 3.28). Preterm birth, pre-eclampsia and placental abruption followed a similar pattern. The odds of having a small-for-gestational-age infant were highest in women whose first birth ended in stillbirth (aOR 1.93, 95% CI 1.66-2.24). The increased odds of having a stillbirth in a third pregnancy when either of the earlier births ended in stillbirth remained when stillbirths associated with congenital anomalies, pregestational and gestational diabetes, hypertension or preterm stillbirths were excluded. However, when preterm stillbirths were excluded, the strength of the association was reduced. CONCLUSIONS: Even when they have had a live-born infant, women with a history of stillbirth have an increased risk of adverse pregnancy outcomes; this cannot be solely accounted for by the recurrence of congenital anomalies or maternal medical disorders. This suggests that women with a history of stillbirth should be offered additional surveillance for subsequent pregnancies.

Association between socioeconomic status with pregnancy and neonatal outcomes: An international multicenter cohort.

INTRODUCTION: Previous evidence examining the association between socioeconomic status and pregnancy complications are conflicted and often limited to using area-based measures of socioeconomic status. In this study, we aimed to examine the association between individual-level socioeconomic factors and a wide range of adverse pregnancy and neonatal outcomes using data from the IMPROvED birth cohort conducted in Sweden, the Netherlands and Republic of Ireland. MATERIAL AND METHODS: The study cohort consisted of women who participated in the IMPROvED birth cohort between 2013 and 2017. Data on socioeconomic factors were self-reported and obtained at 15 weeks' gestation, and included level of education, employment status, relationship status, and income. Data on pregnancy and neonatal outcomes included gestational hypertension, pre-eclampsia, gestational diabetes mellitus, emergency cesarean section, preterm birth, post term delivery, small for gestational age and Apgar score at 1 min. These data were obtained within 72 h following delivery and confirmed using medical records. Multivariable logistic regression examined the association between each socioeconomic variable and each outcome separately adjusting for maternal age, maternal body mass index, maternal smoking, maternal alcohol consumption and cohort center. We also examined the effect of exposure to any ≥2 risk factors compared to none. RESULTS: A total of 2879 participants were included. Adjusted results suggested that those with less than third level of education had an increased odds of gestational hypertension (OR: 1.74, 95% CI: 1.23-2.46), while those on a middle level of income had a reduced odds of emergency cesarean section (OR: 0.59, 95% CI: 0.42-0.84). No significant associations were observed between socioeconomic variables and neonatal outcomes. Exposure to any ≥2 socioeconomic risk factors was associated with an increased risk of preterm birth (OR: 1.75, 95% CI: 1.06-2.89). CONCLUSIONS: We did not find strong evidence of associations between individual-level socioeconomic factors and pregnancy and neonatal outcomes in high-income settings overall, with only few significant associations observed among pregnancy outcomes.

Comparing the results from a Swedish pregnancy cohort using data from three automated placental growth factor immunoassay platforms intended for first-trimester preeclampsia prediction.

INTRODUCTION: Risk evaluation for preeclampsia in early pregnancy allows identification of women at high risk. Prediction models for preeclampsia often include circulating concentrations of placental growth factor (PlGF); however, the models are usually limited to a specific PlGF method of analysis. The aim of this study was to compare three different PlGF methods of analysis in a Swedish cohort to assess their convergent validity and appropriateness for use in preeclampsia risk prediction models in the first trimester of pregnancy. MATERIAL AND METHODS: First-trimester blood samples were collected in gestational week 11+0 to 13+6 from 150 pregnant women at Uppsala University Hospital during November 2018 until November 2020. These samples were analyzed using the different PlGF methods from Perkin Elmer, Roche Diagnostics, and Thermo Fisher Scientific. RESULTS: There were strong correlations between the PlGF results obtained with the three methods, but the slopes of the correlations clearly differed from 1.0: PlGFPerkinElmer = 0.553 (95% confidence interval [CI] 0.518-0.588) * PlGFRoche -1.112 (95% CI -2.773 to 0.550); r = 0.966, mean difference -24.6 (95% CI -26.4 to -22.8). PlGFPerkinElmer = 0.673 (95% CI 0.618-0.729) * PlGFThermoFisher -0.199 (95% CI -2.292 to 1.894); r = 0.945, mean difference -13.8 (95% CI -15.1 to -12.6). PlGFRoche = 1.809 (95% CI 1.694-1.923) * PlGFPerkinElmer +2.010 (95% CI -0.877 to 4.897); r = 0.966, mean difference 24.6 (95% CI 22.8-26.4). PlGFRoche = 1.237 (95% CI 1.113-1.361) * PlGFThermoFisher +0.840 (95% CI -3.684 to 5.363); r = 0.937, mean difference 10.8 (95% CI 9.4-12.1). PlGFThermoFisher = 1.485 (95% CI 1.363-1.607) * PlGFPerkinElmer +0.296 (95% CI -2.784 to 3.375); r = 0.945, mean difference 13.8 (95% CI 12.6-15.1). PlGFThermoFisher = 0.808 (95% CI 0.726-0.891) * PlGFRoche -0.679 (95% CI -4.456 to 3.099); r = 0.937, mean difference -10.8 (95% CI -12.1 to -9.4). CONCLUSION: The three PlGF methods have different calibrations. This is most likely due to the lack of an internationally accepted reference material for PlGF. Despite different calibrations, the Deming regression analysis indicated good agreement between the three methods, which suggests that results from one method may be converted to the others and hence used in first-trimester prediction models for preeclampsia.

