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.

Can short- and long-term maternal and infant risks linked to hypertension and diabetes during pregnancy be reduced by therapy?

Hypertensive disorders of pregnancy (HDP), especially preeclampsia, and diabetes during pregnancy pose significant risks for both maternal and infant health, extending to long-term outcomes such as early-onset cardiovascular disease and metabolic disorders. Current strategies for managing HDP focus on screening, prevention, surveillance, and timely intervention. No disease-modifying therapies exist so far for established preeclampsia; delivery remains the definitive resolution. Preventive measures-including early pregnancy screening, exercise, and low-dose aspirin-show promise. Antihypertensive treatments reduce severe hypertension risks, whereas magnesium sulfate remains the standard for preventing eclampsia. Planned delivery from gestational week 37 can balance maternal benefits and neonatal risks in women with established preeclampsia. Delivery between 34 and 37 weeks gestation in women with preeclampsia has to balance risks for mother and infant. Lifestyle interventions-particularly diet and physical activity-are pivotal in managing gestational diabetes mellitus and type 2 diabetes. The oral antidiabetic metformin has shown benefits in glycaemic control and reducing maternal weight gain, although its long-term effects on offspring remain uncertain. The safety of other peroral antidiabetics in pregnancy is less studied. Advancements in glucose monitoring and insulin administration present encouraging prospects for enhancing outcomes in women with diabetes types 1 and 2. Both HDP and diabetes during pregnancy necessitate vigilant management through a combination of lifestyle modifications, pharmacological interventions, and timely obstetric care. Although certain treatments such as low-dose aspirin and metformin show efficacy in risk reduction, further research is ongoing to ensure safety for both mothers and their offspring to reduce short- and long-term adverse effects.

Effects of hypertension and use of antihypertensive drugs in pregnancy on the risks of childhood cancers in Taiwan.

BACKGROUND: Childhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks. OBJECTIVE: This population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring. METHODS: Data on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers. RESULTS: Offspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth. CONCLUSIONS: In this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

Outcome-Based Risk Stratification Model for the Diagnosis of Placental Maternal Vascular Malperfusion.

The Amsterdam Consensus Statement introduced the term maternal vascular malperfusion (MVM) to group a constellation of findings associated with impaired maternal-placental circulation. In isolation, these findings are relatively common in placentas from normal gestations, and there is uncertainty on how many, and which, are required. We aimed to determine the criteria essential for MVM diagnosis in correlation with obstetrical outcomes. A total of 200 placentas (100 with a reported diagnosis of MVM and 100 controls matched by maternal age and gravida-para-abortus status) were reviewed to document MVM features. Obstetrical outcomes in the current pregnancy were recorded including hypertension, pre-eclampsia with or without severe features, gestational diabetes, prematurity, fetal growth restriction, and intrauterine fetal demise. On univariate logistic regression analysis, adverse outcome was associated with low placental weight (LPW, <10% percentile for gestational age), accelerated villous maturation (AVM), decidual arteriopathy (DA), infarcts (presence and volume), distal villous hypoplasia, and excess multinucleated trophoblast in basal plate ≥2 mm (all P < .01) but not with retroplacental hemorrhage. In a multivariable model DA, infarcts and AVM were significantly associated with adverse outcomes, whereas LPW showed a trend toward significance. A receiver-operating characteristic curve including these 4 parameters showed good predictive ability (area under the curve [AUC], 0.8256). Based on the probability of an adverse outcome, we recommend consistent reporting of DA, AVM, infarcts, and LPW, summarizing them as "diagnostic of MVM" (DA or AVM plus any other feature, yielding a probability of 65%-97% for adverse obstetrical outcomes) or "suggestive of MVM" (if only 1 feature is present, or only 2 features are infarcts plus LPW, yielding a probability of up to 52%). Other features such as distal villous hypoplasia, excess (≥2 mm) multinucleated trophoblast, and retroplacental hemorrhage can also be reported, and their role in MVM diagnosis should be further studied.

