Similar Pro- and Antiangiogenic Profiles Close to Delivery in Different Clinical Presentations of Two Pregnancy Syndromes: Preeclampsia and Fetal Growth Restriction.

The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1-sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR.

Alterations in maternal sFlt-1 and PlGF: Time to labor onset in term-/late-term pregnancies with and without placental dysfunction.

OBJECTIVES: To investigate the placenta-associated biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) longitudinally in late third trimester extending to late-term pregnancies, and their correlation with time to labor onset in pregnancies with and without placental syndromes (ie preeclampsia and/or fetal growth restriction). Also, to compare whether time to labor onset after induction differ between these groups. STUDY DESIGN: Pregnant women (n = 338, of which 75 had a placental syndrome) with serial blood samples from gestational week ≥37 until labor onset were included. Maternal serum PlGF and sFlt-1 concentrations were analyzed by immunoassay postpartum. MAIN OUTCOME MEASURES: Rate of alteration in sFlt-1, PlGF and the sFlt-1/PlGF ratio prior to labor onset. Secondary outcome was rates of delivery within 48 h of labor induction. RESULTS: In placental syndrome pregnancies, sFlt-1 and sFlt-1/PlGF ratio increased more rapidly between the two last samples prior to labor onset compared to uncomplicated pregnancies (both p < 0.01), but there was no difference in the PlGF decrease (p = 0.513). Time to labor onset was significantly shorter in pregnancies with placental syndromes compared to those without (p = 0.001). In the induced deliveries, there was no difference in delivery within 48 h between the two groups. CONCLUSIONS: An increase in sFlt-1 and sFlt-1/PlGF ratio at term prior to labor onset is more rapid in pregnancies with placental syndromes. This more rapid antiangiogenic shift might indicate a pregnancy more prone to acute placental failure and more inflammatory prepared for labor onset. Effect of labor induction was not impacted by placental dysfunction.

The association between decidual vasculopathy and abnormal uterine artery Doppler measurement.

INTRODUCTION: Placental syndrome is an umbrella term encompassing the clinical phenotypes of preeclampsia and fetal growth restriction, and is associated with high maternal and neonatal morbidity. In women with placental syndrome, histologicl examination of the uteroplacental unit commonly demonstrates pathological lesions, such as decidual vasculopathy. Decidual vasculopathy are pathological changes in the spiral arteries, which are associated with adverse outcome in preeclampsia and long-term maternal cardiovascular health. The relation between placental syndrome phenotypes and placental pathology has been previously demonstrated; however, the role of uteroplacental Doppler measurements as a link between placental syndrome phenotypes and the underlying placental pathology is still unclear. We hypothesized that decidual vasculopathy is associated with abnormal uteroplacental Doppler profiles and ultrasound placental parameters, independent of clinical phenotype. MATERIAL AND METHODS: We performed a retrospective analysis of data from a prospective cohort of pregnancies with placental syndrome, as well as cases without hypertensive disease or fetal growth restriction. The study group was divided into women with decidual vasculopathy on histologic analysis of placental specimen and those without the lesions. Outcome parameters included maternal and fetal Dopplers, estimated fetal weight, placental weight and thickness, placental lacunae and abnormal placental calcification. RESULTS: Compared with the women without the lesions (n = 91), the group with decidual vasculopathy (n = 25) had a higher mean uterine artery pulsatility index (1.70 vs 0.81, p < 0.001) and uterine artery pulsatility index percentile (>p99 vs p67, p < 0.001). Decidual vasculopathy was associated with abnormal uterine artery Doppler profile (defined as pulsatility index p > 95 and/or bilateral notch) (82%) compared with women without the lesions (33%) (odds ratio [OR] 9.3, 95% CI 2.4-36.0), which remained significant after adjusting for possible confounding factors preeclampsia, tobacco use and gestational age at birth (OR 7.1, 95% CI 1.3-39.1). Decidual vasculopathy was not associated with fetal Doppler abnormalities or placental parameters and only modestly so with lower cerebroplacental ratio (p = 0.036). CONCLUSIONS: Histologic decidual vasculopathy is associated with abnormal uterine artery Doppler, independent of clinical phenotype during pregnancy.

Placental Syndromes-A New Paradigm in Perinatology.