Does gestational diabetes increase the risk of maternal kidney disease? A Swedish national cohort study.

BACKGROUND: Gestational diabetes (GDM) is associated with increased risk of type 2 diabetes (T2DM) and cardiovascular disease. It is uncertain whether GDM is independently associated with the risk of chronic kidney disease. The aim was to examine the association between GDM and maternal CKD and end-stage kidney disease (ESKD) and to determine whether this depends on progression to overt T2DM. METHODS: A population-based cohort study was designed using Swedish national registry data. Previous GDM diagnosis was the main exposure, and this was stratified according to whether women developed T2DM after pregnancy. Using Cox regression models, we estimated the risk of CKD (stages 3-5), ESKD and different CKD subtypes (tubulointerstitial, glomerular, hypertensive, diabetic, other). FINDINGS: There were 1,121,633 women included, of whom 15,595 (1·4%) were diagnosed with GDM. Overall, GDM-diagnosed women were at increased risk of CKD (aHR 1·81, 95% CI 1·54-2·14) and ESKD (aHR 4·52, 95% CI 2·75-7·44). Associations were strongest for diabetic CKD (aHR 8·81, 95% CI 6·36-12·19) and hypertensive CKD (aHR 2·46, 95% CI 1·06-5·69). These associations were largely explained by post-pregnancy T2DM. Among women who had GDM + subsequent T2DM, strong associations were observed (CKD, aHR 21·70, 95% CI 17·17-27·42; ESKD, aHR 112·37, 95% CI 61·22-206·38). But among those with GDM only, associations were non-significant (CKD, aHR 1·11, 95% CI 0·89-1·38; ESKD, aHR 1·58, 95% CI 0·70-3·60 respectively). CONCLUSION: Women who experience GDM and subsequent T2DM are at increased risk of developing CKD and ESKD. However, GDM-diagnosed women who never develop overt T2DM have similar risk of future CKD/ESKD to those with uncomplicated pregnancies.

Pregnancy outcomes in women with chronic kidney disease and chronic hypertension: a National cohort study.

