Can single-cell and spatial omics unravel the pathophysiology of pre-eclampsia?

Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Characterised by the onset of hypertension and proteinuria in the second half of pregnancy, it can lead to maternal end-organ injury such as cerebral ischemia and oedema, pulmonary oedema and renal failure, and potentially fatal outcomes for both mother and fetus. The causes of the different maternal end-organ phenotypes of pre-eclampsia and why some women develop pre-eclampsia condition early in pregnancy have yet to be elucidated. Omics methods include proteomics, genomics, metabolomics, transcriptomics. These omics techniques, previously mostly used on bulk tissue and individually, are increasingly available at a single cellular level and can be combined with each other. Multi-omics techniques on a single-cell or spatial level provide us with a powerful tool to understand the pathophysiology of pre-eclampsia. This review will explore the status of omics methods and how they can and could contribute to understanding the pathophysiology of pre-eclampsia.

Circulating Chemerin Is Elevated in Women With Preeclampsia.

BACKGROUND: Preeclampsia is a severe complication of pregnancy. Chemerin is an adipokine secreted from adipose tissue and highly expressed in placenta. This study evaluated the biomarker potential of circulating chemerin to predict preeclampsia. METHODS: Maternal plasma and placenta were collected from women with early-onset preeclampsia (<34 weeks), with preeclampsia and eclampsia, or before preeclampsia diagnosis (36 weeks). Human trophoblast stem cells were differentiated into syncytiotrophoblast or extravillous trophoblasts across 96 hours. Cells were cultured in 1% O2 (hypoxia) or 5% O2 (normoxia). Chemerin was measured by enzyme-linked immunosorbent assay (ELISA) and RARRES2 (gene coding chemerin) by reverse transcription-quantitative polymerase chain reaction. RESULTS: Circulating chemerin was increased in 46 women with early-onset preeclampsia (<34 weeks) compared to 17 controls (P < .0006). Chemerin was increased in placenta from 43 women with early-onset preeclampsia compared to 24 controls (P < .0001). RARRES2 was reduced in placenta from 43 women with early-onset preeclampsia vs 24 controls (P < .0001). Chemerin was increased in plasma from 26 women with established preeclampsia (P = .006), vs 15 controls. Circulating chemerin was increased in 23 women who later developed preeclampsia vs 182 who did not (P = 3.23 × 10-6). RARRES2 was reduced in syncytiotrophoblast (P = .005) or extravillous trophoblasts (P < .0001). Hypoxia increased RARRES2 expression in syncytiotrophoblast (P = .01) but not cytotrophoblast cells. CONCLUSIONS: Circulating chemerin was elevated in women with early-onset preeclampsia, established preeclampsia, and preceding preeclampsia diagnosis of preeclampsia. RARRES2 was dysregulated in placenta complicated by preeclampsia and may be regulated through hypoxia. Chemerin may have potential as a biomarker for preeclampsia but would need to be combined with other biomarkers.

Prevalence of Perinatal Depression in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