Placental syndromes include pregnancy loss, fetal growth restriction, preeclampsia, preterm delivery, premature rupture of membranes, placental abruption and intrauterine fetal demise. This paper discusses the common etiopathogenesis of those syndromes and the role of angiogenic biomarkers in their development. Pregnancy implantation, placental development and maternal adaptation are complex processes in which fetal and maternal cells interact. The syncytiotrophoblast, trophoblast, uterine natural killer cells and regulatory T cells interfere and interact in all the above-mentioned processes. The proper angioneogenesis and vasculogenesis of the placenta, as well as maternal circulatory adaptation, are dependent on angiogenic factor expression. Insufficient maternal immunotolerance, dysregulation in uterine natural killer or regulatory T cell function, syncytiotrophoblast and trophoblast ischemia and hypoxia or impaired balance in angiogenic factors are all related to the occurrence of placental syndromes. Differences in the time of impairment onset and its intensity and correlation with other dysfunctions result in the development of a specific syndrome. The clinical manifestations in the form of a combination of specific symptoms determine the diagnosis. However, they are just symptoms of an underlying complex trophoblast disorder.

The association between first trimester placental biomarkers and placental lesions of maternal vascular malperfusion.

INTRODUCTION: Abnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency. METHODS: This retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: MVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome. DISCUSSION: Our findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers.

Gestational lipid profile as an early marker of metabolic syndrome in later life: a population-based prospective cohort study.

BACKGROUND: In pregnancy lipid levels increase with gestation resembling an atherogenic lipid profile. Currently it is unclear whether gestational lipid levels are associated with an adverse cardiovascular risk profile later in life. The aim of this study is to assess the association between gestational lipid levels and lipid levels and prevalence of the metabolic syndrome (MS) six years after pregnancy. METHODS: In plasma of 3510 women from the Generation R Study; a prospective population-based cohort, we measured lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]), and low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated in early pregnancy (median 13.2 weeks, 90% range [10.5 to 17.1]) and six years after pregnancy (median 6.5 years, 90% range [6.2 to 7.8]). MS was assessed six years after pregnancy according to the NCEP/ATP3 criteria. We also examined the influence of pregnancy complications on these associations. RESULTS: Gestational lipid levels were positively associated with corresponding lipid levels six years after pregnancy, independent of pregnancy complications. Six years after pregnancy the prevalence of MS was 10.0%; the prevalence was higher for women with a previous placental syndrome (13.5%). Gestational triglycerides and remnant cholesterol in the highest quartile and HDL-c in the lowest quartile were associated with the highest risk for future MS, independent of smoking and body mass index. CONCLUSIONS: Gestational lipid levels provide an insight in the future cardiovascular risk profile of women in later life. Monitoring and lifestyle intervention could be indicated in women with an unfavorable gestational lipid profile to optimize timely cardiovascular risk prevention.

Impaired Fetal Environment and Gestational Age: What Is Driving Mortality in Neonates With Critical Congenital Heart Disease?

Background Infants with critical congenital heart disease (CCHD) are more likely to be small for gestational age (SGA) or born to mothers with maternal placental syndrome. The objective of this study was to investigate the relationship between maternal placental syndrome, SGA, and gestational age (GA) on 1-year mortality in infants with CCHD. Methods and Results In a population-based administrative database of all live-born infants in California (2007-2012) we identified all infants with CCHD without chromosomal anomalies. Our primary predictor was an impaired fetal environment (IFE), defined as presence of maternal placental syndrome or SGA. We calculated hazard ratios to quantify the association between different components of IFE and 1-year mortality and conducted a causal mediation analysis to assess GA at birth as a mediator. We identified 6863 infants with CCHD. IFE was present in 25.1%. Infants with IFE were more likely to die than infants without IFE (16.6% versus 11.1%; hazard ratios 1.55, 95% CI 1.34-1.78). Only SGA (hazard ratios 1.76, 95% CI 1.50-2.05) and placental abruption (hazard ratios 1.70, 95% CI 1.17-2.48) were significantly associated with mortality; preeclampsia and gestational hypertension had no significant association with mortality. The mediation analysis showed that 32.8% (95% CI 24.9-47.0%) of the relationship between IFE and mortality is mediated through GA. Conclusions IFE is a significant contributor to outcomes in the CCHD population. SGA and placental abruption are the main drivers of postnatal mortality while other maternal placental syndrome components had much less of an impact. Only one third of the effect between IFE and mortality is mediated through GA.

