Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers.

BACKGROUND: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes. OBJECTIVES: Characterize temporal trends and predictors of OPE exposure biomarkers. METHODS: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits. RESULTS: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations. SIGNIFICANCE: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment.

Temporal trends and predictors of phthalate, phthalate replacement, and phenol biomarkers in the LIFECODES Fetal Growth Study.

BACKGROUND: Exposure to many phthalates and phenols is declining as replacements are introduced. There is little information on temporal trends or predictors of exposure to these newer compounds, such as phthalate replacements, especially among pregnant populations. OBJECTIVE: Examine temporal trends and predictors of exposure to phthalates, phthalate replacements, and phenols using single- and multi-pollutant approaches. METHODS: We analyzed data from 900 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured and averaged concentrations of 12 phthalate metabolites, four phthalate replacement metabolites, and 12 phenols in urine at three timepoints during pregnancy. We visualized and analyzed temporal trends and predictors of biomarker concentrations. To examine chemical mixtures, we derived clusters of individuals with shared exposure profiles using a finite mixture model and examined temporal trends and predictors of cluster assignment. RESULTS: Exposure to phthalates and most phenols declined across the study period, while exposure to phthalate replacements (i.e., di(isononyl) cyclohexane-1,2-dicarboxylic acid, diisononyl ester [DINCH] and di-2-ethylhexyl terephthalate [DEHTP]) and bisphenol S (BPS) increased. For example, the sum of DEHTP biomarkers increased multiple orders of magnitude, with an average concentration of 0.92 ng/mL from 2007 to 2008 and 61.9 ng/mL in 2017-2018. Biomarkers of most chemical exposures varied across sociodemographic characteristics, with the highest concentrations observed in non-Hispanic Black or Hispanic participants relative to non-Hispanic White participants. We identified five clusters with shared exposure profiles and observed temporal trends in cluster membership. For example, at the end of the study period, a cluster characterized by high exposure to phthalate replacements was the most prevalent. SIGNIFICANCE: In a large and well-characterized pregnancy cohort, we observed exposure to phthalate replacements and BPS increased over time while exposure to phthalates and other phenols decreased. Our results highlight the changing nature of exposure to consumer product chemical mixtures.

Scaling of Jumping Performance in Click Beetles (Coleoptera: Elateridae).

Click beetles (Coleoptera: Elateridae) are known for their unique clicking mechanism that generates a powerful legless jump. From an inverted position, click beetles jump by rapidly accelerating their center of mass (COM) upwards. Prior studies on the click beetle jump have focused on relatively small species (body length ranging from 7 to 24 mm) and have assumed that the COM follows a ballistics trajectory during the airborne phase. In this study, we record the jump and the morphology of 38 specimens from diverse click beetle genera (body length varying from 7 to 37 mm) to investigate how body length and jumping performance scale across the mass range. The experimental results are used to test the ballistics motion assumption. We derive the first morphometric scaling laws for click beetles and provide evidence that the click beetle body scales isometrically with increasing body mass. Linear and nonlinear statistical models are developed to study the jumping kinematics. Modeling results show that mass is not a predictor of jump height, take-off angle, velocity at take-off, and maximum acceleration. The ballistics motion assumption is strongly supported. This work provides a modeling framework to reconstruct complete morphological data sets and predict the jumping performance of click beetles from various shapes and sizes.

Provider practices for the prevention of eclampsia and attitudes toward magnesium sulfate: results of a nationwide survey.

