Deep survival analysis for interpretable time-varying prediction of preeclampsia risk.

OBJECTIVE: Survival analysis is widely utilized in healthcare to predict the timing of disease onset. Traditional methods of survival analysis are usually based on Cox Proportional Hazards model and assume proportional risk for all subjects. However, this assumption is rarely true for most diseases, as the underlying factors have complex, non-linear, and time-varying relationships. This concern is especially relevant for pregnancy, where the risk for pregnancy-related complications, such as preeclampsia, varies across gestation. Recently, deep learning survival models have shown promise in addressing the limitations of classical models, as the novel models allow for non-proportional risk handling, capturing nonlinear relationships, and navigating complex temporal dynamics. METHODS: We present a methodology to model the temporal risk of preeclampsia during pregnancy and investigate the associated clinical risk factors. We utilized a retrospective dataset including 66,425 pregnant individuals who delivered in two tertiary care centers from 2015 to 2023. We modeled the preeclampsia risk by modifying DeepHit, a deep survival model, which leverages neural network architecture to capture time-varying relationships between covariates in pregnancy. We applied time series k-means clustering to DeepHit's normalized output and investigated interpretability using Shapley values. RESULTS: We demonstrate that DeepHit can effectively handle high-dimensional data and evolving risk hazards over time with performance similar to the Cox Proportional Hazards model, achieving an area under the curve (AUC) of 0.78 for both models. The deep survival model outperformed traditional methodology by identifying time-varied risk trajectories for preeclampsia, providing insights for early and individualized intervention. K-means clustering resulted in patients delineating into low-risk, early-onset, and late-onset preeclampsia groups-notably, each of those has distinct risk factors. CONCLUSION: This work demonstrates a novel application of deep survival analysis in time-varying prediction of preeclampsia risk. Our results highlight the advantage of deep survival models compared to Cox Proportional Hazards models in providing personalized risk trajectory and demonstrating the potential of deep survival models to generate interpretable and meaningful clinical applications in medicine.

Preeclampsia: Pathophysiology, Challenges, and Perspectives

Hypertensive disorders of pregnancy-chronic hypertension, gestational hypertension, and preeclampsia-are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women.

Neurovascular dysfunctions in hypertensive disorders of pregnancy.

Hypertensive disorders in pregnancy pose a huge challenge to the socioeconomic stability of a community; being a major cause of maternal and neonatal morbidity and mortality during delivery. Although there have been recent improvements in management strategies, still, the diversified nature of the underlying pathogenesis undermines their effectiveness. Generally, these disorders are categorized into two; hypertensive disorders of pregnancy with proteinuria (pre-eclampsia and eclampsia) and hypertensive disorders of pregnancy without proteinuria (gestational and chronic hypertension). Each of these conditions may present with unique characteristics that have interwoven symptoms. However, the tendency of occurrence heightens in the presence of any pre-existing life-threatening condition(s), environmental, and/or other genetic factors. Investigations into the cerebrovascular system demonstrate changes in the histoarchitectural organization of neurons, the proliferation of glial cells with an associated increase in inflammatory cytokines. These are oxidative stress indicators which impose a deteriorating impact on the structures that form the neurovascular unit and the blood-brain barrier (BBB). Such a pathologic state distorts the homeostatic supply of blood into the brain, and enhances the permeability of toxins/pathogens through a process called hyperperfusion at the BBB. Furthermore, a notable aspect of the pathogenesis of hypertensive disorders of pregnancy is endothelial dysfunction aggravated when signaling of the vasoprotective molecule, nitric oxide, amongst other neurotransmitter regulatory activities are impaired. This review aims to discuss the alterations in cerebrovascular regulation that determine the incidence of hypertension in pregnancy.

Impact of Hypertension and Preeclampsia Intervention Trial At Near Term-I (HYPITAT-I) on obstetric management and outcome in The Netherlands.