Maternal kidney function during pregnancy: systematic review and meta-analysis.

OBJECTIVES: To review systematically current literature on kidney function changes during pregnancy, in order to estimate the extent of adaptation over the course of both healthy physiological and complicated singleton pregnancies, and to determine healthy pregnancy reference values. METHODS: PubMed (NCBI) and EMBASE (Ovid) electronic databases were searched, from inception to July 2017, for studies on kidney function during uncomplicated and complicated pregnancies. Included studies were required to report a non-pregnant reference value of kidney function (either in a non-pregnant control group or as a prepregnancy or postpartum measurement) and a pregnancy measurement at a predetermined and reported gestational age. Kidney function measures assessed were glomerular filtration rate (GFR) measured by inulin clearance, GFR measured by creatinine clearance and serum creatinine level. Pooled mean differences between pregnancy measurements and reference values were calculated for predefined intervals of gestational age in uncomplicated and complicated pregnancies using a random-effects model described by DerSimonian and Laird. RESULTS: Twenty-nine studies met the inclusion criteria and were included in the analysis. As early as the first trimester, GFR was increased by up to 40-50% in physiological pregnancy when compared with non-pregnant values. Inulin clearance in uncomplicated pregnancy was highest at 36-41 weeks, with a 55.6% (53.7; 95% CI, 44.7-62.6 mL/min) increase when compared with non-pregnant values, and creatinine clearance was highest at 15-21 weeks' gestation, with a 37.6% (36.6; 95% CI, 26.2-46.9 mL/min) increase. Decrease in serum creatinine level in uncomplicated pregnancy was most prominent at 15-21 weeks, with a 23.2% (-0.19; 95% CI, -0.23 to -0.15 mg/dL) decrease when compared with non-pregnant values. Eight studies reported on pregnancies complicated by a hypertensive disorder. Meta-regression analysis showed a significant difference in all kidney function parameters when comparing uncomplicated and hypertensive complicated pregnancies. CONCLUSIONS: In healthy pregnancy, GFR is increased as early as the first trimester, as compared with non-pregnant values, and the kidneys continue to function at a higher rate throughout gestation. In contrast, kidney function is decreased in hypertensive pregnancy. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Labor induction versus expectant management at early term in pregnancies with second trimester elevated human chorionic gonadotropin or alpha fetoprotein.

AIM: Elevated human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) have been linked to placental dysfunction and associated morbidities. We aimed to compare the induction of labor with expectant management at term in those pregnancies for the prevention of neonatal and maternal morbidities. METHODS: Women with second trimester HCG ≥ 2 and/or AFP ≥ 2 multiples of the median, without additional maternal or fetal complications, from their 38th gestational week were offered the choice of labor induction or expectant management. The primary outcomes were maternal composite outcome (composed of cesarean deliveries, pre-eclampsia or placental abruption) and neonatal composite outcome (composed of antenatal or neonatal death, Apgar score at 5 min < 7, admission to the neonatal intensive care unit, need for phototherapy, respiratory abnormalities, birth trauma or neonatal infection). RESULTS: Of 305 women, 124 women chose to undergo labor induction, and 181 women chose expectant management. The composite maternal outcome in the expectant management group was twice the rate of the labor induction group, although it did not reach statistical significance (18 [10%] vs 6 [5%]; P = 0.1; relative risk [expectant/induced] 2.04; 95% confidence interval 0.8-5.0). Increased rate of phototherapy led to increased neonatal composite outcomes in the labor induction group compared with the expectant management group (34 [27%] vs 27 [15%], respectively = 0.007). CONCLUSION: In pregnancies with elevated AFP and/or HCG, early term labor induction initiated a trend towards improvement in maternal outcome but increased the rate of mild neonatal morbidity. The statistical insignificance of the large effect on the maternal outcome might reflect the lack of statistical power. Further research is needed to address this limitation.

Predictive Value of Second-Trimester Biomarkers and Maternal Features for Adverse Pregnancy Outcomes.

