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Importance  Gestational hypertension, preeclampsia, and eclampsia are established risk factors for stroke and dementia later in life. Whether these pregnancy complications are associated with an increased risk of new-onset neurological disorders within months to years after giving birth is not known.

Objective  To explore whether gestational hypertension, preeclampsia, and eclampsia are associated with new-onset migraine, headache, epilepsy, sleep disorder, or mental fatigue within months to years after giving birth.

Design, Setting, and Participants  In this register-based cohort study, exposures were identified in the Swedish Medical Birth Register from 2005 to 2018. Follow-up was conducted using the National Patient Register, containing diagnoses from specialized inpatient and outpatient care. Follow-up started 42 days after delivery and continued until the first event, death, emigration, or the end of the follow-up period (2019). The risk was calculated with Cox regression analysis and expressed as adjusted hazard ratio (aHR) with a 95% CI. Through the Swedish Medical Birth Register, 659 188 primiparous women with singleton pregnancies between 2005 and 2018 were identified. Women with a diagnosis of chronic hypertension (n = 4271) or a prepregnancy neurological disorder (n = 6532) were excluded. The final study population included 648 385 women. Data analyses were conducted in 2023.

Exposures  Gestational hypertension, preeclampsia, and eclampsia.

Main outcome  The primary outcome was a composite neurological outcome of migraine, headache, epilepsy, sleep disorder, or mental fatigue.

Results  The study included 648 385 women with a mean age of 28.5 (SD, 5.0) years at the time of their first pregnancy. Women with gestational hypertension (n = 11 133), preeclampsia (n = 26 797), and eclampsia (n = 625) all had an association with increased risk for a new-onset neurological disorder compared with women with normotensive pregnancies. The aHR for gestational hypertension was 1.27 (95% CI, 1.12-1.45), 1.32 (95% CI, 1.22-1.42) for preeclampsia, and 1.70 (95% CI, 1.16-2.50) for eclampsia. When exploring individual outcomes, women with eclampsia were associated with more than a 5 times increased risk of epilepsy (aHR, 5.31; 95% CI, 2.85-9.89).

Conclusion and Relevance  In this study, gestational hypertension, preeclampsia, and eclampsia were associated with an increased risk of new-onset migraine, headache, epilepsy, sleep disorder, or mental fatigue within months to years after giving birth. Guidelines recommend follow-up after delivery for women with gestational hypertension and preeclampsia for their increased risk of cardiovascular disease. At these visits, caregivers should also pay attention to persisting or new-onset of neurological symptoms, since this group of women appears to be vulnerable to developing or experiencing neurological disorders.

Importance It is unclear whether a higher dose (150-160 mg) or a lower dose (75 mg) of aspirin should be used to prevent preeclampsia. Objectives To compare the risk of preeclampsia and bleeding complications between women using 150 to 160 mg of aspirin and those using 75 mg of aspirin for preeclampsia prevention. Design, Setting, and ParticipantsThis nationwide cohort study included 13 828 women giving birth at 22 weeks' gestation or later in Sweden between January 2017 and December 2020 who used low dose aspirin (75-160 mg) during pregnancy. Data were analyzed from October to November 2023. Exposure The use of 150 to 160 mg or 75 mg of aspirin in pregnancy. Main Outcome and MeasuresThe main outcome was a preeclampsia diagnosis recorded in the maternal birth record at the time of hospital discharge. The main safety outcome was postpartum hemorrhage, defined as bleeding more than 1000 mL after delivery. Relative risks (RRs) and 95% CIs were estimated using a doubly robust inverse probability-weighted regression adjustment model controlling for background characteristics. Results In the total cohort of 13 828 women, the mean (SD) age was 33.0 (5.5) years and 3003 women (21.7%) were nulliparous. Of the women, 4687 (33.9%) were prescribed 150 to 160 mg of aspirin, and 9141 (66.1%) were prescribed 75 mg of aspirin. A total of 10 635 women (76.9%) had at least 2 dispensed prescriptions of low-dose aspirin. Among women using 150 to 160 mg of aspirin, 443 (9.5%) developed preeclampsia compared with 812 (8.9%) of those using 75 mg of aspirin (adjusted RR [aRR], 1.07; 95% CI, 0.93-1.24). Additionally, the risk of postpartum hemorrhage between the groups was similar, with 326 women (6.9%) using 150 to 160 mg of aspirin experiencing a postpartum hemorrhage compared with 581 (6.4%) in the 75-mg group (aRR, 1.08; 95% CI, 0.90-1.30). Conclusions and Relevance In this cohort study of 13 828 women, no difference was found in preeclampsia incidence or bleeding complications between those using 150 to 160 mg of aspirin vs 75 mg of aspirin during pregnancy for preeclampsia prevention. These findings suggest that either dose may be a reasonable choice when using aspirin to prevent preeclampsia. However, large randomized trials investigating aspirin dose in pregnancy are still needed.