OBJECTIVE: The Hypertension and Preeclampsia Intervention Trial At near Term-I (HYPITAT-I) randomized controlled trial showed that, in women with gestational hypertension or mild pre-eclampsia at term, induction of labor, compared with expectant management, was associated with improved maternal outcome without compromising neonatal outcome. The aim of the current study was to evaluate the impact of these findings on obstetric management and maternal and perinatal outcomes in The Netherlands. METHODS: We retrieved data for the period 2000-2014 from the Dutch National Perinatal Registry, including 143 749 women with gestational hypertension or pre-eclampsia and a singleton fetus in cephalic presentation, delivered between 36 + 0 and 40 + 6 weeks of gestation (hypertensive disorder of pregnancy (HDP) group). Pregnant women without HDP were used as the reference group (n = 1 649 510). The HYPITAT-I trial was conducted between 2005 and 2008. To study the impact of HYPITAT-I, we compared rate of induction of labor, mode of delivery and maternal and perinatal outcomes in the periods before (2000-2005) and after (2008-2014) the trial. We also differentiated between hospitals that participated in HYPITAT-I and those that did not. RESULTS: In the HDP group, the rate of induction of labor increased from 51.1% before the HYPITAT-I trial to 64.2% after it (relative risk (RR), 1.26; 95% CI, 1.24-1.27). Maternal mortality decreased from 0.022% before the trial to 0.004% after it (RR, 0.20; 95% CI, 0.06-0.70) and perinatal death decreased from 0.49% to 0.27% (RR, 0.54; 95% CI, 0.45-0.65), which was attributable mostly to a decrease in fetal death. Both the increase in induction rate and the reduction in hypertensive complications were more pronounced in hospitals that participated in the HYPITAT-I trial than in those that did not. Following HYPITAT-I, the rate of induction of labor also increased (by 4.6 percentage points) in the reference group; however, the relative increase in the HDP group (13.1 percentage points) was significantly greater (P < 0.001 for the interaction). The reduction in maternal and perinatal deaths did not differ significantly between the HDP and reference groups. There was a decreased incidence of placental abruption in both HDP and reference groups, which was significantly greater in the HDP than in the reference group (P < 0.001 for the interaction). There was also an increased incidence of emergency Cesarean section in both HDP and reference groups; however, this change was significantly greater in the reference than in the HDP group (P < 0.001 for the interaction). CONCLUSION: Following the HYPITAT-I trial, there was a higher rate of induction of labor and improved obstetric outcome in term pregnancies complicated by HDP in The Netherlands. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Maternal near miss and mortality attributable to hypertensive disorders in a tertiary hospital, Tanzania; a cross-sectional study.

BACKGROUND: Hypertensive disorders in pregnancy is the second most common direct cause of maternal deaths accounting for 14% of maternal deaths worldwide. Severe pre-eclampsia and eclampsia are among the hypertensive disorders in pregnancy causing significant morbidity and mortality, hence categorized as Maternal Near Miss. At Muhimbili National Hospital these are the leading causes of maternal deaths accounting for 19.9% of maternal death. This study aimed to determine the proportion of severe maternal outcomes and maternal near-miss indices among patients with severe pre-eclampsia and eclampsia at Muhimbili National Hospital in Tanzania. METHODS: A descriptive cross-sectional study was conducted between September 2017 to January 2018 at Muhimbili National Hospital. Women with severe pre-eclampsia and eclampsia were recruited. Data were extracted from patient files after admission, and followed up until discharge or death; after discharge was categorized as maternal near miss or death as maternal death. The outcome indicators were calculated using the total number of live births during the study period, the number of maternal deaths and maternal near-miss due to severe pre-eclampsia/ eclampsia in the same period. RESULTS: Nearly two-thirds of women recruited, 199 (62.2%) had severe preeclampsia while 121 (37.8%) had eclampsia, 71 (22.1%) had severe maternal outcome whereby 63 had maternal near-miss with organ dysfunction and 8 maternal deaths. The overall maternal near-miss ratio was 87.4 while that for severe pre-eclampsia was 54, and 33 per 1000 live births for eclampsia. Overall severe maternal outcome ratio was 19.4 while that for severe pre-eclampsia was 12 and that for eclampsia was 9.5 per 1000 live births. Mortality index was 11% and the Case fatality rate was 2.5%. CONCLUSION: There is a high proportion of women with severe maternal outcome attributable to severe pre-eclampsia and eclampsia, with a reduced proportion of maternal deaths. This signifies improvement of performance in our facility in dealing with patients with severe morbidities due to severe pre-eclampsia and eclampsia, however, more effort should be put to further reduce maternal mortality.

Placental growth factor for the prognosis of women with preeclampsia (fullPIERS model extension): context matters.