BACKGROUND: Maternal chronic kidney disease and chronic hypertension have been linked with adverse pregnancy outcomes. We aimed to examine the association between these conditions and adverse pregnancy outcomes over the last 3 decades. OBJECTIVE: We conducted this national cohort study to assess the association between maternal chronic disease (CH, CKD or both conditions) and adverse pregnancy outcomes with an emphasis on the effect of parity, maternal age, and BMI on these associations over the last three decades. We further investigated whether different subtypes of CKD had differing effects. STUDY DESIGN: We used data from the Swedish Medical Birth Register, including 2,788,490 singleton births between 1982 and 2012. Women with chronic kidney disease and chronic hypertension were identified from the Medical Birth Register and National Patient Register. Logistic regression models were performed to assess the associations between maternal chronic disease (chronic hypertension, chronic kidney disease, or both conditions) and pregnancy outcomes, including preeclampsia, in-labor and prelabor cesarean delivery, preterm birth, small for gestational age, and stillbirth. RESULTS: During the 30-year study period, 22,397 babies (0.8%) were born to women with chronic kidney disease, 13,279 (0.48%) to women with chronic hypertension and 1079 (0.04%) to women with both conditions. Associations with chronic hypertension were strongest for preeclampsia (adjusted odds ratio, 4.57; 95% confidence interval, 4.33-4.84) and stillbirth (adjusted odds ratio, 1.65; 95% confidence interval, 1.35-2.03) and weakest for spontaneous preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.96-1.20). The effect of chronic kidney disease varied from (adjusted odds ratio, 2.05; 95% confidence interval, 1.92-2.19) for indicated preterm birth to no effect for stillbirth (adjusted odds ratio, 1.16; 95% confidence interval, 0.95-1.43). Women with both conditions had the strongest associations for in-labor cesarean delivery (adjusted odds ratio, 1.86; 95% confidence interval, 1.49-2.32), prelabor cesarean delivery (adjusted odds ratio, 2.68; 95% confidence interval, 2.18-3.28), indicated preterm birth (adjusted odds ratio, 9.09; 95% confidence interval, 7.61-10.7), and small for gestational age (adjusted odds ratio, 4.52; 95% confidence interval, 3.68-5.57). The results remained constant over the last 3 decades. Stratified analyses of the associations by parity, maternal age, and body mass index showed that adverse outcomes remained independently higher in women with these conditions, with worse outcomes in multiparous women. All chronic kidney disease subtypes were associated with higher odds of preeclampsia, in-labor cesarean delivery, and medically indicated preterm birth. Different subtypes of chronic kidney disease had differing risks; strongest associations of preeclampsia (adjusted odds ratio, 3.98; 95% confidence interval, 2.98-5.31) and stillbirth (adjusted odds ratio, 2.73; 95% confidence interval, 1.13-6.59) were observed in women with congenital kidney disease, whereas women with diabetic nephropathy had the most pronounced increase odds of in-labor cesarean delivery (adjusted odds ratio, 3.54; 95% confidence interval, 2.06-6.09), prelabor cesarean delivery (adjusted odds ratio, 7.50; 95% confidence interval, 4.74-11.9), and small for gestational age (adjusted odds ratio, 4.50; 95% confidence interval, 2.92-6.94). In addition, women with renovascular disease had the highest increased risk of preterm birth in both spontaneous preterm birth (adjusted odds ratio, 3.01; 95% confidence interval, 1.57-5.76) and indicated preterm birth (adjusted odds ratio, 8.09; 95% confidence interval, 5.73-11.4). CONCLUSION: Women with chronic hypertension, chronic kidney disease, or both conditions are at an increased risk of adverse pregnancy outcomes which were independent of maternal age, body mass index, and parity. Multidisciplinary management should be provided with intensive clinical follow-up to support these women during pregnancy, particularly multiparous women. Further research is needed to evaluate the effect of disease severity on adverse pregnancy outcomes.

Study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT): a study protocol for a Swedish prospective multicentre cohort study.

INTRODUCTION: First-trimester pregnancy risk evaluation facilitates individualised antenatal care, as well as application of preventive strategies for pre-eclampsia or birth of a small for gestational age infant. A range of early intervention strategies in pregnancies identified as high risk at the end of the first trimester has been shown to decrease the risk of preterm pre-eclampsia (<37 gestational weeks). The aim of this project is to create the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) database; a nationwide database with individual patient data, including predictors recorded at the end of the first trimester and later pregnancy outcomes, to identify women at high risk of pre-eclampsia. A second aim is to link the IMPACT database to a biobank with first-trimester blood samples. METHODS AND ANALYSIS: This is a Swedish prospective multicentre cohort study. Women are included between the 11th and 14th weeks of pregnancy. At inclusion, pre-identified predictors are retrieved by interviews and medical examinations. Blood samples are collected and stored in a biobank. Additional predictors and pregnancy outcomes are retrieved from the Swedish Pregnancy Register. Inclusion in the study began in November 2018 with a targeted sample size of 45 000 pregnancies by end of 2021. Creation of a new risk prediction model will then be developed, validated and implemented. The database and biobank will enable future research on prediction of various pregnancy-related complications. ETHICS AND DISSEMINATION: Confidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (Uppsala 2018-231) and national biobank approval at Uppsala Biobank (18237 2 2018 231). Results from the current as well as future studies using information from the IMPACT database will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03831490.