Prepregnancy plant-based diets and risk of hypertensive disorders of pregnancy.

BACKGROUND: Plant-based diets have been associated with a lower risk of cardiovascular disease in nonpregnant adults, but specific evidence for their effects on risk of hypertensive disorders of pregnancy is scarce. OBJECTIVE: This study aimed to evaluate the prospective association between adherence to plant-based diets before pregnancy and the risk for hypertensive disorders of pregnancy. We hypothesized that women with higher adherence to plant-based diets would have a lower risk for hypertensive disorders of pregnancy. STUDY DESIGN: We followed 11,459 parous women (16,780 singleton pregnancies) without chronic diseases, a history of preeclampsia, and cancers who participated in the Nurses' Health Study II (1991-2009), which was a prospective cohort study. Diet was assessed every 4 years using a validated food frequency questionnaire from which we calculated the plant-based diet index (higher score indicates higher adherence) to evaluate the health associations of plant-based diets among participants while accounting for the quality of plant-based foods. Participants self-reported hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension. We estimated the relative risk of hypertensive disorders of pregnancy in relation to plant-based diet index adherence in quintiles using generalized estimating equations log-binomial regression while adjusting for potential confounders and accounting for repeated pregnancies for the same woman. RESULTS: The mean (standard deviation) age at first in-study pregnancy was 35 (4) years. A total of 1033 cases of hypertensive disorders of pregnancy, including 482 cases of preeclampsia (2.9%) and 551 cases of gestational hypertension (3.3%) were reported. Women in the highest quintile of plant-based diet index were significantly associated with a lower risk for hypertensive disorders of pregnancy than women in the lowest quintile (relative risk, 0.76; 95% confidence interval, 0.62-0.93). There was an inverse dose-response relationship between plant-based diet index and risk for hypertensive disorders of pregnancy. The multivariable-adjusted relative risk (95% confidence interval) of hypertensive disorders of pregnancy for women in increasing quintiles of plant-based diet index were 1 (ref), 0.93 (0.78-1.12), 0.86 (0.72-1.03), 0.84 (0.69-1.03), and 0.76 (0.62-0.93) with a significant linear trend across quintiles (P trend=.005). This association was slightly stronger for gestational hypertension (relative risk, 0.77; 95% confidence interval, 0.60-0.99) than for preeclampsia (relative risk, 0.80; 95% confidence interval, 0.61-1.04). Mediation analysis suggested that body mass index evaluation for dietary assessment and pregnancy explained 39% (95% confidence interval, 15%-70%]) of the relation between plant-based diet index and hypertensive disorders of pregnancy and 48% (95% confidence interval, 12%-86%]) of the relation between plant-based diet index and gestational hypertension. CONCLUSION: Higher adherence to plant-based diets was associated with a lower risk of developing hypertensive disorders of pregnancy. Much of the benefit seems to be related to improved weight control.

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.

Sexual orientation disparities in gestational diabetes and hypertensive disorders of pregnancy.