BACKGROUND: The fullPIERS risk prediction model was developed to identify which women admitted with confirmed diagnosis of preeclampsia are at highest risk of developing serious maternal complications. The model discriminates well between women who develop (vs. those who do not) adverse maternal outcomes. It has been externally validated in several populations. We assessed whether placental growth factor (PlGF), a biomarker associated with preeclampsia risk, adds incremental value to the fullPIERS model. METHODS: Using a cohort of women admitted into tertiary hospitals in well-resourced settings (the USA and Canada), between May 2010 to February 2012, we evaluated the incremental value of PlGF added to fullPIERS for prediction of adverse maternal outcomes within 48 h after admission with confirmed preeclampsia. The discriminatory performance of PlGF and the fullPIERS model were assessed in this cohort using the area under the receiver's operating characteristic curve (AUROC) while the extended model (fullPIERS +PlGF) was assessed based on net reclassification index (NRI) and integrated discrimination improvement (IDI) performances. RESULTS: In a cohort of 541 women delivered shortly (< 1 week) after presentation, 8.1% experienced an adverse maternal outcome within 48 h of admission. Prediction of adverse maternal outcomes was not improved by addition of PlGF to fullPIERS (NRI: -8.7, IDI - 0.06). Discriminatory performance (AUROC) was 0.67 [95%CI: 0.59-0.75] for fullPIERS only and 0.67 [95%CI: 0.58-0.76]) for fullPIERS extended with PlGF, a performance worse than previously documented in fullPIERS external validation studies (AUROC > 0.75). CONCLUSIONS: While fullPIERS model performance may have been affected by differences in healthcare context between this study cohort and the model development and validation cohorts, future studies are required to confirm whether PlGF adds incremental benefit to the fullPIERS model for prediction of adverse maternal outcomes in preeclampsia in settings where expectant management is practiced.

Preeclampsia knowledge among postpartum women treated for preeclampsia and eclampsia at Korle Bu Teaching Hospital in Accra, Ghana.

BACKGROUND: Preeclampsia/eclampsia is a major cause of maternal morbidity and mortality worldwide, yet patients' perspectives about their diagnosis are not well understood. Our study examines patient knowledge among women with preeclampsia/eclampsia in a large urban hospital in Ghana. METHODS: Postpartum women diagnosed with preeclampsia or eclampsia were asked to complete a survey 2-5 days after delivery that assessed demographic information, key obstetric factors, and questions regarding provider counseling. Provider counseling on diagnosis, causes, complications, and future health effects of preeclampsia/eclampsia was quantified on a 4-point scale ('Counseling Composite Score'). Participants also completed an objective knowledge assessment regarding preeclampsia/eclampsia, scored from 0 to 22 points ('Preeclampsia/Eclampsia Knowledge Score' (PEKS)). Linear regression was used to identify predictors of knowledge score. RESULTS: A total of 150 participants were recruited, 88.7% (133) with preeclampsia and 11.3% (17) with eclampsia. Participants had a median age of 32 years, median parity of 2, and mean number of 5.4 antenatal visits. Approximately half of participants reported primary education as their highest level of education. While 74% of women reported having a complication during pregnancy, only 32% of participants with preeclampsia were able to correctly identify their diagnosis, and no participants diagnosed with eclampsia could correctly identify their diagnosis. Thirty-one percent of participants reported receiving no counseling from providers, and only 11% received counseling in all four categories. Even when counseled, 40-50% of participants reported incomplete understanding. Out of 22 possible points on a cumulative knowledge assessment scale, participants had a mean score of 12.9 ± 0.38. Adjusting for age, parity, and the number of antenatal visits, higher scores on the knowledge assessment are associated with more provider counseling (ß 1.4, SE 0.3, p < 0.001) and higher level of education (ß 1.3, SE 0.48, p = 0.008). CONCLUSIONS: Counseling by healthcare providers is associated with higher performance on a knowledge assessment about preeclampsia/eclampsia. Patient knowledge about preeclampsia/eclampsia is important for efforts to encourage informed healthcare decisions, promote early antenatal care, and improve self-recognition of warning signs-ultimately improving morbidity and reducing mortality.

An Observational Pilot Study Evaluating the Utility of Minimally Invasive Tissue Sampling to Determine the Cause of Stillbirths in South African Women.

BACKGROUND: Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting. METHODS: This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths. RESULTS: A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%). CONCLUSIONS: In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause.

Putting the "M" back in maternal-fetal medicine: A 5-year report card on a collaborative effort to address maternal morbidity and mortality in the United States.

