Maternal vascular-placental axis in the third trimester in women with gestational diabetes mellitus, hypertensive disorders, and unaffected pregnancies.

BACKGROUND: Hypertensive disorders of pregnancy and gestational diabetes mellitus are characterized by vascular dysfunction and are associated with long term cardiovascular risks. OBJECTIVE: This study aimed to compare different markers of maternal vascular function in women with gestational diabetes mellitus, preeclampsia, or gestational hypertension and in women whose pregnancies were unaffected by these complications and to assess the association between maternal vascular function and markers of placental perfusion and maternal vascular-placental axis in 4 groups of women. STUDY DESIGN: This was a prospective observational study of women who had routine hospital visits at 35 0/7 to 36 6/7 weeks of gestation at King's College Hospital, London, United Kingdom. The routine hospital visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, Doppler studies of the uterine arteries and ophthalmic arteries, carotid-femoral pulse wave velocity measurements, estimation of the augmentation index and total peripheral resistance, and measurements of serum placental growth factor and soluble fms-like tyrosine kinase 1. Linear regression analysis was performed for the outcomes of uterine artery pulsatility index multiple of the median, placental growth factor multiple of the median, and soluble fms-like tyrosine kinase 1 multiple of the median. The ophthalmic artery peak systolic velocity ratio, pulse wave velocity, augmentation index, and total peripheral vascular resistance were assessed as potential predictors. This analysis was performed on all women and separately in the different groups. RESULTS: The study population of 6502 women included 614 (9.4%) with gestational diabetes mellitus, 140 (2.1%) who subsequently developed preeclampsia, and 129 (2.0%) who developed gestational hypertension. Women with gestational diabetes mellitus had increased pulse wave velocity compared with those with pregnancies unaffected by gestational diabetes mellitus, preeclampsia, or gestational hypertension. Women with preeclampsia or gestational hypertension had lower placental growth factor multiple of the median and higher uterine artery pulsatility index multiple of the median, soluble fms-like tyrosine kinase 1 multiple of the median, augmentation index, pulse wave velocity, total peripheral resistance, and ophthalmic artery peak systolic velocity ratio than those with unaffected pregnancies. In women with unaffected pregnancies, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, and ophthalmic artery peak systolic velocity ratio, augmentation index, total peripheral resistance, and pulse wave velocity were predictive of the placental growth factor multiple of the median and the soluble fms-like tyrosine kinase 1 multiple of the median. In women with gestational diabetes mellitus, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median; the ophthalmic artery peak systolic velocity ratio, total peripheral resistance, and pulse wave velocity were predictive of the placental growth factor multiple of the median; and total peripheral resistance was predictive of the soluble fms-like tyrosine kinase 1 multiple of the median. In women with preeclampsia, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, placental growth factor multiple of the median, and soluble fms-like tyrosine kinase 1 multiple of the median. In women unaffected by gestational diabetes mellitus, preeclampsia, or gestational hypertension, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, and the augmentation index, total peripheral resistance, pulse wave velocity, and the ophthalmic artery peak systolic velocity ratio were predictive of the placental growth factor multiple of the median and the soluble fms-like tyrosine kinase 1 multiple of the median. CONCLUSION: In the third trimester of pregnancy, women with preeclampsia, gestational hypertension, and gestational diabetes mellitus present with increased arterial stiffness. In addition, women diagnosed with hypertensive complications showed increased peripheral vascular resistance. The ophthalmic artery peak systolic velocity ratio provided predictive information for placental perfusion and function in all pregnant women, whereas vascular indices were more informative for placental function in women with unaffected pregnancies and those with gestational diabetes mellitus than in those with preeclampsia or gestational hypertension. Our data suggest that vascular assessment in women during pregnancy not only may provide information about maternal vascular health but also can be used to provide information about individual risk factors for placental insufficiency. The selection of the vascular index will have to be tailored according to the maternal profile and pregnancy complication.