Hypertensive disorders of pregnancy and the risk of chronic kidney disease: A Swedish registry-based cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) (preeclampsia, gestational hypertension) are associated with an increased risk of end-stage kidney disease (ESKD). Evidence for associations between HDP and chronic kidney disease (CKD) is more limited and inconsistent. The underlying causes of CKD are wide-ranging, and HDP may have differential associations with various aetiologies of CKD. We aimed to measure associations between HDP and maternal CKD in women who have had at least one live birth and to identify whether the risk differs by CKD aetiology. METHODS AND FINDINGS: Using data from the Swedish Medical Birth Register (MBR), singleton live births from 1973 to 2012 were identified and linked to data from the Swedish Renal Register (SRR) and National Patient Register (NPR; up to 2013). Preeclampsia was the main exposure of interest and was treated as a time-dependent variable. Gestational hypertension was also investigated as a secondary exposure. The primary outcome was maternal CKD, and this was classified into 5 subtypes: hypertensive, diabetic, glomerular/proteinuric, tubulointerstitial, and other/nonspecific CKD. Cox proportional hazard regression models were used, adjusting for maternal age, country of origin, education level, antenatal BMI, smoking during pregnancy, gestational diabetes, and parity. Women with pre-pregnancy comorbidities were excluded. The final sample consisted of 1,924,409 women who had 3,726,554 singleton live births. The mean (±SD) age of women at first delivery was 27.0 (±5.1) years. Median follow-up was 20.7 (interquartile range [IQR] 9.9-30.0) years. A total of 90,917 women (4.7%) were diagnosed with preeclampsia, 43,964 (2.3%) had gestational hypertension, and 18,477 (0.9%) developed CKD. Preeclampsia was associated with a higher risk of developing CKD during follow-up (adjusted hazard ratio [aHR] 1.92, 95% CI 1.83-2.03, p < 0.001). This risk differed by CKD subtype and was higher for hypertensive CKD (aHR 3.72, 95% CI 3.05-4.53, p < 0.001), diabetic CKD (aHR 3.94, 95% CI 3.38-4.60, p < 0.001), and glomerular/proteinuric CKD (aHR 2.06, 95% CI 1.88-2.26, p < 0.001). More modest associations were observed between preeclampsia and tubulointerstitial CKD (aHR 1.44, 95% CI 1.24-1.68, p < 0.001) or other/nonspecific CKD (aHR 1.51, 95% CI 1.38-1.65, p < 0.001). The risk of CKD was increased after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who had gestational hypertension also had increased risk of developing CKD (aHR 1.49, 95% CI 1.38-1.61, p < 0.001). This association was strongest for hypertensive CKD (aHR 3.13, 95% CI 2.47-3.97, p < 0.001). Limitations of the study are the possibility that cases of CKD were underdiagnosed in the national registers, and some women may have been too young to have developed symptomatic CKD despite the long follow-up time. Underreporting of postpartum hypertension is also possible. CONCLUSIONS: In this study, we found that HDP are associated with increased risk of maternal CKD, particularly hypertensive or diabetic forms of CKD. The risk is higher after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who experience HDP may benefit from future systematic renal monitoring.

Risk of long-term renal disease in women with a history of preterm delivery: a population-based cohort study.

BACKGROUND: Preterm delivery is an independent risk factor for maternal cardiovascular disease. Little is known about the association between preterm delivery and maternal renal function. This study aimed to examine whether women who experience preterm delivery are at increased risk of subsequent chronic kidney disease (CKD) and end-stage kidney disease (ESKD). METHODS: Using data from the Swedish Medical Birth Register, singleton live births from 1973 to 2012 were identified and linked to data from the Swedish Renal Register and National Patient Register (up to 2013). Gestational age at delivery was the main exposure and treated as a time-dependent variable. Primary outcomes were maternal CKD or ESKD. Cox proportional hazard regression models were used for analysis. RESULTS: The dataset included 1,943,716 women who had 3,760,429 singleton live births. The median follow-up was 20.6 (interquartile range 9.9-30.0) years. Overall, 162,918 women (8.4%) delivered at least 1 preterm infant (< 37 weeks). Women who had any preterm delivery (< 37 weeks) were at increased risk of CKD (adjusted hazard ratio (aHR) 1.39, 95% CI 1.32-1.45) and ESKD (aHR 2.22, 95% CI 1.90-2.58) compared with women who only delivered at term (≥ 37 weeks). Women who delivered an extremely preterm infant (< 28 weeks) were at increased risk of CKD (aHR 1.84, 95% CI 1.52-2.22) and ESKD (aHR 3.61, 95% CI 2.03-6.39). The highest risk of CKD and ESKD was in women who experienced preterm delivery + preeclampsia (vs. non-preeclamptic term deliveries, for CKD, aHR 2.81, 95% CI 2.46-3.20; for ESKD, aHR 6.70, 95% CI 4.70-9.56). However, spontaneous preterm delivery was also associated with increased risk of CKD (aHR 1.32, 95% CI 1.25-1.39) and ESKD (aHR 1.99, 95% CI 1.67-2.38) independent of preeclampsia or small for gestational age (SGA). CONCLUSIONS: Women with history of preterm delivery are at increased risk of CKD and ESKD. The risk is higher among women who had very preterm or extremely preterm deliveries, or whose preterm delivery was medically indicated. Women who experience spontaneous preterm delivery are at increased risk of long-term renal disease independent of preeclampsia or SGA. Preterm delivery may act as a risk marker for adverse maternal renal outcomes.