BACKGROUND: Sexual minority (SM) individuals (e.g., those with same-sex attractions/partners or who identify as lesbian/gay/bisexual) experience a host of physical and mental health disparities. However, little is known about sexual orientation-related disparities in gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP; gestational hypertension [gHTN] and preeclampsia). OBJECTIVE: To estimate disparities in GDM, gHTN and preeclampsia by sexual orientation. METHODS: We used data from the Nurses' Health Study II-a cohort of nurses across the US enrolled in 1989 at 25-42 years of age-restricted to those with pregnancies ≥20 weeks gestation and non-missing sexual orientation data (63,518 participants; 146,079 pregnancies). Our primary outcomes were GDM, gHTN and preeclampsia, which participants reported for each of their pregnancies. Participants also reported their sexual orientation identity and same-sex attractions/partners. We compared the risk of each outcome in pregnancies among heterosexual participants with no same-sex experience (reference) to those among SM participants overall and within subgroups: (1) heterosexual with same-sex experience, (2) mostly heterosexual, (3) bisexual and (4) lesbian/gay participants. We used modified Poisson models to estimate risk ratios (RR) and 95% confidence intervals (CI), fit via weighted generalised estimating equations, to account for multiple pregnancies per person over time and informative cluster sizes. RESULTS: The overall prevalence of each outcome was ≤5%. Mostly heterosexual participants had a 31% higher risk of gHTN (RR 1.31, 95% CI 1.03, 1.66), and heterosexual participants with same-sex experience had a 31% higher risk of GDM (RR 1.31, 95% CI 1.13, 1.50), compared to heterosexual participants with no same-sex experience. The magnitudes of the risk ratios were high among bisexual participants for gHTN and preeclampsia and among lesbian/gay participants for gHTN. CONCLUSIONS: Some SM groups may be disparately burdened by GDM and HDP. Elucidating modifiable mechanisms (e.g., structural barriers, discrimination) for reducing adverse pregnancy outcomes among SM populations is critical.

Heterogeneity in the risk of cardiovascular disease mortality after the hypertensive disorders of pregnancy across mothers' lifetime reproductive history.

BACKGROUND: Prior studies on maternal cardiovascular disease (CVD) mortality and hypertensive disorders of pregnancy (HDP) have focused only on a woman's first birth and have not accounted for successive affected pregnancies. OBJECTIVES: The objective of this study is to identify mothers' risk of CVD mortality considering lifetime reproductive history. METHODS: We used data from the Medical Birth Registry of Norway, the Norwegian Cause of Death Registry, and the Norwegian National Population Register to identify all mothers who gave birth from 1967 to 2020. Our outcome was mothers' CVD death before age 70. The primary exposure was the lifetime history of HDP. The secondary exposure was the order of HDP and gestational age at delivery of pregnancies with HDP. We used Cox regression models to estimate hazard ratio (HR) and 95% confidence interval (CI), adjusting for education, mother's age, and year of last birth. These models were stratified by the lifetime number of births. RESULTS: Among 987,378 mothers, 86,294 had HDP in at least one birth. The highest CVD mortality, relative to mothers without HDP, was among those with a pre-term HDP in their first two births, although this represented 1.0% of mothers with HDP (HR 5.12, 95% CI 2.66, 9.86). Multiparous mothers with term HDP in their first birth only had no increased risk of CVD relative to mothers without HDP (36.9% of all mothers with HDP; HR 1.12, 95% CI 0.95, 1.32). All other mothers with HDP had a 1.5- to 4-fold increased risk of CVD mortality. CONCLUSIONS: This study identified heterogeneity in the risk of CVD mortality among mothers with a history of HDP. A third of these mothers are not at higher risk compared to women without HDP, while some less common patterns of HDP history are associated with severe risk of CVD mortality.

Machine learning prediction of hypertension and diabetes in twin pregnancies using characteristics at prenatal care entry: a nationwide study.