Preeclampsia is a syndrome that continues to be a major contributor to maternal and neonatal mortality, especially in low-income countries. Lowdose aspirin reduces the risk of preeclampsia, but the mechanism is still unknown. Risk factors to identify women at risk of preeclampsia are based on clinical characteristics. Women identified as high-risk would benefit from aspirin treatment initiated, preferably at the end of the first trimester. Current efforts have largely focused on developing screening algorithms that incorporate clinical risk factors, maternal biomarkers, and uterine artery Doppler evaluated in the first trimester. However, most studies on preeclampsia are conducted in high-income settings, raising uncertainties about whether the information gained can be totally applied in low-resource settings. In low- and middle-income countries, lack of adequate antenatal care and late commencement of antenatal care visits pose significant challenges for both screening for preeclampsia and initiating aspirin treatment. Furthermore, the preventive effect of first-trimester screening based on algorithms and subsequent aspirin treatment is primarily seen for preterm preeclampsia, and reviews indicate minimal or no impact on reducing the risk of term preeclampsia. The lack of evidence regarding the effectiveness of aspirin in preventing term preeclampsia is a crucial concern, as 75% of women will develop this subtype of the syndrome. Regarding adverse outcomes, low-dose aspirin has been linked to a possible higher risk of postpartum hemorrhage, a condition as deadly as preeclampsia in many low- and middle-income countries. The increased risk of postpartum hemorrhage among women in low-income settings should be taken into consideration when discussing which pregnant women would benefit from the use of aspirin and the ideal aspirin dosage for preventing preeclampsia. In addition, women's adherence to aspirin during pregnancy is crucial for determining its effectiveness and complications, an aspect often overlooked in trials. In this review, we analyze the knowledge gaps that must be addressed to safely increase lowdose aspirin use in low- and middle-income countries, and we propose directions for future research.

Objectives

To assess whether plasma concentrations of the circulating inflammatory proteins Interleukin-6 (IL-6), Vascular Cell Adhesion Molecule-1 (VCAM-1) and C-Reactive Protein (CRP) are increased in women with preeclampsia with end-organ complications, compared with women with preeclampsia without end-organ complications.

Study design

We used samples from a large prospective biobank collection (Preeclampsia Obstetric Adverse Event biobank), and two large, randomized preeclampsia therapeutic treatment trials. All samples were collected in Cape Town, South Africa. The last plasma sample collected prior to birth was analyzed for IL-6, VCAM-1 and CRP concentrations. We categorized cases according to disease severity and compared circulating levels of these analytes. Covariate adjustment was performed.

Results

183 women were included. Compared with women without end-organ complications (n = 119), those with preeclampsia with two or more end-organ complications (n = 15) had a 4.9-fold (95 % CI, 1.81–13.09, p = 0.001) increase in IL-6 and a 1.7-fold (95 % CI, 1.11–2.72, p = 0.012) increase in VCAM-1 plasma concentrations. Comparing women with two or more end-organ complications to those with one end-organ complication (n = 49), plasma concentrations of IL-6 were 3.2-fold (95 % CI, 1.18–8.39, p = 0.018) increased, while there was no statistically significant difference for VCAM-1 (1.2-fold higher, 95 % CI, 0.79–1.91, p = 0.50). Plasma concentrations of CRP did not differ between the groups.

Conclusions

Plasma concentrations of IL-6 and VCAM-1, but not CRP, were increased among women with preeclampsia and end-organ complications, compared with women without end-organ complications. IL-6 and VCAM-1 could be drivers of disease in preeclampsia and potentially useful to identify women at high risk of severe disease.

Introduction: Maternal SARS-CoV-2 infection can affect pregnancy outcome, but the placental response to and the effect of timing of infection is not well studied. The aim of this study was to investigate the placental levels of inflammatory and cardiovascular markers in pregnancies complicated by SARS-CoV-2 infection compared to non-infected pregnancies, and to investigate whether there was an association between time point of infection during pregnancy and placental inflammatory and cardiovascular protein levels.