Stillbirth is associated with increased risk of long-term maternal renal disease: a nationwide cohort study.

BACKGROUND: Stillbirth is a devastating adverse pregnancy outcome that may occur without any obvious reason or may occur in the context of fetal growth restriction, preeclampsia, or other obstetric complications. There is increasing evidence that women who experience stillbirths are at greater risk of long-term cardiovascular disease, but little is known about their risk of chronic kidney disease and end-stage renal disease. We conducted the largest study to date to investigate the subsequent risk of maternal chronic kidney disease and end-stage renal disease following stillbirth. OBJECTIVE: To identify whether pregnancy complicated by stillbirth is associated with subsequent risk of maternal chronic kidney disease and end-stage renal disease, independent of underlying medical or obstetric comorbidities. STUDY DESIGN/METHODS: We conducted a population-based cohort study using nationwide data from the Swedish Medical Birth Register, National Patient Register, and Swedish Renal Register. We included all women who had live births and stillbirths from 1973 to 2012, with follow-up to 2013. Women with preexisting renal disease were excluded. Cox proportional hazard regression models were used to estimate adjusted hazard ratios and 95% confidence intervals for associations between stillbirth and maternal chronic kidney disease and end-stage renal disease respectively. We controlled for maternal age, year of delivery, country of origin, parity, body mass index, smoking, gestational diabetes, preeclampsia, and small for gestational age deliveries. Women who had a history of medical comorbidities, which may predispose to renal disease (prepregnancy cardiovascular disease, hypertension, diabetes, lupus, systemic sclerosis, hemoglobinopathy, or coagulopathy), were excluded from the main analysis and examined separately. RESULTS: There were 1,941,057 unique women who had 3,755,444 singleton pregnancies, followed up over 42,313,758 person-years. The median follow-up time was 20.7 years (interquartile range, 9.9-30.0 years). 13,032 women (0.7%) had at least 1 stillbirth. Women who had experienced at least 1 stillbirth had a greater risk of developing chronic kidney disease (adjusted hazard ratio, 1.26; 95% confidence interval, 1.09-1.45) and end-stage renal disease (adjusted hazard ratio, 2.25; 95% confidence interval, 1.55-3.25) compared with women who only had live births. These associations persisted after removing all stillbirths that occurred in the context of preeclampsia, and small for gestational age or congenital malformations (for chronic kidney disease, adjusted hazard ratio, 1.33; 95% confidence interval, 1.13-1.57; for end-stage renal disease, adjusted hazard ratio, 2.95; 95% confidence interval, CI 1.86-4.68). There was no significant association observed between stillbirth and either chronic kidney disease or end-stage renal disease in women who had preexisting medical comorbidities (chronic kidney disease, adjusted hazard ratio, 1.13; 95% confidence interval, 0.73-1.75 or end-stage renal disease, adjusted hazard ratio, 1.49; 95% confidence interval, 0.78-2.85). CONCLUSION: Women who have a history of stillbirth may be at increased risk of chronic kidney disease and end-stage renal disease compared with women who have only had live births. This association persists independently of preeclampsia, and small for gestational age, maternal smoking, obesity, and medical comorbidities. Further research is required to determine whether affected women would benefit from closer surveillance and follow-up for future renal disease.

Adverse Pregnancy Outcomes and Long-term Maternal Kidney Disease: A Systematic Review and Meta-analysis.