OBJECTIVES: To develop a prediction model for hypertensive disorders in pregnancy (HDP) and gestational diabetes (GDM) in twin pregnancies utilizing characteristics at the prenatal care entry level. METHODS: Cross-sectional study using the US national live birth data between 2016 and 2021. The association of all prenatal candidate variables with HDP and GDM was tested with uni- and multi-variable logistic regression analyses. Prediction models were built with generalized linear models using the logit link function and classification and regression tree approach (XGboost) machine learning (ML) algorithm. Performance was assessed with repeated 2-fold cross-validation and performance metrics we considered were area under the curve (AUC). P value <0.001 was considered statistically significant. RESULTS: A total of 707,198 twin pregnancies were included in the HDP analysis and 723,882 twin pregnancies for the GDM analysis. The incidence of HDP and GDM significantly increased from 12.2% in 2016 to 15.4% in 2021 and from 8.1% in 2016 to 10.7% in 2021, respectively. Factors that increase the risk of HDP in twin gestations are maternal age <20, age≥35, infertility, prepregnancy DM, non-Hispanic Black population, obesity, and those with Medicaid insurance (p<0.001). Factors that more than doubled the risk are obesity class II and III (p<0.001). Factors that increase the risk of GDM in twin gestations are age <25, age≥30, history of infertility, prepregnancy hypertension, non-Hispanic Asian population, non-US nativity, and obesity (p<0.001). Factors that more than doubled the risk are maternal age ≥ 30 years, non-Hispanic Asian, and class I, II, and III maternal obesity ( p<0.001). For both HDP and GDM, the performance of the ML and logistic regression model was mostly similar with negligible difference in terms of all tested performance domains. The AUC of the final ML model for HDP and GDM were 0.62±0.004, and 0.67±0.004, respectively. CONCLUSIONS: The incidence of HDP and GDM in twin gestations is increasing. The predictive accuracy of the machine learning model for both HDP and GDM in twin gestations is similar to that of the logistic regression model. Both models had modest performance, well-calibrated, and neither had a poor fit. This article is protected by copyright. All rights reserved.

Propensity score analysis of low-dose aspirin and bleeding complications in pregnancy.

OBJECTIVE: Low-dose aspirin (LDA) has been shown to reduce the risk of preterm pre-eclampsia and it has been suggested that it should be recommended for all pregnancies. However, some studies have reported an association between LDA and an increased risk of bleeding complications in pregnancy. Our aim was to evaluate the risk of placental abruption and postpartum hemorrhage (PPH) in patients for whom their healthcare provider had recommended prophylactic aspirin. METHODS: This multicenter cohort study included 72 598 singleton births at 19 hospitals in the USA, between January 2019 and December 2021. Pregnancies complicated by placenta previa/accreta, birth occurring at less than 24 weeks' gestation, multiple pregnancy or those with data missing for aspirin recommendation were excluded. Propensity scores were calculated using 20 features spanning sociodemographic factors, medical history, year and hospital providing care. The association between LDA recommendation and placental abruption or PPH was estimated by inverse-probability treatment weighting using the propensity scores. RESULTS: We included 71 627 pregnancies in the final analysis. Aspirin was recommended to 6677 (9.3%) and was more likely to be recommended for pregnant individuals who were 35 years or older (P < 0.001), had a body mass index of 30 kg/m2 or higher (P < 0.001), had prepregnancy hypertension (P < 0.001) and who had a Cesarean delivery (P < 0.001). Overall, 1.7% of the study cohort (1205 pregnancies) developed preterm pre-eclampsia: 1.3% in the no-aspirin and 5.8% in the aspirin group. After inverse-probability weighting with propensity scores, aspirin was associated with increased risk of placental abruption (adjusted odds ratio (aOR), 1.44 (95% CI, 1.04-2.00)) and PPH (aOR, 1.21 (95% CI, 1.05-1.39)). The aOR translated to a number needed to harm with LDA of 79 (95% CI, 43-330) for PPH and 287 (95% CI, 127-3151) for placental abruption. CONCLUSIONS: LDA recommendation in pregnancy was associated with increased risk for placental abruption and for PPH. Our results support the need for more research into aspirin use and bleeding complications in pregnancy before recommending it beyond the highest-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler and biomarkers of impaired placentation at 36 weeks' gestation in pregnancies with small fetuses.