OBJECTIVE: To establish the predictive probability for placenta-associated morbidities using second-trimester α-fetoprotein (AFP), human chorionic gonadotropin (HCG), and maternal features. PATIENTS AND METHODS: A retrospective database of all singleton deliveries with available second-trimester HCG and AFP results from 2005 to 2012 was built and divided into 0, 1, or 2 elevated markers (defined as ≥2 multiples of the median [MoM]). For each group, we analyzed the risk for adverse obstetric outcome - comprising preeclampsia, placental abruption, and birth weight below the 10th percentile - and the time of delivery in those pregnancies. Additionally, prediction models for adverse obstetric outcome, using logistic regression incorporating AFP, HCG, and other maternal characteristics, were calculated. RESULTS: Among 22,124 women who delivered, 16,197 (73%) had AFP and HCG results. Compared with the group with normal markers, the adverse obstetric outcome rate was mildly increased with elevated HCG or AFP, but it was markedly increased when both markers were elevated (13 vs. 31%, OR 2.9, 95% CI 2.0-4.3). Delivery of newborns with adverse obstetric outcome was earlier with each additional elevated marker. The accuracy of predicting adverse obstetric outcome was improved by using prediction models for women with HCG or AFP ≥1.2 MoM that incorporated maternal age, BMI, parity, and chronic hypertension (C-statistic 61-75%). CONCLUSION: HCG and AFP combined with other maternal characteristics are useful tools for predicting the risk for adverse obstetric outcome.

Circulating Fibronectin and Plasminogen Activator Inhibitor-2 Levels as Possible Predictors of Recurrent Placental Syndrome: An Exploratory Study.

BACKGROUND/AIM: Placental syndromes (PS) are characterized by endothelial dysfunction complicating placental dysfunction. Possible markers for endothelial dysfunction and amount of trophoblast are fibronectin and plasminogen activator inhibitor-2 (PAI-2), respectively. We aimed (1) to determine whether in women with recurrent PS (rPS), this complication is preceded by deviating fibronectin- and PAI-2-levels, and (2) whether this is dependent on pre-pregnant plasma volume (PV). METHODS: In 36 former patients, we determined fibronectin- and PAI-2-levels in blood-samples collected preconceptionally and at 12-16 weeks in their next pregnancy. Differences were analyzed between pregnancies with rPS (n = 12) and without rPS (non-rPS, n = 24) using linear mixed models, with subanalyses based on pre-pregnant normal or subnormal PV. RESULTS: We observed higher fibronectin-levels at 12-16 weeks (p < 0.05 and p < 0.01, respectively) and lower PAI-2-levels at 16 weeks (p < 0.01) in the rPS subgroup, the intergroup differences being larger in women with subnormal PV. CONCLUSION: We showed that former PS patients who developed rPS have raised fibronectin- and reduced PAI-2-levels already in early/mid pregnancy. These deviations are even more prominent in women with subnormal pre-pregnant PV, supporting development of a 2-step screening program for former patients to identify the high-risk subgroup of women who may benefit from closer surveillance.

Using Doppler ultrasound of the uterine and umbilical arteries and disordered angiogenesis markers (sFlt-1/PlGF) in unified monitoring of ischemic placental syndrome patients.

OBJECTIVE: The shared pathogenesis of placental ischemia entitles us to create a single treatment model. We attempted to develop a unified method for monitoring ischemic placental syndrome patients using Doppler ultrasound of the uterine and umbilical arteries and disordered angiogenesis markers sFlt-1 and PlGF. MATERIAL AND METHODS: 182 pregnant women suffering from the ischemic placental syndrome were divided into four groups depending on the severity of their lesions revealed in the Doppler ultrasound examination and weeks of pregnancy. We analyzed the behavior of clinical and biochemical parameters in these groups and the correlations between the ultrasound examination and the disordered angiogenesis markers. RESULTS: In the group of patients demonstrating more severe Doppler ultrasound lesions, the clinical and biochemical parameters were significantly more expressed, whereas unfavorable obstetric events occurred either earlier or more frequently. Lesions revealed in Doppler occur more commonly in groups before 34th week of pregnancy. Disordered angiogenesis markers are significantly correlated with ultrasound examination results. CONCLUSIONS: A unified method for monitoring the ischemic placental syndrome based on pathogenetic, biophysical (Doppler ultrasound), and biochemical (sFlt-1/PlGF) parameters is feasible and constitutes a valuable supplement to the existing standards, while the high correlations between Doppler ultrasound examinations and both sFlt-1 and PlGF point to a shared pathogenesis of the lesions. Intensity of Doppler changes is connected with time of testing and pregnancy duration.