Importance: Adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery, are associated with increased risk of maternal cardiovascular disease. Little is known about whether adverse pregnancy outcomes are associated with increased risk of maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Objective: To review and synthesize the published literature on adverse pregnancy outcomes (hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery) and subsequent maternal CKD and ESKD. Data Sources: PubMed, Embase, and Web of Science were searched from inception to July 31, 2019, for cohort and case-control studies of adverse pregnancy outcomes and maternal CKD and ESKD. Study Selection: Selected studies included the following: a population of pregnant women, exposure to an adverse pregnancy outcome of interest, and at least 1 primary outcome (CKD or ESKD) or secondary outcome (hospitalization or death due to kidney disease). Adverse pregnancy outcomes included exposure to hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, or chronic hypertension), preterm delivery (<37 weeks), and gestational diabetes. Three reviewers were involved in study selection. Of 5656 studies retrieved, 23 were eligible for inclusion. Data Extraction and Synthesis: The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines were followed throughout. Three reviewers extracted data and appraised study quality. Random-effects meta-analyses were used to calculate overall pooled estimates using the generic inverse variance method. Main Outcomes and Measures: Primary outcomes included CKD and ESKD diagnosis, defined using established clinical criteria (estimated glomerular filtration rate or albuminuria values) or hospital records. The protocol for this systematic review was registered on PROSPERO (CRD42018110891). Results: Of 23 studies included (5 769 891 participants), 5 studies reported effect estimates for more than 1 adverse pregnancy outcome. Preeclampsia was associated with significantly increased risk of CKD (pooled adjusted risk ratio [aRR], 2.11; 95% CI, 1.72-2.59), ESKD (aRR, 4.90; 95% CI, 3.56-6.74), and kidney-related hospitalization (aRR, 2.65; 95% CI, 1.03-6.77). Gestational hypertension was associated with increased risk of CKD (aRR, 1.49; 95% CI, 1.11-2.01) and ESKD (aRR, 3.64; 95% CI, 2.34-5.66). Preterm preeclampsia was associated with increased risk of ESKD (aRR, 5.66; 95% CI, 3.06-10.48); this association with ESKD persisted for women who had preterm deliveries without preeclampsia (aRR, 2.09; 95% CI, 1.64-2.66). Gestational diabetes was associated with increased risk of CKD among black women (aRR, 1.78; 95% CI, 1.18-2.70), but not white women (aRR, 0.81; 95% CI, 0.58-1.13). Conclusions and Relevance: In this meta-analysis, exposure to adverse pregnancy outcomes, including hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery, was associated with higher risk of long-term kidney disease. The risk of ESKD was highest among women who experienced preeclampsia. A systematic approach may be warranted to identify women at increased risk of kidney disease, particularly after hypertensive disorders of pregnancy, and to optimize their long-term follow-up.

Correction: Preeclampsia and risk of end stage kidney disease: A Swedish nationwide cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002875.].

Preeclampsia and risk of end stage kidney disease: A Swedish nationwide cohort study.