OBJECTIVES: First, to compare ophthalmic artery peak systolic velocity (PSV) ratio and biomarkers of impaired placentation at 36 weeks' gestation in women who delivered a small-for-gestational-age (SGA) or growth-restricted (FGR) neonate, in the absence of hypertensive disorder, with those of women who developed pre-eclampsia (PE) or gestational hypertension (GH) and of women unaffected by SGA, FGR, PE or GH. Second, to examine the associations of PSV ratio, uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) with birth-weight Z-score or percentile. METHODS: This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, UtA-PI, PlGF and sFlt-1. Values of PSV ratio, UtA-PI, PlGF and sFlt-1 were converted to multiples of the median (MoM) or delta values. Median MoM or deltas of these biomarkers in the SGA, FGR, PE and GH groups were compared with those in the unaffected group. Regression analysis was used to examine the relationship of PSV ratio delta, UtA-PI MoM, PlGF MoM and sFlt-1 MoM with birth-weight Z-score, after exclusion of PE and GH cases. RESULTS: The study population of 9033 pregnancies included 7696 (85.2%) that were not affected by FGR, SGA, PE or GH, 182 (2.0%) complicated by FGR in the absence of PE or GH, 698 (7.7%) with SGA in the absence of FGR, PE or GH, 236 (2.6%) with PE and 221 (2.4%) with GH. Compared with unaffected pregnancies, in the FGR and SGA groups, the PSV ratio delta and sFlt-1 MoM were increased and PlGF MoM was decreased; UtA-PI MoM was increased in the FGR group but not the SGA group. The magnitude of the changes in biomarker values relative to the unaffected group was smaller in the FGR and SGA groups than that in the PE and GH groups. In non-hypertensive pregnancies, there were significant inverse associations of PSV ratio delta and UtA-PI MoM with birth-weight Z-score, such that the values were increased in small babies and decreased in large babies. There was a quadratic relationship between PlGF MoM and birth-weight Z-score, with low PlGF levels in small babies and high PlGF levels in large babies. There was no significant association between sFlt-1 MoM and birth-weight Z-score. CONCLUSIONS: Ophthalmic artery PSV ratio, reflective of peripheral vascular resistance, and UtA-PI, PlGF and sFlt-1, biomarkers of impaired placentation, are altered in pregnancies complicated by hypertensive disorder and, to a lesser extent, in non-hypertensive pregnancies delivering a SGA or FGR neonate. The associations between the biomarkers and birth-weight Z-score suggest the presence of a continuous physiological relationship between fetal size and peripheral vascular resistance and placentation, rather than a dichotomous relationship of high peripheral resistance and impaired placentation in small compared to non-small fetuses. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ambient air pollution and hypertensive disorders of pregnancy in Rome.

BACKGROUND: Ambient air pollution has been associated with hypertensive disorders of pregnancy (HDP), but few studies rely on assessment of fine-scale variation in air quality, specific subtypes and multi-pollutant exposures. AIM: To study the impact of long-term exposure to individual and mixture of air pollutants on all and specific subtypes of HDP. METHODS: We obtained data from 130,470 liveborn singleton pregnacies in Rome during 2014-2019. Spatiotemporal land-use random-forest models at 1 km spatial resolution assigned to the maternal residential addresses were used to estimate the exposure to particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), and ozone (O3). RESULTS: For PM2.5, PM10 and NO2, there was suggestive evidence of increased risk of preeclampsia (PE, n = 442), but no evidence of increased risk for all subtypes of HDP (n = 2297) and gestational hypertension (GH, n = 1901). For instance, an interquartile range of 7.0 µg/m3 increase in PM2.5 exposure during the first trimester of pregnancy was associated with an odds ratio (OR) of 1.06 (95% confidence interval: 0.81, 1.39) and 1.04 (0.92, 1.17) after adjustment for NO2 and the corresponding results for a 15.7 µg/m3 increase in NO2 after adjustment for PM2.5 were 1.11 (0.92, 1.34) for PE and 0.83 (0.76, 0.90) for HDP. Increased risks for HDP and GH were suggested for O3 in single-pollutant models and for PM after adjustment for NO2, but all other associations were stable or attenuated in two-pollutant models. CONCLUSIONS: The results of our study suggest that PM2.5, PM10 and NO2 increases the risk of PE and that these effects are robust to adjustment for O3 while the increased risks for GH and HDP suggested for O3 attenuated after adjustment for PM or NO2. Additional studies are needed to evaluate the effects of source-specific component of PM on subtypes as well as all types of HDP which would help to target preventive actions.