OBJECTIVE: To survey OB-GYNs regarding their practice patterns and perspectives when it comes to using magnesium sulfate (magnesium) in the prevention of eclampsia. STUDY DESIGN: We conducted a cross-sectional web-based 18-item survey given to 564 practicing OB-GYNs in the Pregnancy-Related Care Research Network. The survey used clinical scenarios to look at provider practices for preventing eclampsia in patients who have preeclampsia and relative contraindications to magnesium. Next, we assessed provider attitudes toward magnesium and inquired about their experiences with complications related to its use. The survey also contained an embedded educational component that addressed the signs and symptoms of magnesium toxicity followed by a 2-item quiz for those providers who self-identified as having never treated magnesium toxicity. RESULTS: Nearly 30% of OB-GYNs contacted completed the survey. For patients with preeclampsia and a contraindication to magnesium such as myasthenia gravis, 44.4% of respondents would administer an alternative antiepileptic and 42.5% of them would administer no antiepileptic at all. For patients with pulmonary edema complicating preeclampsia, 32.5% would give magnesium at the usual dose, 33.1% would give magnesium at less than the usual dose, 12.3% would give an alternative antiepileptic and 22.1% would give no antiepileptic at all. For patients with laboratory evidence of renal compromise complicating preeclampsia, most respondents (89.6%) said they would give magnesium at less than the usual dose. Regarding complications of magnesium that clinicians have encountered, over one-third of respondents have administered calcium gluconate for magnesium toxicity in patients with preeclampsia. For those providers who have not treated magnesium toxicity and were prompted to receive the educational component and quiz, all knew the correct initial bolus dosing of magnesium and the majority were able to identify symptoms of toxicity. The majority (81.8%) of respondents said that continuous magnesium infusions cause an increased demand for dedicated personnel to care for the patients on them. Almost 57% of respondents endorsed the need for an alternative antiepileptic to magnesium in the prevention of eclampsia. Most write-in responses supporting this need cited a concern with magnesium's safety and side effects. CONCLUSION: There is wide variation among OB-GYNs regarding the prevention of eclampsia and complications of magnesium are not uncommon. The survey revealed that OB-GYNs are using alternative antiepileptics in scenarios where there is concern for magnesium's safety profile. In addition, over half of those surveyed believe there is a need for validated antiepileptics other than magnesium for the prevention of eclampsia in patients with preeclampsia. These findings suggest that OB-GYNs would support further research into alternative antiepileptics in the prevention of eclampsia.

Prenatal exposure to consumer product chemical mixtures and size for gestational age at delivery.

BACKGROUND: While fetal growth is a tightly regulated process, it is sensitive to environmental exposures that occur during pregnancy. Many commonly used consumer products contain chemicals that can disturb processes underlying fetal growth. However, mixtures of these chemicals have been minimally examined. We investigated associations between prenatal exposure to 33 consumer product chemicals (nine organophosphate ester flame retardant [OPE] metabolites, 12 phthalate metabolites, and 12 phenols) and the odds of small- or large-for-gestational age (SGA and LGA) births. METHODS: This case-control study was comprised of SGA (N = 31), LGA (N = 28), and appropriate for gestational age control (N = 31) births selected from the larger LIFECODES cohort. Biomarkers of exposure to consumer product chemicals were quantified in maternal urine collected from up to three study visits during pregnancy. In a single-pollutant approach, odds ratios (OR) and 95% confidence intervals (CI) of SGA and LGA associated with an interquartile range (IQR)-increase in exposure biomarkers were estimated using multinomial logistic regression. In a multi-pollutant approach, quantile g-computation was used to jointly estimate the OR (95% CI) of SGA and LGA per simultaneous one quartile-change in all biomarkers belonging to each chemical class. RESULTS: Among the 33 biomarkers analyzed, 20 were detected in at least 50% of the participants. After adjusting for potential confounders, we observed reduced odds of LGA in association with higher urinary concentrations of several exposure biomarkers. For example, an IQR-increase in the OPE metabolite, diphenyl phosphate, was associated with lower odds of LGA (OR: 0.40 [95% CI: 0.18, 0.87]). Using quantile g-computation, we estimated lower odds of an LGA birth for higher OPE metabolite concentrations (OR: 0.49 [95% CI: 0.27, 0.89]) and phthalate metabolite concentrations (OR: 0.23 [95% CI: 0.07, 0.73]). Associations between consumer product chemicals and SGA were largely null. CONCLUSIONS: Joint exposure to OPEs and phthalates was associated with lower odds of delivering LGA. Associations with LGA could indicate a specific impact of these exposures on the high end of the birth weight spectrum. Future work to understand this nuance in the associations between consumer product chemical mixtures and fetal growth is warranted.

Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study.

OBJECTIVE: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy. DESIGN: Case-control study. SETTING AND POPULATION: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array. METHODS: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES: Genetic predisposition to medical conditions and relationship with pre-eclampsia. RESULTS: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association. CONCLUSIONS: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACT: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

Vitamin D and bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.

Analysis of changes in maternal circulating angiogenic factors throughout pregnancy for the prediction of preeclampsia.

OBJECTIVE: To assess whether changes in maternal angiogenic factors throughout pregnancy predict the development of preeclampsia. STUDY DESIGN: Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 receptor (sFlt-1) were measured in 2355 women at 10, 18, 26 and 35 weeks gestation. Receiver operator characteristic analysis was used to calculate test characteristics for changes in analytes between time points. Linear mixed-effects models generated slopes of analytes throughout pregnancy, which in turn were used as predictors in adjusted logistic regression models. RESULT: Changes in analytes yielded positive predictive values of 9 to 19% and negative predictive values of 93 to 97%. Individuals with lowest quartile slopes in PlGF had sixfold greater odds (95% confidence interval (CI): 3.5, 10.2) of preeclampsia compared with individuals in the highest quartile. With respect to sFlt-1, the highest quartile had 5.1 times greater odds (95% CI: 3.1, 8.4) than the lowest quartile. CONCLUSION: Measuring the trend in PlGF and sFlt-1 across pregnancy segregates women at increased risk of preeclampsia. However, changes in these factors throughout pregnancy lack clinically useful predictive power.