Importance: Women who experience depression during or within a year of pregnancy are at increased risk of morbidity and mortality. Although those living in low- and middle-income countries are thought to be at increased risk of perinatal depression, the true prevalence remains unclear. Objective: To determine the prevalence of depression among individuals living in low- and middle-income countries during pregnancy and up 1 year post partum. Data Sources: MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and the Cochrane Library were searched from database inception until April 15, 2021. Study Selection: Studies were included that reported the prevalence of depression using a validated method during pregnancy or up to 12 months post partum in countries defined by the World Bank as low, lower-middle, and upper-middle income. Data Extraction and Synthesis: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Two reviewers independently assessed study eligibility, extracted data, and assessed studies for bias. Prevalence estimates were calculated using a random-effects meta-analysis model. Subgroup analyses were performed among women who were considered at increased risk of developing perinatal depression. Main Outcomes and Measures: Point prevalence of perinatal depression was the main outcome measured as percentage point estimates with corresponding 95% CIs. Results: The search identified 8106 studies, of which data were extracted from 589 eligible studies reporting outcomes of 616 708 women from 51 countries. The pooled prevalence of perinatal depression across all studies was 24.7% (95% CI, 23.7%-25.6%). The prevalence of perinatal depression varied slightly by country income status. The highest prevalence was found in lower-middle-income countries, with a pooled prevalence of 25.5% (95% CI, 23.8%-27.1%; 197 studies from 23 countries including 212 103 individuals). In upper-middle-income countries, the pooled prevalence was 24.7% (95% CI, 23.6%-25.9%; 344 studies from 21 countries including 364 103 individuals) and in low-income countries, the pooled prevalence was 20.7% (95% CI, 18.4%-23.0%; 50 studies from 7 countries including 40 502 individuals). The East Asia and the Pacific region had the lowest prevalence of perinatal depression at 21.4% (95% CI, 19.8%-23.1%) and was significantly increased in the Middle East and North Africa at 31.5% (95% CI, 26.9%-36.2%; between-group comparison: P < .001). In subgroup analyses, the highest prevalence of perinatal depression was found among women who experienced intimate partner violence, at 38.9% (95% CI, 34.1%-43.6%). revalence of depression was also high among women with HIV (35.1% [95% CI, 29.6%-40.6%]) and those who had experienced a natural disaster (34.8% [95% CI, 29.4%-40.2%]). Conclusions and Relevance: This meta-analysis found that depression was common in low- and middle-income countries, affecting 1 in 4 perinatal women. Accurate estimates of the prevalence of perinatal depression in low- and middle-income countries are essential in informing policy, allocating scarce resources, and directing further research to improve outcomes for women, infants, and families.

Associations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia.

Background The angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are postulated to be pathogenic disease drivers of preeclampsia. If true, then circulating levels should become more deranged with increasing disease severity. Methods and Results We investigated the association between circulating sFlt-1 and PlGF levels and severe adverse maternal outcomes among 348 women with preeclampsia. Compared with 125 women with preeclampsia without severe features, 25 women with preeclampsia and any of hemolysis, elevated liver enzymes, low platelet count syndrome, disseminated intravascular coagulation, or severe renal involvement had sFlt-1 levels that were 2.63-fold higher (95% CI, 1.81-3.82), sFlt-1/PlGF levels that were 10.07-fold higher (95% CI, 5.36-18.91) and PlGF levels that were 74% lower (adjusted fold change, 0.26 [95% CI, 0.18-0.39]). Compared with 125 women with preeclampsia without severe features, 37 with eclampsia had sFlt-1 levels that were 2-fold higher (2.02 [95% CI, 1.32-3.09]), sFlt-1/PIGF levels that were 4.71-fold higher (95% CI, 2.30-9.66) and PIGF levels that were 63% lower (0.43-fold change [95% CI, 0.27-0.68]). Compared with those without severe features, preeclampsia with severe hypertension (n=146) was also associated with altered angiogenic levels (sFlt-1, 1.71-fold change [95% CI, 1.39-2.11]; sFlt/PlGF, 2.91 [95% CI, 2.04-4.15]; PlGF, 0.59 [95%CI 0.47-0.74]). We also found that sFlt-1 and PlGF levels were altered by the number of maternal complications experienced. Conclusions Further angiogenic imbalance among women with preeclampsia is likely a pathogenic disease driver responsible for the life-threatening maternal complications.

Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia.

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non-pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9-61.6%) lower compared to non-pregnant, most likely due to inhibition of CYP2C19. In non-pregnant participants after repeated dosing, clearance was 54.9% (48.2-63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0-52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non-pregnant individuals, since CYP2C19 is already inhibited due to pregnancy.

Low-Dose Aspirin for Preventing Birth of a Small-For-Gestational Age Neonate in a Subsequent Pregnancy.