The Centers for Disease Control and Prevention have demonstrated continuous increased risk for maternal mortality and severe morbidity with racial disparities among non-Hispanic black women an important contributing factor. More than 50,000 women experienced severe maternal morbidity in 2014, with a mortality rate of 18.0 per 100,000, higher than in many other developed countries. In 2012, the first "Putting the 'M' back in Maternal-Fetal Medicine" session was held at the Society for Maternal-Fetal Medicine's (SMFM) Annual Meeting. With the realization that rising risk for severe maternal morbidity and mortality required action, the "M in MFM" meeting identified the following urgent needs: (i) to enhance education and training in maternal care for maternal-fetal medicine (MFM) fellows; (ii) to improve the medical care and management of pregnant women across the country; and (iii) to address critical research gaps in maternal medicine. Since that first meeting, a broad collaborative effort has made a number of major steps forward, including the proliferation of maternal mortality review committees, advances in research, increasing educational focus on maternal critical care, and development of comprehensive clinical strategies to reduce maternal risk. Five years later, the 2017 M in MFM meeting served as a "report card" looking back at progress made but also looking forward to what needs to be done over the next 5 years, given that too many mothers still experience preventable harm and adverse outcomes.

Maternal near-miss and death among women with hypertensive disorders in pregnancy: a secondary analysis of the Nigeria Near-miss and Maternal Death Survey.

OBJECTIVE: To investigate life-threatening maternal complications related to hypertensive disorders of pregnancy (HDP) in Nigerian public tertiary hospitals. DESIGN: Secondary analysis of a nationwide cross-sectional study. SETTING: Forty-two tertiary hospitals. POPULATION: Women admitted for pregnancy, childbirth or puerperal complications. METHOD: All cases of severe maternal outcome (SMO: maternal near-miss or maternal death) due to HDP were prospectively identified using the WHO criteria over a 1-year period. MAIN OUTCOME MEASURES: Incidence of SMO, health service events, case fatality rate, and mortality index (% of maternal death/SMO). RESULTS: Out of 100 107 admissions for maternal complications, 6753 (6.8%) women had HDP. Pre-eclampsia (PE) (54.5%) and eclampsia (E) (30.4%) were the most common HDP recorded. SMO occurred in 587 women with HDP: 298 maternal near-misses and 289 maternal deaths. The majority (93%) of the women with SMO due to HDP were admitted in a critical condition. The median diagnosis-definitive intervention interval was over 4 hours in a quarter of women who died from HDP. For PE and E, case fatality rates were 1.9 and 10.4%, respectively, although both conditions had a similar mortality index of 49.3%. Lack of antenatal care and place of residence further than 5 km from the hospital were associated with maternal death. CONCLUSIONS: Severe maternal outcomes from HDP were due to late presentations and health system challenges. To reduce maternal deaths from HDP, health system strengthening that would engender early hospital presentation and prompt treatment is recommended. FUNDING: The original research that generated the data for this secondary analysis was funded by the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a co-sponsored programme executed by the World Health Organization (WHO). We have no other funding issue to declare for our study. TWEETABLE ABSTRACT: Eclampsia is the leading cause of maternal death in Nigerian hospitals.

Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and value of retesting.

OBJECTIVES: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. METHODS: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. RESULTS: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks). CONCLUSION: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Human chorionic gonadotropin and risk of pre-eclampsia: prospective population-based cohort study.

OBJECTIVES: Abnormal placentation in early pregnancy may play a role in the pathogenesis of pre-eclampsia. Human chorionic gonadotropin (hCG) regulates placental development and angiogenesis and may affect the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the serum. The aims of this study were to investigate the association of total hCG with the risk of pre-eclampsia and to examine the potential effect of pro- and anti-angiogenic factors on this association. METHODS: This was a population-based prospective cohort study of 7754 women with a singleton pregnancy. Total hCG was measured in the first available sample (median gestational age, 14.4 weeks; 95% range, 10.1-26.1 weeks) and sFlt-1 and PlGF concentrations in early (< 18 weeks; median, 13.2 weeks; 95% range, 9.6-17.6 weeks) and in mid- (18-25 weeks; median, 20.4 weeks; 95% range, 18.5-23.5 weeks) pregnancy. We tested the association of hCG concentration and risk of pre-eclampsia using regression analysis, adjusting for maternal age, ethnicity, body mass index, parity, education level, smoking status and fetal sex. Additionally, we assessed whether this association was affected by the sFlt-1/PlGF ratio. RESULTS: High hCG concentration was associated with a 1.5-2.7-fold increased risk of pre-eclampsia (P = 0.0001), depending on the cut-off used, and with increased sFlt-1/PlGF ratio during early pregnancy (P < 0.0001). The association between high hCG and pre-eclampsia attenuated by roughly 40% after adjustment for early-pregnancy sFlt-1/PlGF ratio (ß-estimate change from 0.19 ± 0.10 (P = 0.052) to 0.12 ± 0.10 (P = 0.22)). CONCLUSIONS: High total hCG concentration in early pregnancy is associated with an increased risk of pre-eclampsia. The effect of high hCG concentration on the balance between pro- and anti-angiogenic factors during pregnancy may have a role in the pathophysiology of pre-eclampsia. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Policy review on the management of pre-eclampsia and eclampsia by community health workers in Mozambique.