Hypertensive disorders of pregnancy among women with cardiovascular disease in Norway: A historical cohort study.

INTRODUCTION: Women with cardiovascular disease may be at increased risk of hypertensive disorders of pregnancy (HDP). We aimed to: (1) Investigate the occurrence of HDP in a cohort of pregnant women with cardiovascular disease and compare it with the occurrence in the general population. (2) Assess the association between maternal cardiovascular risk and risk of HDP. MATERIAL AND METHODS: We reviewed clinical data on a cohort of 901 pregnancies among 708 women with cardiovascular disease who were followed at the National Unit for Pregnancy and Heart Disease and gave birth at Oslo University Hospital between 2003 and 2018. The exposure under study was maternal cardiovascular risk, classified as low, moderate, or high based on a modified classification by the World Health Organization. The main outcome of interest was HDP, which included pre-eclampsia and gestational hypertension. The proportion of HDP cases in the general population in the same period was extracted from the Medical Birth Registry of Norway. We used logistic regression to estimate crude and adjusted odds ratios (OR) of HDP, with associated 95% confidence intervals (CIs), for women with moderate- and high cardiovascular risk compared to women with low risk. RESULTS: The occurrence of HDP in the study cohort was 12.1% (95% CI: 10.0%-14.4%) and varied between 8.7% (95% CI: 6.5%-11.3%) in the low-risk group, 15.7% (95% CI: 11.1%-21.4%) in the moderate-risk group, and 22.2% (95% CI: 15.1%-30.8%) in the high-risk group. By contrast, the nationwide occurrence of HDP was 5.1% (95% CI: 5.1%-5.2%). In the study cohort, the proportions of pregnancies with gestational hypertension and pre-eclampsia were similar (6.3% and 5.8%, respectively). Compared to pregnancies with low cardiovascular risk, the adjusted OR of HDP was 2.04 (95% CI: 1.21-3.44) in the moderate-risk group and 2.99 (95% CI: 1.73-5.18) in the high-risk group. CONCLUSIONS: The occurrence of hypertensive disease of pregnancy in the study cohort was more than doubled compared to the general population in Norway. The risk of HDP increased with maternal cardiovascular risk group. We recommend taking into account maternal cardiovascular risk group when assessing risk and prophylaxis of HDP.

The relationship between hypertensive disorders in pregnancy and endometriosis: a systematic review and meta-analysis.

BACKGROUND: Endometriosis is a chronic and debilitating disease that can affect the entire reproductive life course of women, with potential adverse effects on pregnancy. The aim of the present study is to investigate the association between hypertensive disorders in pregnancy and endometriosis. METHOD: Relevant articles were searched from the Cochrane Library, PubMed, Scopus and Web of Science from inception up to December 2023. The full-text observational studies published in English that had a confirmed diagnosis of endometriosis were included. The case group included pregnant women diagnosed with endometriosis at any stage, while the control group consisted of pregnant women who had not been previously diagnosed with endometriosis. Two authors extracted and analyzed the data independently. Disagreements were reconciled by reviewing the full text by a third author. Endnote X9 was used for screening and data extraction. We used fixed and random effects models in Review Manager 5.3 to analyze the pooled data. The quality of the included studies was assessed using the Downs and Black checklist. RESULTS: Out of the 9863 articles reviewed, 23 were selected for meta-analysis. According to the results of this study, there was an association between endometriosis and gestational hypertension (OR = 1.11, 95% CI: 1.06, 1.16; I2 = 45%, P < 0.00001; N = 8), pre-eclampsia (OR = 1.26, 95% CI: 1.18, 1.36; I2 = 37%, P < 0.00001; N = 12), and hypertensive disorders in pregnancy (OR = 1.13, 95% CI: 1.06, 1.21; I2 = 8%, P = 0.0001; N = 8). CONCLUSIONS: This study confirmed that endometriosis may elevate the risk of developing gestational hypertensive disorders. Raising awareness of this issue will help to identify effective strategies for screening and early diagnosis of hypertensive disorders in pregnancy.