OBJECTIVE: To estimate whether low-dose aspirin use is associated with an altered risk of delivering a small-for-gestational age (SGA) neonate among women with a history of having an SGA neonate in a prior pregnancy. METHODS: We performed a Swedish register-based cohort study including women in their second pregnancy who had a history of having an SGA neonate (birth weight less than the 10th percentile). The association between use of low-dose aspirin in subsequent pregnancy and birth of an SGA neonate or a severely SGA neonate (birth weight less than the third percentile) were estimated using inverse propensity-weighted estimation, accounting for potential confounders. RESULTS: Among 8,416 women who gave birth to an SGA neonate in their first pregnancy, 801 (9.5%) used low-dose aspirin during their second pregnancy. The incidence of SGA neonates was similar among women using low-dose aspirin (21.7%) and those who did not use aspirin (20.7%). Low-dose aspirin use in pregnancy was not associated with an altered risk of having an SGA neonate (adjusted relative risk [aRR] 0.86, 95% CI 0.67-1.10) or a severely SGA neonate (aRR 0.98, 95% CI 0.71-1.34). Given the strong association between preeclampsia and SGA, we performed subgroup analyses based on preeclampsia status. Among women who had an SGA neonate and co-existing preeclampsia in their first pregnancy, low-dose aspirin was not associated with an altered risk of having an SGA (aRR 0.83, 95% CI 0.63-1.10) or severely SGA (aRR 1.02, 95% CI 0.73-1.44) neonate. Additionally, no association was seen among women who developed preeclampsia in their second pregnancy. CONCLUSION: Among women with a history of having an SGA neonate, low-dose aspirin was not associated with a decreased risk of having an SGA or severely SGA neonate in subsequent pregnancy. These findings suggest that low-dose aspirin should not be used to prevent recurrent SGA.

Circulating SPINT1 Is Reduced in a Preeclamptic Cohort with Co-Existing Fetal Growth Restriction.

Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile). SPINT1 is also reduced in FGR diagnosed before 34 weeks' gestation. We hypothesised that circulating SPINT1 would be decreased in co-existing preterm preeclampsia and FGR. Plasma SPINT1 was measured in samples obtained from two double-blind, randomised therapeutic trials. In the Preeclampsia Intervention with Esomeprazole trial, circulating SPINT1 was decreased in women with preeclampsia who delivered SGA infants (n = 75, median = 18,857 pg/mL, IQR 10,782-29,890 pg/mL, p < 0.0001), relative to those delivering AGA (n = 22, median = 40,168 pg/mL, IQR 22,342-75,172 pg/mL). This was confirmed in the Preeclampsia Intervention 2 with metformin trial where levels of SPINT1 in maternal circulation were reduced in SGA pregnancies (n = 95, median = 57,764 pg/mL, IQR 42,212-91,356 pg/mL, p < 0.0001) compared to AGA controls (n = 40, median = 107,062 pg/mL, IQR 70,183-176,532 pg/mL). Placental Growth Factor (PlGF) and sFlt-1 were also measured. PlGF was significantly reduced in the SGA pregnancies, while ratios of sFlt-1/SPINT1 and sFlt1/PlGF were significantly increased. This is the first study to demonstrate significantly reduced SPINT1 in co-existing FGR and preeclamptic pregnancies.

Maternal characteristics and pregnancy outcomes of hospitalized pregnant women with SARS-CoV-2 infection in South Africa: An International Network of Obstetric Survey Systems-based cohort study.

OBJECTIVE: To describe risk factors and outcomes of pregnant women infected with SARS-CoV-2 admitted to South African healthcare facilities. METHODS: A population-based cohort study was conducted utilizing an amended International Obstetric Surveillance System protocol. Data on pregnant women with SARS-CoV-2 infection, hospitalized between April 14, 2020, and November 24, 2020, were analyzed. RESULTS: A total of 36 hospitals submitted data on 673 infected hospitalized pregnant women; 217 (32.2%) were admitted for COVID-19 illness and 456 for other indications. There were 39 deaths with a case fatality rate of 6.3%: 32 (14.7%) deaths occurred in women admitted for COVID-19 illness compared to 7 (1.8%) in women admitted for other indications. Of the women, 106 (15.9%) required critical care. Maternal tuberculosis, but not HIV co-infection or other co-morbidities, was associated with admission for COVID-19 illness. Rates of cesarean delivery did not differ significantly between women admitted for COVID-19 and those admitted for other indications. There were 179 (35.4%) preterm births, 25 (4.7%) stillbirths, 12 (2.3%) neonatal deaths, and 162 (30.8%) neonatal admissions. Neonatal outcomes did not differ significantly from those of infected women admitted for other indications. CONCLUSION: The maternal mortality rate was high among women admitted with SARS-CoV-2 infection and higher in women admitted primarily for COVID-19 illness with tuberculosis being the only co-morbidity associated with admission.

Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial.

OBJECTIVE: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Referral hospital in Cape Town, South Africa. PARTICIPANTS: 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. INTERVENTION: 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. MAIN OUTCOME MEASURE: The primary outcome was prolongation of gestation. RESULTS: Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. CONCLUSIONS: This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.

Blood pressure as a risk factor for eclampsia and pulmonary oedema in pre-eclampsia.

OBJECTIVE: We evaluated whether blood pressure and change in blood pressure measurements during pregnancy were associated with eclampsia or pulmonary oedema among women with pre-eclampsia. STUDY DESIGN: Observational study of women with eclampsia, pre-eclampsia complicated by pulmonary oedema and pre-eclampsia without end-organ complications (pre-eclampsia controls) at a large referral center in Cape Town, South Africa. MAIN OUTCOME MEASURES: Blood pressure measurements at presentation for antenatal care were compared to measurements after a diagnosis of pre-eclampsia. Mean blood pressures and changes in blood pressures were also calculated and compared between groups at different time points. A sub analysis including women who presented for antenatal care before 20 weeks of gestation was performed. RESULTS: When diagnosed with pre-eclampsia, women with pulmonary oedema had increased systolic blood pressures and women with eclampsia had increased diastolic blood pressures compared to pre-eclampsia controls. There were no differences in blood pressure measurements in early pregnancy between women who later developed eclampsia or pulmonary oedema compared to pre-eclampsia controls. CONCLUSION: Blood pressure measurements in early pregnancy do not seem useful as a risk factor for the development of eclampsia or pulmonary oedema among women diagnosed with pre-eclampsia. Increased systolic or diastolic pressure at diagnosis of pre-eclampsia may be useful as a risk factor for the development of pulmonary oedema or eclampsia. Further research is needed to confirm these findings.

Pre-eclampsia.

Pre-eclampsia is a multisystem pregnancy disorder characterised by variable degrees of placental malperfusion, with release of soluble factors into the circulation. These factors cause maternal vascular endothelial injury, which leads to hypertension and multi-organ injury. The placental disease can cause fetal growth restriction and stillbirth. Pre-eclampsia is a major cause of maternal and perinatal mortality and morbidity, especially in low-income and middle-income countries. Prophylactic low-dose aspirin can reduce the risk of preterm pre-eclampsia, but once pre-eclampsia has been diagnosed there are no curative treatments except for delivery, and no drugs have been shown to influence disease progression. Timing of delivery is planned to optimise fetal and maternal outcomes. Clinical trials have reported diagnostic and prognostic strategies that could improve fetal and maternal outcomes and have evaluated the optimal timing of birth in women with late preterm pre-eclampsia. Ongoing studies are evaluating the efficacy, dose, and timing of aspirin and calcium to prevent pre-eclampsia and are evaluating other drugs to control hypertension or ameliorate disease progression.

Predictive Value of the Signs and Symptoms Preceding Eclampsia: A Systematic Review.

OBJECTIVE: To estimate the predictive value of signs and symptoms that occur before onset of eclampsia among pregnant women. DATA SOURCES: Electronic databases, including MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched from inception to 2018. Search terms included eclampsia, predict, likelihood ratio, predictive value, and risk. METHODS OF STUDY SELECTION: Abstracts and later full texts were selected for review if a diagnosis of eclampsia was made, a comparator arm included (women without a diagnosis of eclampsia), and predictors of imminent eclampsia reported. Of 2,791 retrieved records, 11 were selected. Significant heterogeneity existed between studies, with differing designs, settings, participants, and signs or symptoms. In total, 28 signs or symptoms were reported, with visual disturbances and epigastric pain most common (six studies), followed by headache (five studies), and any edema (four studies). TABULATION, INTEGRATION, AND RESULTS: Data on study characteristics and predictive value of signs or symptoms were extracted, and, where appropriate, bivariate mixed-effect meta-analysis was applied to raw data. None of the pooled estimates were able to accurately predict eclampsia nor rule out eclampsia in their absence, with moderate specificity (83-94%) and poor sensitivity (29-56%). CONCLUSION: There is a dearth of high-quality studies investigating the predictive value of imminent signs and symptoms of eclampsia. Owing to the small number of studies, heterogeneity, and inconsistent reporting, it is difficult to provide accurate estimates of the predictive value of prodromal symptoms of eclampsia. Of the most commonly reported symptoms-visual disturbances, epigastric pain, and headache-none were able to accurately predict, nor rule out, imminent eclampsia. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018095076.