Association between iron status, preeclampsia and gestational hypertension: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Several recent observational studies have reported that iron overload during pregnancy is associated with preeclampsia (PE) and gestational hypertension (GH). However, the causal association between iron status, PE, and GH is still not clear. METHODS: We performed a two-sample Mendelian randomization (MR) study using the genome-wide association study (GWAS) summary statistics of iron status, included serum iron, ferritin, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) from the largest available GWAS meta-analysis, and the summary statistics of PE and GH were obtained from the FinnGen consortium. Fixed-effect inverse variance weighted (IVW), random-effect IVW, maximum likelihood (ML), MR-Egger regression, weighted median, and MR-PRESSO methods were used. RESULTS: A total of 21, 58, 28, and 22 SNPs were used as IVs for serum iron, ferritin, TIBC, and TSAT, respectively. The F-statistics of IVs ranged from 95.23 to 421.36. The results of the fixed effects IVW method suggested that for per SD unit increase in serum iron, the risk of PE increases by 24 % (OR = 1.24, 95 % CI: 1.03-1.50, P = 0.02). No significant heterogeneity or horizontal pleiotropy was found. The association between ferritin, TIBC, TSAT and PE were statistically insignificant (P>0.05). Furthermore, the results of each MR methods do not support a causal association between iron status and GH, nor a reverse causal association between PE and GH and iron status. CONCLUSION: This two-sample MR study provides evidence supporting a causal association between serum iron level and PE.

The effects of proton pump inhibitors during pregnancy on treatment of preeclampsia, and related outcomes: a systematic review and meta-analysis.

OBJECTIVE: This systematic review evaluated the available evidence of the effects of PPIs during pregnancy on preeclampsia and related maternal, fetal and neonatal outcomes. DATA SOURCES: Five electronic databases (MEDLINE, Embase, CINAHL, Cochrane CENTRAL, and Global Medicus Index) were searched on 17 November 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials involving pregnant women, using any class or dose of PPIs, were eligible. STUDY APPRAISAL AND SYNTHESIS METHODS: Meta-analysis was conducted for all outcomes of interest, with random-effects models. Results were presented as risk ratios or mean difference. Quality assessment was performed using the Risk of Bias 2 tool, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment was completed to evaluate the certainty of the evidence. The study was registered on PROSPERO (CRD42023423673). RESULTS: Our search identified 3,879 records, which were screened by two authors independently. Nine reports (describing eight trials) met our eligibility criteria, however six trials were ultimately excluded from our analysis as women were only given PPIs immediately prior to Cesarean section for acid aspiration prevention. The two trials included in the meta-analysis evaluated the treatment of 177 women with diagnosed preeclampsia. For the primary outcomes, moderate-certainty evidence showed there is likely no effect of the use of PPIs on risk of HELLP syndrome (RR 1.21, 95% CI 0.37 - 3.99, I²â€¯= 0%) or perinatal mortality (RR 0.81, 95% CI 0.36 - 1.79, I²â€¯= 0%), while there were insufficient data to meta-analyse all other primary outcomes, including eclampsia and neonatal mortality. No trials investigated PPIs for preventing preeclampsia. CONCLUSIONS: Given the limited outcome data we are uncertain of the effect of PPIs in women with preeclampsia. Further trials are required to determine what (if any) effects PPIs might have for preeclampsia prevention or treatment.

Causal association of sex hormone-binding globulin on gestational hypertension and pre-eclampsia: a two-sample Mendelian randomization study.

OBJECTIVES: Pre-eclampsia (PE) and gestational hypertension (GH) are two different categories of hypertensive disorders of pregnancy. Given earlier observational research, the relationship between sex hormone-binding globulin (SHBG) and a higher risk of GH/PE is still up for dispute. Hence, the present investigation aimed to examine the possible link between SHBG and the likelihood of GH/PE. METHODS: As a first stage, single nucleotide polymorphisms from summary-level genome-wide association studies were tightly screened using quality-control techniques. Afterward, we utilized a two-sample Mendelian randomization (MR) study to examine the causal impact of SHBG on the likelihood of GH/PE. There was no indication of a relationship between blood SHBG level (n = 214,989) and GH/PE (1864 cases and 461,069 controls) in the initial study. Consensus results were obtained from the replicated analysis, which utilized MR estimates based on serum SHBG level(n = 214,989) for GH (4255 cases and 114,735 controls). RESULTS: The findings did not indicate any proof of a cause-and-effect connection between SHBG and the likelihood of GH/PE (odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.999 - 1.00, p = .34). Replicate analysis also revealed similar patterns (OR = 0.92, 95%CI = 0.82-1.05, p = .21). The above findings were demonstrated to have a strong level of robustness. CONCLUSIONS: The findings of this research did not offer definitive proof to endorse the idea that SHBG has a direct causal impact on the likelihood of GH/PE, which goes against numerous widely accepted observational studies. To ascertain the potential processes behind the relationships seen in observational studies, more investigation is needed.