Association of ACE*(Insertion/Deletion) Variant with the Elevated Risk of Preeclampsia Among Gestational Women.

The renin-angiotensin-aldosterone system has an indispensable function in the uteroplacental circulation, placental growth, and blood pressure optimization. The angiotensin I converting enzyme (ACE) gene is a critical integrator for electrolyte balance, and water retention, along with inhibiting preeclampsia. The main goal of this pertaining study is to assess the contribution of ACE*(Ins/Del) variant with the susceptibility for preeclampsia with focus on the severity of the disease among gestational hypertensive women. This retrospective study included 225 participants [125 PE gestational women, and 100 normotensive healthy controls] matching with age, and geographical region. PE women classified into 82 early-onset PE women, accompanied with 43 late-onset PE women. Additionally, PE women categorized into 59 mild PE women, together with 66 severe PE women. The genotyping and characterization of ACE*(Ins/Del) variant were applied using the PCR technique. Our findings indicated higher frequency of the ACE*(Del/Del) genotype and ACE*(D allele) with elevated risk of preeclampsia compared to normotensive controls under recessive (OR = 2.09, and p-value = 0.007), and allelic (OR = 1.75, and p-value = 0.012) models. In addition, testing logistic regression revealed that the levels of endothelin-1 and malondialdehyde exposed significant difference for the ACE*(Del/Del) genotype among early-onset and late-onset PE women (p-value = 0.024, and 0.23, respectively). Furthermore, carriers of the ACE*(Del/Del) genotype observed statistically significant with lower sodium concentrations among severe PE women (p-value = 0.034). The ACE*(Del/Del) genotype and ACE*(D allele) were associated with increased risk preeclampsia among gestational women. Furthermore, early-onset PE and late-onset PE were correlated with endothelin-1 and malondialdehyde concentrations among Egyptian women.

Association between prenatal perfluorinated compounds exposure and risk of pregnancy complications: A meta-analysis.

BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.

Association between serum hormone levels in early pregnancy and risk of hypertensive diseases of pregnancy in women undergoing assisted reproduction.

PURPOSE: We examined the association between progesterone (P4), estradiol (E2), and human chorionic gonadotropin (hCG) levels in early pregnancy and the development of hypertensive diseases of pregnancy among women undergoing assisted reproduction. METHODS: Retrospective study including patients who underwent frozen embryo transfer (FET), ovarian stimulation (OS), or unassisted conception (UC) and had a live singleton birth. The primary outcome was the development of hypertensive diseases of pregnancy (gestational hypertension, preeclampsia, HELLP, or eclampsia). Secondary outcomes were the development of fetal intrauterine growth restriction (IUGR), gestational diabetes mellitus, birth weight, and pre-term birth. Hormone levels and the development of the outcomes were correlated. RESULTS: A total of 681 patients were included; 189 had FET, 193 had OS, and 299 had UC. Patients undergoing FET or OS were not more likely to develop hypertensive diseases of pregnancy compared with UC patients. While median levels of E2 and P4 were significantly different between P-FET and NC-FET patients (E2: 252 vs 317 pg/mL, P4: 64 vs 29 ng/mL, respectively; both p < 0.01), rates of hypertensive diseases of pregnancy did not significantly differ between those two groups. In the multivariate analyses, P4, E2, and hCG were not associated with the development of hypertensive diseases of pregnancy, but progesterone levels were significantly higher among those with IUGR. This remained consistent when the analysis was limited to FET patients. CONCLUSION: P4, E2, and hCG levels did not correlate with the development of hypertensive diseases of pregnancy but elevated progesterone levels did correlate with the development of IUGR.

The relationship between Toll-like receptor-4 genes and preeclampsia outcomes.