BACKGROUND: Preeclampsia has been suggested to increase the risk of end-stage kidney disease (ESKD); however, most studies were unable to adjust for potential confounders including pre-existing comorbidities such as renal disease and cardiovascular disease (CVD). We aimed to examine the association between preeclampsia and the risk of ESKD in healthy women, while taking into account pre-existing comorbidity and potential confounders. METHODS AND FINDINGS: Using data from the Swedish Medical Birth Register (MBR), women who had singleton live births in Sweden between 1982 and 2012, including those who had preeclampsia, were identified. Women with a diagnosis of chronic kidney disease (CKD), CVD, hypertension, or diabetes prior to the first pregnancy were excluded. The outcome was a diagnosis of ESKD, identified from the Swedish Renal Registry (SRR) from January 1, 1991, onwards along with the specified cause of renal disease. We conducted Cox proportional hazards regression analysis to examine the association between preeclampsia and ESKD adjusting for several potential confounders: maternal age, body mass index (BMI), education, native country, and smoking. This analysis accounts for differential follow-up among women because women had different lengths of follow-up time. We performed subgroup analyses according to preterm preeclampsia, small for gestational age (SGA), and women who had 2 pregnancies with preeclampsia in both. The cohort consisted of 1,366,441 healthy women who had 2,665,320 singleton live births in Sweden between 1982 and 2012. At the first pregnancy, women's mean (SD) age and BMI were 27.8 (5.13) and 23.4 (4.03), respectively, 15.2% were smokers, and 80.7% were native Swedish. The overall median (interquartile range [IQR]) follow-up was 7.4 years (3.2-17.4) and 16.4 years (10.3-22.0) among women with ESKD diagnosis. During the study period, 67,273 (4.9%) women having 74,648 (2.8% of all pregnancies) singleton live births had preeclampsia, and 410 women developed ESKD with an incidence rate of 1.85 per 100,000 person-years. There was an association between preeclampsia and ESKD in the unadjusted analysis (hazard ratio [HR] = 4.99, 95% confidence interval [CI] 3.93-6.33; p < 0.001), which remained in the extensively adjusted (HR = 4.96, 95% CI 3.89-6.32, p < 0.001) models. Women who had preterm preeclampsia (adjusted HR = 9.19; 95% CI 5.16-15.61, p < 0.001) and women who had preeclampsia in 2 pregnancies (adjusted HR = 7.13, 95% CI 3.12-16.31, p < 0.001) had the highest risk of ESKD compared with women with no preeclampsia. Considering this was an observational cohort study, and although we accounted for several potential confounders, residual confounding cannot be ruled out. CONCLUSIONS: The present findings suggest that women with preeclampsia and no major comorbidities before their first pregnancy are at a 5-fold increased risk of ESKD compared with parous women with no preeclampsia; however, the absolute risk of ESKD among women with preeclampsia remains small. Preeclampsia should be considered as an important risk factor for subsequent ESKD. Whether screening and/or preventive strategies will reduce the risk of ESKD in women with adverse pregnancy outcomes is worthy of further investigation.

Adverse pregnancy outcomes and long-term risk of maternal renal disease: a systematic review and meta-analysis protocol.

INTRODUCTION: Adverse pregnancy outcomes, such as hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM) and preterm birth have been linked to maternal cardiovascular disease in later life. Pre-eclampsia (PE) is associated with an increased risk of postpartum microalbuminuria, but there is no clear consensus on whether HDP increases the risk of maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Similarly, it is uncertain whether GDM, preterm birth and delivery of low birth-weight infants independently predict the risk of maternal renal disease in later life. The aims of this proposed systematic review and meta-analysis are to summarise the available evidence examining the association between adverse outcomes of pregnancy (HDP, GDM, preterm birth, delivery of low birth-weight infant) and later maternal renal disease and to synthesise the results of relevant studies. METHODS AND ANALYSIS: A systematic search of PubMed, EMBASE and Web of Science will be undertaken using a detailed prespecified search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction and appraise the quality of included studies using a bias classification tool. Original case-control and cohort studies published in English will be considered for inclusion. Primary outcomes of interest will be CKD and ESKD; secondary outcomes will be hospitalisation for renal disease and deaths from renal disease. Meta-analyses will be performed to calculate the overall pooled estimates using the generic inverse variance method. The systematic review will follow the Meta-analyses Of Observational Studies in Epidemiology guidelines. ETHICS AND DISSEMINATION: This systematic review and meta-analysis will be based on published data, and thus there is no requirement for ethics approval. The results will be shared through publication in a peer reviewed journal and through presentations at academic conferences. PROSPERO REGISTRATION NUMBER: CRD42018110891.

[Invasive fetal therapy]. / Invasiv fosterterapi utvecklas allt mer - Från intrauterin blodtransfusion till fetoskopisk kirurgi, shuntinläggning, laserbehandling och radiofrekvensablation.

Invasive fetal therapy  Invasive fetal therapy in Sweden consists of fetoscopic interventions to treat twin-to-twin transfusion syndrome (TTS) or twin anemia polycytemia sequence (TAPS) in monochorionic twin or triplet pregnancies and for selective reduction in monochorionic twins complicated by discordant anomalies or severe growth retardation in one fetus. Alternative methods, such as intrafetal laser ablation and radio frequency ablation, are also used for selective reduction and rarely to treat fetal tumors. Ultrasound guided intrauterine blood transfusions to treat fetal anemia have been performed for a long time with excellent results. Placement of thoraco-amniotic shunts and vesico-amniotic shunts is indicated in a few cases per year in Sweden. Since these rare interventions were centralized to one national center in 2013, the outcome of the fetal interventions has improved consistently.

Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.

Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

Pregnancy outcome for fetuses with increased nuchal translucency but normal karyotype.

OBJECTIVE: To investigate pregnancy outcome for fetuses with nuchal translucency (NT) ≥3.5 mm but normal karyotype in the Stockholm (Sweden) area. METHODS: A retrospective population-based cohort study. From 2006 to 2012, fetal NT was measured in 55123 singleton pregnancies. There were 341 pregnancies with NT thickness ≥3.5 mm; 139 had a normal karyotype, 164 had an abnormal karyotype and 38 were removed from the study. Pregnancy outcome was defined as adverse (termination of pregnancy [TOP], miscarriage [MC], intrauterine fetal death [IUFD], or delivery of a child with structural defects or genetic disorders), or favourable (delivery of a child without any structural defects or genetic disorders diagnosed before discharge). RESULTS: Of the 139 high NT pregnancies with normal karyotype, 110 (79.2%) resulted in live births, one (0.7%) IUFD, 23 (16.5%) TOP and five (3.6%) MC. The risk of an adverse pregnancy outcome increased with increasing NT. Structural fetal defects were found in 28 (19.5%) of pregnancies undergoing second trimester ultrasound screening, of which seven resulted in live births and 21 were terminated. The most common structural defect was cardiac defects. CONCLUSIONS: Adverse pregnancy outcome increased with increasing NT, even with normal karyotype, however, the prognosis is good if the second trimester ultrasound screening is normal.

First trimester contingent testing with either nuchal translucency or cell-free DNA. Cost efficiency and the role of ultrasound dating.

OBJECTIVE: To evaluate the performance and cost efficacy of different first-trimester contingent screening strategies based on an initial analysis of biochemical markers. DESIGN: Retrospective study. SETTING: Swedish National Quality Register for prenatal diagnosis. POPULATION: 35,780 women with singleton pregnancies. METHODS: Serum values from first trimester biochemistry were re-analyzed in a contingent approach. For risks between 1:40 and 1:1000, risk estimates from nuchal translucency measurements were added and outcomes were compared using either a final cut-off risk of 1:200 to proceed with invasive testing or offering non-invasive prenatal testing. In a subgroup of 12,836 women with regular menstrual cycles the same analyses were performed using data on the last menstrual period for determining gestational age. The costs of detecting one case of aneuploidy were compared. MAIN OUTCOME MEASURES: Comparison of screening strategies. RESULTS: The detection rate was the same (87%) in the contingent group as in complete combined screening, with only 41% requiring a nuchal translucency scan. As an alternative, offering non-invasive prenatal testing to the intermediate risk group would result in a detection rate of 98%, but the cost to detect one case of trisomy 21 would be 83% higher than the cost associated with traditional combined screening. CONCLUSIONS: First trimester examination using a contingent approach will achieve similar results compared with full combined screening. Non-invasive prenatal testing will not be cost-effective when a high proportion of pregnancies need further testing.

Causes of stillbirth at different gestational ages in singleton pregnancies.

OBJECTIVE: To compare causes of stillbirth in preterm and term pregnancies. DESIGN: Cohort study. SETTING: All delivery wards in Stockholm, 1998-2009. POPULATION: Stillbirths from singleton pregnancies of gestational age ≥22(+0) (n = 1089) extracted from a web-based database including all stillbirths in the major Stockholm area since 1998. METHODS: The parents of the stillborns were all offered an extensive standardized investigation. The causes of death were assigned in a perinatal audit using the Stockholm classification of stillbirth. Singleton stillbirths were divided into preterm (gestational week 22(+0) -36(+6) ) and term/post-term (gestational week ≥37(+0) ). The term/post-term group was subdivided into term (gestational week 37(+0) -40(+6) ) and post-term stillbirths (gestational week ≥41(+0) ). MAIN OUTCOME MEASURE: Causes of stillbirth at different gestational ages. RESULTS: A higher proportion of placental abruption and preeclampsia/hypertension was seen in preterm stillbirths compared with term/post-term stillbirths, which instead had a higher proportion of umbilical cord complications and infection. Infection was more common in post-term than term stillbirths (46.5 vs. 19.8%, p < 0.001). CONCLUSION: Increased knowledge of causes of stillbirth in different gestational ages may be valuable in developing strategies for prevention of fetal death. The high proportion of infection in post-term stillbirths could be clinically important and warrants further studies.