BACKGROUND: Pre-eclampsia is one of the leading causes of maternal death in Mozambique. Limited access to health care facilities and a lack of skilled health professionals contribute to the high maternal morbidity and mortality rates in Mozambique and indicate a need for community-level interventions. The aim of this review was to identify and characterise health policies related to the role of CHWs in the management of pre-eclampsia and eclampsia in Mozambique. METHODS: The policy review was based on three methods: a desk review of relevant documents from the Mozambique Ministry of Health (n = 7), contact with 28 key informants in the field of health policy in Mozambique (n = 5) and literature review (n = 699). Policy documents obtained included peer-reviewed articles, government and institutional policies, reports and action plans. Seven hundred and eleven full-text documents were assessed for eligibility and included based on pre-defined criteria. Qualitative analysis was done to identify main themes using content analysis. RESULTS: A total of 56 papers informed the timeline of key events. Three main themes were identified from the qualitative review: establishment of the community health worker programme and early challenges, revitalization of the CHW programme and the integration of maternal health in the community health tasks. In 1978, following the Alma Alta Declaration, the Mozambique government brought in legislation establishing primary health care and the CHW programme. Between the late 1980s and early 1990s, this programme was scaled down due to several factors including a prolonged civil war; however, the decision to revitalise the programme was made in 1995. In 2010, a revitalised programme was re-launched and expanded to include the management of common childhood illnesses, detection of warning signs of pregnancy complications, referrals for maternal health and basic health promotion. To date, their role has not included management of emergency conditions of pregnancy including pre-eclampsia and eclampsia. CONCLUSION: The role of CHWs has evolved over the last 40 years to include care of childhood diseases and basic maternal health counselling. Studies to assess the impact of CHWs in providing services to reduce maternal morbidity and mortality are recommended.

Contribution of hypertension to severe maternal morbidity.

BACKGROUND: Maternal mortality and severe maternal morbidity are growing public health concerns in the United States. The Centers for Disease Control and Prevention Severe Maternal Morbidity measure provides insight into processes underlying maternal mortality and may highlight modifiable risk factors for adverse maternal health outcomes. OBJECTIVE: The primary objective of this study was to evaluate the association between hypertensive disorders and severe maternal morbidity at a regional perinatal referral center. We hypothesized that women with preeclampsia with severe features would have a higher rate of severe maternal morbidity compared to normotensive women. We also assessed the proportion of severe maternal morbidity diagnoses that were present on admission, in contrast to those arising during the delivery hospitalization. STUDY DESIGN: In this retrospective cross-sectional analysis, we assessed rates of severe maternal morbidity diagnoses (eg, renal insufficiency, shock, and sepsis) and procedures (eg, transfusion and hysterectomy) for all 7025 women who delivered at the University of Washington Medical Center from Oct. 1, 2013, through May 31, 2017. Severe maternal morbidity was determined from prespecified International Classification of Diseases diagnosis and procedure codes; all diagnoses were confirmed by chart review. Present-on-admission rates were calculated for each diagnosis through hospital administrative data provided by the Vizient University Health System Consortium. Maternal demographic and clinical characteristics were compared for women with and without severe maternal morbidity. The χ2 and Fisher exact tests were used to determine statistical significance. Odds ratios and 95% confidence intervals were calculated for the associations between maternal demographic and clinical characteristics and severe maternal morbidity. RESULTS: Of 7025 deliveries, 284 (4%) had severe maternal morbidity; 154 had transfusion only, 27 had other procedures, and 103 women had 149 severe maternal morbidity diagnoses (26 women had multiple diagnoses). Severe preeclampsia occurred in 438 deliveries (6.2%). Notably, hypertension was associated with severe maternal morbidity in a dose-dependent fashion, with the strongest association observed for preeclampsia with severe features (odds ratio, 5.4; 95% confidence interval, 3.9-7.3). Severe maternal morbidity was also significantly associated with preeclampsia without severe features, chronic hypertension, preterm delivery, pregestational diabetes, and multiple gestation. Among women with severe maternal morbidity, over one third of preterm births were associated with maternal hypertension. American Indian/Alaskan Native women had significantly higher severe maternal morbidity rates compared to other racial/ethnic groups (11.7% vs 3.9% for Whites, P < .01). Overall, 39.6% of severe maternal morbidity diagnoses were present on admission. CONCLUSION: Hypertensive disorders in pregnancy are strongly associated with severe maternal morbidity in a dose-dependent relationship, suggesting that strategies to address rising maternal morbidity rates should include early recognition and management of hypertension. Prevention strategies focused on hypertension might also impact medically indicated preterm deliveries. The finding of increased severe maternal morbidity among American Indian/Alaskan Native women, a disadvantaged population in Washington State, underscores the role that socioeconomic factors may play in adverse maternal health outcomes. As 39% of severe maternal morbidity diagnoses were present on admission, this measure should be risk-adjusted if used as a quality metric for comparison between hospitals.