Therapeutic potential of Omega-3 polyunsaturated fatty acids on the immune function of patients with hypertensive disorder complicating pregnancy and preeclampsia.

BACKGROUND: This paper aims to explore the mechanism of Omega-3 polyunsaturated fatty acids (PUFA) on the immune function of patients having pregnancy induced hypertension (PIH). METHODS: Through a retrospective study, 168 patients with PIH syndrome who were cured at the First Affiliated Hospital of Hebei North University (January 2020 to December 2021) were randomly divided into the Omega-3 treated group and the control group, with 84 cases in each group. The control group received treatment with magnesium sulfate. The other group was treated with PUFAs based on the magnesium sulfate treatment. To evaluate the differences in diastolic pressure, systolic pressure and inflammatory factors between the Omega-3 treated group and control group, statistical analysis was conducted using SPSS 23.0 software. The measurement data were subject to t-test, and x 2 test was adopted for counting data. RESULTS: The treatment efficiency of the Omega-3 treated group and the control group was 95.24% and 80.95%, respectively, with a significant difference (P<0.05). Before receiving treatment, there was no difference in diastolic and systolic pressure, various inflammatory factors and various immune functions between these two groups (P>0.05). The group treated with omega-3 had lower CD3+, CD4+ and the CD4+/CD8+ ratio than the control group (P<0,05). The Omega-3 treated group had significantly higher IL-4 and CD8+ than those in the control group (P<0.05). CONCLUSION: Intravenous injection of Omega-3 can reduce blood pressure, improve immune function, and reduce inflammatory reactions in patients with gestational hypertension.

Exploring the Spectrum of Electrolyte Imbalances in Preeclampsia: Mechanisms, Implications, and Clinical Insights.

Preeclampsia, a complex and perplexing disorder unique to pregnancy, is widely recognized as primarily originating from placental dysfunction and can only be resolved by the delivery of the fetus in severe cases. Preeclampsia is a prevalent medical issue during pregnancy and is associated with elevated rates of maternal and infant mortality and morbidity. The exact cause of preeclampsia remains uncertain, although multiple factors have been implicated in its development based on current knowledge. Preeclampsia is characterized by maternal endothelial dysfunction due to the presence of fetal-derived circulatory substances from the placenta. The condition is associated with various risk factors, including maternal comorbidities such as chronic renal disease, hypertension (HTN), and obesity. Additionally, a family history of preeclampsia, nulliparity, multiple gestations, previous instances of preeclampsia, or intrauterine fetal growth restriction (IUGR) are considered risk factors. Electrolytes, including sodium, potassium, and chloride, play a critical role in the function of vascular smooth muscles and may potentially contribute to the pathophysiology of hypertension. In this review, we have summarized the literature on electrolytes in preeclampsia by conducting an extensive systematic search of databases such as PubMed, Excerpta Medica database (EMBASE), and Medical Literature Analysis and Retrieval System Online (MEDLINE).

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

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.

The Hidden Relationship between Intestinal Microbiota and Immunological Modifications in Preeclampsia Pathogenesis.

Preeclampsia is a multifactorial gestational syndrome characterized by increased blood pressure during pregnancy associated with multiorgan involvement. The impact of this disease on maternal and neonatal health is significant, as it can lead to various fetal comorbidities and contribute to the development of maternal comorbidities later in life. Consistent evidence has shown that the microbiota acts as a regulator of the immune system, and it may, therefore, influence the development of preeclampsia by modulating immune factors. This narrative review aims to investigate the role of the immune system in the pathogenesis of preeclampsia and to summarize the most recent literature on the possible link between preeclampsia and alterations in the intestinal microbiota. To this end, we conducted a literature search, aiming to perform a narrative review, on PubMed and Embase from January 1990 to March 2024, focusing on the latest studies that highlight the main differences in microbial composition between patients with and without preeclampsia, as well as the effects of microbial metabolites on the immune system. From the review of 28 studies assessing the intestinal microbiota in preeclamptic women, preeclampsia could be associated with a state of dysbiosis. Moreover, these patients showed higher plasmatic levels of endotoxin, pro-inflammatory cytokines, and T helper 17 cells; however, the findings on specific microbes and metabolites that could cause immune imbalances in preeclampsia are still preliminary.