Esomeprazole to treat women with preterm preeclampsia: a randomized placebo controlled trial.

BACKGROUND: Preterm preeclampsia has a high rate of fetal death or disability. There is no treatment to slow the disease, except delivery. Preclinical studies have identified proton pump inhibitors as a possible treatment. OBJECTIVE: The purpose of this study was to examine whether esomeprazole could prolong pregnancy in women who have received a diagnosis of preterm preeclampsia. STUDY DESIGN: We performed a double-blind, randomized controlled trial at Tygerberg Hospital in South Africa. Women with preterm preeclampsia (gestational age 26 weeks+0 days to 31 weeks+6 days) were assigned randomly to 40-mg daily esomeprazole or placebo. The primary outcome was a prolongation of gestation of 5 days. Secondary outcomes were maternal and neonatal outcomes. We compared circulating markers of endothelial dysfunction that was associated with preeclampsia and performed pharmacokinetic studies. RESULTS: Between January 2016 and April 2017, we recruited 120 participants. One participant was excluded because of incorrect randomization, which left 59 participants in the esomeprazole and 60 participants in the placebo group. Median gestational age at enrolment was 29+4 weeks gestation. There were no between-group differences in median time from randomization to delivery: 11.4 days (interquartile range, 3.6-19.7 days) in the esomeprazole group and 8.3 days (interquartile range, 3.8-19.6 days) in the placebo group (3 days longer in the esomeprazole arm; 95% confidence interval, -2.9-8.8; P=.31). There were no placental abruptions in the esomeprazole group and 6 (10%) in the placebo group (P=.01, P=.14 adjusted). There were no differences in other maternal or neonatal outcomes or markers of endothelial dysfunction. Esomeprazole and its metabolites were detected in maternal blood among those treated with esomeprazole, but only trace amounts in the umbilical cord blood. CONCLUSION: Daily esomeprazole (40 mg) did not prolong gestation in pregnancies with preterm preeclampsia or decrease circulating soluble fms-like tyrosine kinase 1 concentrations. Higher levels in the maternal circulation may be needed for clinical effect.

Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol.

INTRODUCTION: Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far greater numbers of fetal losses. There is no definitive treatment other than delivery. A drug that can quench the disease process could be useful to treat early onset pre-eclampsia, as it could allow pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have generated preclinical data to show esomeprazole, a proton pump inhibitor used for gastric reflux, has potent biological effects that makes it a worthwhile therapeutic candidate. Esomeprazole potently decreases soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion from placenta and endothelial cells, and has biological actions to mitigate endothelial dysfunction and oxidative stress. METHODS AND ANALYSIS: We propose undertaking a phase II, double blind, randomised controlled clinical trial to examine whether administering 40 mg esomeprazole daily may prolong gestation in women with early onset pre-eclampsia. We will recruit 120 women (gestational age of 26+0 to 31+6 weeks) who will be randomised to receive either esomeprazole or an identical placebo. The primary outcome will be the number of days from randomisation to delivery. Secondary outcomes include maternal, fetal and neonatal composite and individual outcomes. Maternal outcomes include maternal death, eclampsia, pulmonary oedema, severe renal impairment, cerebral vascular events and liver haematoma or rupture. Neonatal outcomes include neonatal death within 6 weeks after the due date, intraventricular haemorrhage, necrotising enterocolitis and bronchopulmonary dysplasia. We will examine whether esomeprazole can decrease serum sFlt-1 and soluble endoglin levels and we will record the safety of esomeprazole in these pregnancies. ETHICS AND DISSEMINATION: This study has ethical approval (Protocol V.2.4, M14/09/038, Federal Wide assurance Number 00001372, IRB0005239), and is registered with NHREC (ID 3649) and the Pan African Clinical Trial Registry (PACTR201504000771349). Data will be presented at international conferences and published in peer-reviewed journals.