Causal inference in studies of preterm babies: a simulation study.

OBJECTIVE: Using a simple simulation, we illustrate why associations estimated from studies restricted to preterm births cannot be interpreted causally. DESIGN, SETTING AND POPULATION: Data simulation involving a hypothetical cohort of fetuses who may be healthy or have one or more of four pathological factors (termed A through D, increasing in severity) with known effects on gestational length and risk of mortality. We focus on babies born at ≤32 weeks of gestation. METHODS: We visually represent the simulated population and compare the association between A (which may represent pre-eclampsia) and neonatal death. We then repeat the exercise with D (standing in for chorioamnionitis) as the exposure of interest. MAIN OUTCOME MEASURES: Odds ratios of neonatal death in the simulated data. RESULTS: In most weeks, and for both A and D, the calculated odds ratios are substantially biased and underestimate the true risk of neonatal death associated with each pathology. For example, factor A has a true causal odds ratio of 1.50, yet it appears protective among births ≤32 weeks (estimated crude odds ratio 0.39; gestational age-adjusted odds ratio 0.71). CONCLUSIONS: Among very preterm births, virtually all babies are born with pathologies that increase the risk of adverse outcomes. Hence, babies exposed to one factor (e.g. pre-eclampsia) are compared with babies who have a mix of other pathologies. Such selection bias affects studies carried out among very preterm births (e.g. where pre-eclampsia appears to reduce risk of adverse neonatal outcomes). TWEETABLE ABSTRACT: Selection bias affects studies of preterm births, complicating interpretation.

Oral antioxidant therapy for prevention and treatment of preeclampsia: Meta-analysis of randomized controlled trials.

AIMS: To determine whether oral antioxidant therapies, of various types and doses, are able to prevent or treat women with preeclampsia. DATA SYNTHESIS: The following databases were searched: MEDLINE, CENTRAL, LILACS, and Web of Science. Inclusion criteria were: a) randomized clinical trials; b) oral antioxidant supplementation; c) study in pregnant women; d) control group, treated or not with placebo. Papers were excluded if they evaluated antioxidant nutrient supplementation associated with other non-antioxidant therapies. Data were extracted and the risk of bias of each study was assessed. Heterogeneity was analyzed using the Cochran Q test, and I2 statistics and pre-specified sensitivity analyses were performed. Meta-analyses were conducted on prevention and treatment studies, separately. The primary outcome was the incidence of preeclampsia in prevention trials, and of perinatal death in treatment trials. Twenty-nine studies were included in the analysis, 19 for prevention and 10 for treatment. The antioxidants used in these studies were vitamins C and E, selenium, l-arginine, allicin, lycopene and coenzyme Q10, none of which showed beneficial effects on the prevention of preeclampsia (RR: 0.89, CI 95%: [0.79-1.02], P = 0.09; I2 = 39%, P = 0.04) and other outcomes. The antioxidants used in the treatment studies were vitamins C and E, N-acetylcysteine, l-arginine, and resveratrol. A beneficial effect was found in intrauterine growth restriction. CONCLUSIONS: Antioxidant therapy had no effects in the prevention of preeclampsia but did show beneficial effects in intrauterine growth restriction, when used in the treatment of this condition.