Serum Uric Acid Levels as a Risk Stratification Tool in Hypertensive Disorders of Pregnancy: A Retrospective Study.

BACKGROUND: Worldwide, hypertensive disorders of pregnancy (HDP) are among the leading causes of maternal and fetal morbidity and mortality. Serum uric acid is a test that can evaluate the severity of HDP and the associated maternal and fetal morbidity and mortality. AIM: To examine the relationship between maternal serum uric acid levels and the severity of HDP and overall pregnancy outcomes. MATERIAL AND METHODS: A retrospective study was conducted on women with a gestational age > 20 weeks and BP >140/90 mmHg over three years. A total of 134 patients were included in the study. Patients with chronic hypertension, hyperuricemia without hypertension, and other major illnesses were excluded. Data were collected from medical records, including age, gravida, parity, weight, height, gestational age, blood pressure at admission, urine albumin, and serum uric acid levels. RESULTS: Of the 134 enrolled women with HDP, 76 had gestational hypertension, 41 had preeclampsia, and 17 had eclampsia. Mean uric acid levels in mg/dL were 6.06±1.651, 6.20±0.824, and 7.38±1.26 in gestational hypertension, preeclampsia, and eclampsia, respectively, which was a significant association (p=0.002). Mean uric acid in mg/dL was 5.86±1.27 in intensive care unit (ICU) patients compared to 6.45±1.39 in ward patients (p=0.015). There was a significantly increased risk of ICU admission and preterm delivery (r=-0.401, p<0.001) in patients with elevated uric acid levels. There was a significantly increased risk of low-birth-weight babies with elevated uric acid levels (r=-0.278, p=0.001). However, there was no statistically significant increased risk of newborn intensive care unit admissions (p=0.264) with elevated uric acid levels. CONCLUSION: Serum uric acid levels vary significantly in HDP and were found to be elevated in severe preeclampsia and eclampsia. It can be considered for risk stratification in HDP based on disease severity; however, its role in determining outcomes is debatable. Using serum uric acid levels in predictive models along with known biomarkers may determine its possible additional value in disease prediction and severity.

Circulating vascular endothelial growth factor receptor-3, a pro-lymphangiogenic and pro-angiogenic mediator, is decreased in pre-eclampsia.

OBJECTIVE: To compare circulating levels of vascular endothelial growth factor receptor 3 (VEGFR-3) in women with pregnancy-induced hypertension (PIH) and in non-pregnant (NP) and healthy pregnant (HP) women. METHODS: We conducted a case-control study including PIH (n = 135), HP (n = 68), and NP (n = 49) women from southeastern Brazil. PIH were diagnosed according to international guidelines, and defined as gestational hypertension (GH, n = 61) or pre-eclampsia (n = 74). VEGFR-3 was measured in plasma using ELISA. RESULTS: Plasma VEGFR-3 was increased in HP (1207 pg/mL) compared with NP (133 pg/mL) women; however, PIH (729 pg/mL) patients exhibited lower levels than HP women (both p < 0.05). In addition, plasma VEGFR-3 was decreased in pre-eclampsia compared with GH (537 versus 980 pg/mL; p < 0.05). When pre-eclampsia was classified according to different clinical presentations, plasma VEGFR-3 was further decreased in the cases identified as pre-eclampsia with severe features, preterm pre-eclampsia, and pre-eclampsia accompanied by small for gestational age (all p < 0.05). CONCLUSION: Our data indicate reduced circulating VEGFR-3 levels in patients with PIH, specifically in those diagnosed with pre-eclampsia. Moreover, decreased VEGFR-3 was associated with adverse clinical outcomes in pre-eclampsia. These findings expand previous evidence of reduced VEGFR-3 expression in pre-eclampsia. Future studies should investigate whether it can be used as a predictive biomarker and/or therapeutic target for pre-eclampsia.