PURPOSE: The study aimed to analyse the relationship of the rs4986790 locus of the TLR4 gene with the overall risk of preeclampsia, including both its early and late forms. METHODS: The study used standard genetic analysis methods such as DNA extraction, PCR amplification, and genotyping of the rs4986790 locus of the TLR4 gene to assess the association with the development of preeclampsia and peripartal stroke in 207 pregnant women from the southern regions of Kazakhstan from 2016 to 2022, of whom 103 had peripartal stroke on the background of preeclampsia (the main group) and 104 preeclampsia (comparative group). RESULTS: The results of the study demonstrate that the AG and AG + GG genotypes at the rs4986790 locus of the TLR4 gene are significantly associated with an increased risk of developing an early form of preeclampsia. This opens up a new perspective in the identification of genetic markers that can serve as indicators of a tendency to develop preeclampsia in earlier periods of pregnancy. CONCLUSION: It was noted that the rs4986790 locus did not show a statistically significant association with the risk of late preeclampsia. An important aspect of the study revealed the relationship of genotypes with the development of peripartal stroke on the background of preeclampsia. This study offers practical insights for creating targeted genetic screening and personalised treatments for preeclampsia, aiming to improve patient outcomes. To fully understand the molecular mechanisms underlying the identified association, additional research is required to identify deeper molecular pathways and relationships, and to develop new strategies for the prevention and treatment of preeclampsia.

Expression of long non-coding RNA GAS5 by first trimester screening predicts the occurrence of gestational hypertension and pre-eclampsia.

AIMS: Hypertensive disorders of pregnancy (HDP) is a unique disease during gestational period, which is detrimental to pregnancy outcome. This study examined the clinical significance of long non-coding RNA GAS5 in gestational hypertension (GH) and preeclampsia (PE), aiming to explore potential biomarkers for the disease detection. METHODS: 180 pregnant women with HPD including 90 cases with GH and 90 cases with PE, and another 100 healthy pregnant women were enrolled. Serum GAS5 levels were measured by RT-qPCR method. The diagnostic performance of GAS5 was assessed in GH and PE through plotting receiver operating characteristic (ROC) curve. Logistic regression was applied for the identification of independent factors. RESULTS: Elevated serum GAS5 was identified in GH patients, and its diagnostic performance in discriminating GH cases from healthy people was determined by ROC curve. Serum GAS5 was positively associated with SBP, DBP, LDL-C and CRP values. Cases with PE had an increased serum GAS5 level relative to those with GH. Serum GAS5 was identified to be an independent predictor for PE, and can differentiate PE cases from GH ones. with a good diagnositc performance. Cases with high levels of serum GAS5 had a high risk of poor pregnancy outcomes. CONCLUSION: Elevated serum GAS5 could serve as an effective diagnostic biomarker in discriminating GH patients from healthy people by first trimester screening. Detection of serum GAS5 level has a certain predictive value for PE.

Genetically predicted circulating concentrations of micronutrients and risk of hypertensive disorders of pregnancy: a Mendelian randomization study.

PURPOSE: Epidemiological studies examining the association between circulating micronutrients and the risk of hypertensive disorders during pregnancy (HDP) have produced inconsistent results. Therefore, we conducted a Mendelian randomization (MR) analysis to evaluate the potential causal relationship between micronutrients and HDP. METHODS: Nine micronutrients (beta-carotene, vitamin B6, vitamin B12, calcium, zinc, selenium, copper, folate, and phosphorus) were selected as the exposure factors. Summary data for gestational hypertension (14,727 cases and 196,143 controls) and preeclampsia/eclampsia (7212 cases and 174,266 controls) were extracted from the FinnGen consortium. The MR analysis employed the inverse variance weighted method and conducted a range of sensitivity analyses. RESULTS: The inverse variance weighted method indicated no significant causal relationship between nine genetically predicted micronutrient concentrations and gestational hypertension, as well as preeclampsia/eclampsia. Sensitivity analyses suggested the absence of pleiotropy. CONCLUSION: There is no strong evidence to support the causation between circulating micronutrients and hypertensive disorder during pregnancy.