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.

BACKGROUND: Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia, and may help to prevent preterm birth. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18 September 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-randomised trials, comparing high-dose calcium supplementation (at least 1 g daily of calcium) during pregnancy with placebo. For low-dose calcium we included quasi-randomised trials, trials without placebo, trials with cointerventions and dose comparison trials. DATA COLLECTION AND ANALYSIS: Two researchers independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two researchers assessed the evidence using the GRADE approach. MAIN RESULTS: We included 27 studies (18,064 women). We assessed the included studies as being at low risk of bias, although bias was frequently difficult to assess due to poor reporting and inadequate information on methods.High-dose calcium supplementation (≥ 1 g/day) versus placeboFourteen studies examined this comparison, however one study contributed no data. The 13 studies contributed data from 15,730 women to our meta-analyses. The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a reduction in the risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: average RR 0.45, 95% CI 0.31 to 0.65; I² = 70%; low-quality evidence). This effect was clear for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) but not those with adequate calcium diets. The effect appeared to be greater for women at higher risk of pre-eclampsia, though this may be due to small-study effects (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42). These data should be interpreted with caution because of the possibility of small-study effects or publication bias. In the largest trial, the reduction in pre-eclampsia was modest (8%) and the CI included the possibility of no effect.The composite outcome maternal death or serious morbidity was reduced with calcium supplementation (four trials, 9732 women; RR 0.80, 95% CI 0.66 to 0.98). Maternal deaths were no different (one trial of 8312 women: one death in the calcium group versus six in the placebo group). There was an anomalous increase in the risk of HELLP syndrome in the calcium group (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82, high-quality evidence), however, the absolute number of events was low (16 versus six).The average risk of preterm birth was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%; low-quality evidence); this reduction was greatest amongst women at higher risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%). Again, these data should be interpreted with caution because of the possibility of small-study effects or publication bias. There was no clear effect on admission to neonatal intensive care. There was also no clear effect on the risk of stillbirth or infant death before discharge from hospital (11 trials, 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09).One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87).Low-dose calcium supplementation (< 1 g/day) versus placebo or no treatmentTwelve trials (2334 women) evaluated low-dose (usually 500 mg daily) supplementation with calcium alone (four trials) or in association with vitamin D (five trials), linoleic acid (two trials), or antioxidants (one trial). Most studies recruited women at high risk for pre-eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium reduced the risk of pre-eclampsia (nine trials, 2234 women: RR 0.38, 95% CI 0.28 to 0.52). There was also a reduction in high BP (five trials, 665 women: RR 0.53, 95% CI 0.38 to 0.74), admission to neonatal intensive care unit (one trial, 422 women, RR 0.44, 95% CI 0.20 to 0.99), but not preterm birth (six trials, 1290 women, average RR 0.83, 95% CI 0.34 to 2.03), or stillbirth or death before discharge (five trials, 1025 babies, RR 0.48, 95% CI 0.14 to 1.67).High-dose (=/> 1 g) versus low-dose (< 1 g) calcium supplementationWe included one trial with 262 women, the results of which should be interpreted with caution due to unclear risk of bias. Risk of pre-eclampsia appeared to be reduced in the high-dose group (RR 0.42, 95% CI 0.18 to 0.96). No other differences were found (preterm birth: RR 0.31, 95% CI 0.09 to 1.08; eclampsia: RR 0.32, 95% CI 0.07 to 1.53; stillbirth: RR 0.48, 95% CI 0.13 to 1.83). AUTHORS' CONCLUSIONS: High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of pre-eclampsia and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers.The limited evidence on low-dose calcium supplementation suggests a reduction in pre-eclampsia, hypertension and admission to neonatal high care, but needs to be confirmed by larger, high-quality trials.

[Preeclampsia - a disease of pregnant women]. / Preeklampsja ­ choroba kobiet w ciazy.