Maternal-placental syndrome and future risk of accelerated cardiovascular events in Parous Swedish women with systemic lupus erythematosus - a population-based retrospective cohort study with time-to-event analysis.

OBJECTIVES: Women with SLE are at increased risk of cardiovascular events (CVEs), but a relationship with traditional cardiovascular and SLE-specific risk factors has not been established. In unselected populations, adverse pregnancy outcomes linked to maternal-placental syndrome (MPS) are associated with an increased risk of CVEs. However, the effect of MPS on CVEs is unknown in women with SLE. The aim of this study was to determine if MPS increased the risk and accelerated the development of CVEs in women with SLE. METHODS: Utilizing Swedish population registries, parous women with SLE were identified. Exposures were the following: MPS defined as hypertensive disorders of pregnancy; small-for-gestational-age; placental abruption and stillbirth; and preterm delivery <34 weeks. Outcomes were CVE encompassing cardiovascular morbidity and mortality. Risk of an event was modelled using Cox proportional hazards adjusted for year of delivery, age at CVE, severity of SLE and cardiovascular risk factors. Time-to-CVE was estimated using Kaplan-Meier methods. RESULTS: Over the 38-year study period, there were 3977 women with 7410 pregnancies, of whom 413 (10.2%) suffered a CVE. Hazard of CVE was higher in those with MPS, particularly when MPS (adjusted HR = 1.64; 95% CI: 1.31, 2.05) was combined with preterm delivery < 34 weeks' gestation (adjusted HR 1.99; 95% CI 1.39, 2.84). There was accelerated development of CVEs in women with MPS of 10.5% (vs 7.3% in uncomplicated pregnancies) over the 38-year interval (P < 0.05). CONCLUSION: Pregnancy complicated by MPS and preterm delivery exerts an independent effect to increase the risk and accelerate the development of CVEs in parous women with SLE.

Metabolic syndrome after pregnancies complicated by pre-eclampsia or small-for-gestational-age: a retrospective cohort.

OBJECTIVE: To study the prevalence of metabolic syndrome in women after a pregnancy complicated by pre-eclampsia or small-for-gestational-age (SGA), both epitomes of placental syndrome. DESIGN: A retrospective cohort study. SETTING: Single tertiary centre for maternal medicine in the Netherlands. POPULATION: Women with a history of pre-eclampsia in absence of SGA (n = 742) or pregnancy complicated by normotensive SGA (n = 147) between 1996 and 2010. METHODS: Women were routinely screened for underlying cardiometabolic and cardiovascular risk factors at least 6 months postpartum. Logistic regression analysis was used to calculate the odds ratio and adjusted odds ratio for each group. Adjustments were made for age, maternal height, smoking, parity, and interval between delivery and measurement. MAIN OUTCOME MEASURES: Prevalence of the metabolic syndrome. RESULTS: The prevalence of the metabolic syndrome in our population was two-fold higher for women with a history of pre-eclampsia (13.9%) compared with women with a history of SGA (7.6%). Calculated odds ratios for metabolic syndrome, fasting insulin, HOMA, and microalbuminuria were all higher for women with a history of pre-eclampsia compared with women with SGA. This difference persisted after adjustment for confounding factors: metabolic syndrome (adjusted odds ratio, aOR 2.11; 95% confidence interval, 95% CI 1.00-4.47) and hyperinsulinaemia (aOR 1.78; 95% CI 1.13-2.81) insulin resistance (HOMAIR ; aOR 1.80; 95% CI 1.14-2.86). Microalbuminuria (aOR 1.58; 95% CI 0.85-2.93) did not reach the level of significance after adjustment for confounding factors. CONCLUSIONS: A history of pre-eclampsia, rather than SGA, was associated with metabolic syndrome, suggesting that it relates to maternal rather than fetal etiology of placental syndrome.