Methods: Placental samples from a prospectively recruited pregnancy cohort of SARS-CoV-2-infected (n = 53) and non-infected (n = 50) women were analysed for 177 inflammatory and cardiovascular proteins, using an antibodybased proximity extension assay. In the SARS-CoV-2-infected group, half of the women were infected before 20 weeks of gestation, and five women were hospitalised for severe SARS-CoV-2 infection. Single-protein analyses were performed with linear mixed effects models, followed by Benjamini-Hochberg correction for multiple testing. Multiprotein analyses were performed using principal component analysis and machine learning algorithms.

Results: The perinatal outcomes and the placental levels of inflammatory or cardiovascular proteins in women with SARS-CoV-2 infection were similar to those in non-infected women. There were no differences in inflammatory or cardiovascular protein levels between early and late pregnancy SARS-CoV-2 infection, nor any linear correlations between protein levels and gestational age at time of infection.

Discussion: Women with SARS-CoV-2 infection during pregnancy without clinical signs of placental insufficiency have no changes in inflammatory or cardiovascular protein patterns in placenta at time of birth regardless of the timing of the infection.

Background: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy.

Methods: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes.

Results: from both countries were then combined in a meta-analysis using a random effects model. Results The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]).

Conclusions: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks’ gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Background

Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality. If women at high risk for developing complications could be identified early, level of care could be triaged, limited resources could be correctly allocated and targeted interventions to prevent complications could be implemented.

Methods

We updated a systematic review and meta-analysis and added single outcomes. Women with hypertensive disorders of pregnancy were included. Exposures were tests predicting adverse maternal and/or perinatal outcomes. We searched Medline, Embase, CINAHL, and Cochrane library from January 2016–February 2024. We included studies identified from the previous review. We calculated effect measures. For similar predictive tests and outcomes, area under the receiver-operating-characteristic curve (AUROC) were pooled. This study was registered by PROSPERO: CRD42022336368.

Findings

Of the 2898 studies identified, 80 were included. Thirty were added from the previous review resulting in 110 included studies with 506,178 women. Despite more than 1500 tests being performed, most outcomes could not be pooled due to heterogeneity in populations, tests, and outcome definitions. For maternal outcomes, only studies reporting on the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) model could be pooled. For the composite outcome within 48-h the AUROC was 0.78 (95% CI 0.71–0.86, N = 8). There was significant heterogeneity (I² = 95.7%). For perinatal outcomes, data were pooled for pulsatility index in the umbilical artery and soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio. Biomarkers like the sFlt-1/PlGF ratio showed promising predictive performance for some outcomes but were not externally validated.

Interpretation

Despite including over 100 studies with more than 1500 predictors, we were unable to pool any single maternal outcomes and only a few individual perinatal outcomes. The fullPIERS model was externally validated, showing moderate accuracy which varied across studies and should be validated in each new population. Angiogenic biomarkers showed promise but need validation. Future studies should use standardized outcome measures and validate promising tests.

Cardiovascular disease (CVD) is the leading cause of premature death and disability for female individuals around the world and the rates are increasing in those aged 35-44 years. Certain pregnancy complications (Pregnancy-associated Cardiovascular Risks (P-CVR))are linked to an increased risk of future CVD making pregnancy and the postpartum period as an ideal time to screen individuals for underlying, often unrecognized, cardiovascular risk factors. Pregnancy complications associated with an increased risk of future CVD including the hypertensive disorders of pregnancy, gestational diabetes, idiopathic preterm birth, delivery of a growth restricted baby and a placental abruption that leads to delivery. A number of guidelines and research groups recommend postpartum CVR screening, counseling and lifestyle intervention for all those who have had one or more of P-CVRs starting within the first six months postpartum. An individualized plan for postpartum screening should be created with the individual and lifestyle interventions discussed.

Preeclampsia is a maternal syndrome characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation associated with multisystemic complications, including brain alterations. Indeed, brain complications associated with preeclampsia are the leading direct causes of fetal and maternal morbidity and mortality, especially in low- and middle-income countries. In addition to the well-recognized long-term adverse cardiovascular effects of preeclampsia, women who have had preeclampsia have higher risk of stroke, dementia, intracerebral white matter lesions, epilepsy, and perhaps also cognitive decline postpartum. Furthermore, increasing evidence has also associated preeclampsia with similar cognitive and cerebral disorders in the offspring. However, the mechanistic links between these associations remain unresolved. This article summarizes the current knowledge about the cerebrovascular complications elicited by preeclampsia and the potential pathophysiological mechanisms involved, emphasizing the impaired brain vascular function in the mother and their offspring.