Preeclampsia, also known as EPH-gestosis, is a pregnancy-specific syndrome. It affects 3-5% of pregnant women and is characterized by edemas, high blood pressure and proteinuria. Moreover, in women with preeclampsia dysfunction of many organs, such as kidney and liver, is diagnosed, while in the case of fetus growth restriction is observed. Preeclampsia, when left untreated, can lead to death. In low-income countries, this disorder is one of the main causes of maternal and child mortality. Preeclampsia predisposes women in later life to cardiovascular diseases. So far, in acute cases of preeclampsia stabilization of the mother and fetus and finally termination of pregnancy at a time optimal for both sides can only be considered. In this work, available literature data concerning the causes of preeclampsia, its symptoms, techniques for diagnosis, methods for prevention and new approaches to treatment were collected.

Outcome reporting across randomised controlled trials evaluating therapeutic interventions for pre-eclampsia.

BACKGROUND: Standardising outcome collection and reporting in pre-eclampsia trials requires an appraisal of current outcome reporting. OBJECTIVES: To map maternal and offspring outcome reporting across randomised trials evaluating therapeutic interventions for pre-eclampsia. SEARCH STRATEGY: Randomised trials were identified by searching bibliographical databases from inception to January 2016. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We systematically extracted and categorised outcome reporting. MAIN RESULTS: Seventy-nine randomised trials, reporting data from 31 615 maternal participants and 28 172 of their offspring, were included. Fifty-five different interventions were evaluated. Included trials reported 119 different outcomes, including 72 maternal outcomes and 47 offspring outcomes. Maternal outcomes were inconsistently reported across included trials; for example, 11 trials (14%) reported maternal mortality, reporting data from 12 422 participants, and 16 trials (20%) reported cardiovascular morbidity, reporting data from 14 963 maternal participants. Forty-three trials (54%) reported fetal outcomes and 23 trials (29%) reported neonatal outcomes. Twenty-eight trials (35%) reported offspring mortality. There was poor reporting of childhood outcomes: six trials (8%) reported neurodevelopmental outcomes. Less than half of included trials reported any relevant information regarding harms for maternal participants and their offspring. CONCLUSIONS: Most randomised trials evaluating interventions for pre-eclampsia are missing information on clinically important outcomes, and in particular have neglected to evaluate efficacy and safety in the offspring of participants. Developing and implementing a minimum data set, known as a core outcome set, in future pre-eclampsia trials could help to address these issues. TWEETABLE ABSTRACT: Future #preeclampsia research requires a core outcome set to reduce #research waste. @coreoutcomes @jamesmnduffy International Prospective Register of Systematic Reviews: CRD42015015529; www.crd.york.ac.uk/PROSPERO/display_record.aspID=CRD42015015529.

Serious maternal complications in relation to severe pre-eclampsia: a retrospective cohort study of the impact of hospital volume.

OBJECTIVE: We examined rates of serious maternal complications in relation to severe pre-eclampsia based on the delivering hospital's annualised volume. DESIGN: Retrospective cohort study. POPULATION AND SETTING: Singleton deliveries (n = 25 782 235) in 439 hospitals in the USA. METHODS: Annualised hospital volume was categorised as 25-500, 501-1000, 1001-2000 and >2000. MAIN OUTCOME MEASURES: Rates of in-hospital maternal death and serious maternal complications, including puerperal cerebrovascular disorders, pulmonary oedema, disseminated intravascular coagulation, acute renal, heart and liver failure, sepsis, haemorrhage and intubation in relation to severe pre-eclampsia. We derived adjusted risk ratio (RR) and 95% confidence interval (CI), from hierarchical Poisson regression models. RESULTS: Severe pre-eclampsia was associated with an 8.7-fold (95% CI 7.6, 10.1) risk of composite maternal complications, with similar RRs across levels of hospital volumes. However, compared with hospitals with low annual volume (<2000), maternal mortality rates in relation to severe pre-eclampsia were lower in high volume hospitals. The rates of serious maternal complications were 410.7 per 10 000 to women who delivered in hospitals with a high rate of severe pre-eclampsia (≥2.12%) and 584.8 per 10 000 to women who delivered in hospitals with low severe pre-eclampsia rates (≤0.41; RR 1.75, 95% CI 1.24, 2.45). CONCLUSIONS: While the risks of serious maternal complications in relation to severe pre-eclampsia was similar across hospital delivery volume categories, deaths showed lower rates in large delivery volume hospitals than in smaller volume hospitals. The risk of complications was increased in hospitals with low compared with high severe pre-eclampsia rates. TWEETABLE ABSTRACT: Hospital volume had little impact on the association between severe pre-eclampsia and maternal complications.