Low incidence of port-site metastasis after robotic assisted surgery for endometrial cancer staging: descriptive analysis.

The purpose of this study was to evaluate the incidence and characteristics of patients with port-site metastasis following robotic assisted surgery for gynecological malignancies. Patients who underwent robotic assisted total laparoscopic hysterectomy and surgical staging at a single institution from November 2006 through November 2011 were retrospectively identified. Medical records were reviewed and the following information was extracted: diagnosis, histology, tumor extension, procedure, complications and post-surgical intervention. Port-site metastases were differentiated between isolated and not isolated. All metastases were confirmed with biopsy and treated with chemotherapy and radiotherapy as indicated. Four hundred forty-six patients with endometrial carcinoma were identified who had undergone robotic assisted hysterectomy and staging. Eight patients were converted to laparotomy and excluded from the study. Of 438 patients, 384 patients were diagnosed with early stages (stages 1 and 2), and 54 were diagnosed with advanced stages (stages 3 and 4). A total of 332 patients underwent pelvic lymphadenectomy regardless of the endometrial cancer stage; of those, 283 with early stage disease underwent pelvic lymphadenectomy, while 49 with advanced stage disease underwent pelvic lymphadenectomy. One hundred seventy-six patients received adjuvant treatment after surgical staging. Four patients were identified with port-site metastases (0.9 %), two patients were reported as isolated metastases. The mean patient age was 63 and mean BMI was 37 kg/m(2). The incidence of port-site metastasis is low after robotic assisted surgery for treatment of endometrial cancer (0.9 %). There is no clear risk factor for development of port-site metastasis or easily identifiable prevention.

Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy.

INTRODUCTION: Phthalates and bisphenol-a (BPA) are endocrine disrupting compounds with widespread exposure that have been linked to adverse birth outcomes and developmental effects. We hypothesized that these associations may be mediated in part through altered placental development and function consequent to exposure. To investigate this question, we examined associations between plasma biomarkers of angiogenesis and urinary biomarkers of exposure to phthalates and bisphenol-a (BPA) measured at repeated time points across pregnancy. METHODS: We utilized a nested case-control population of 130 mothers who delivered preterm and 352 who delivered term from a prospective birth cohort. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in plasma samples collected from up to four visits during pregnancy (median 10, 18, 26, and 35 weeks). Phthalate metabolites and BPA were measured in urine samples collected at the same visits as indices of exposure. RESULTS: In linear mixed effects models adjusted for urine dilution and gestational age at sample collection, oxidized di-2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio. These results were slightly attenuated in fully adjusted models. Other phthalate metabolites did not show consistent relationships with either sFlt-1 or PlGF. BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models. DISCUSSION: We observed associations between urinary DEHP metabolites and BPA and biomarkers of angiogenesis during pregnancy that may be indicative of disrupted placental development and/or function during gestation.

Prenatal vitamin use and vitamin D status during pregnancy, differences by race and overweight status.

OBJECTIVE: We aimed to study whether prenatal vitamin (PNV) use protects against low 25-hydroxyvitamin D (25[OH]D) levels in all women and particularly in obese and black women who are both at risk of vitamin D deficiency and poor pregnancy outcomes. STUDY DESIGN: We studied 1019 women enrolled in a prospective study at Brigham and Women's Hospital in Boston, from 2007 to 2009. We used multivariable logistic regression to analyze associations of PNV use and odds of vitamin D deficiency defined as 25[OH]D levels <50 nmol l(-1). RESULT: In all, 56% of black and 86% of white women reported pre- and/or postconceptional PNV use. In the first trimester, 75% of black and 19% of white women were vitamin D deficient. Lack of PNV use among black women was not associated with vitamin D deficiency (adjusted odds ratio (OR) 1.0, 95% confidence interval (CI) 0.4, 2.3) but was among white women (OR 3.5, 95% CI 2.1, 5.8) (interaction P<0.01). CONCLUSIONS: Ongoing trials of vitamin D supplementation during pregnancy should consider potential effect modification by race/ethnicity.

Perinatal systemic inflammatory responses of growth-restricted preterm newborns.

AIM: To compare the early post-natal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers. METHODS: We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. RESULTS: Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1ß, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. CONCLUSION: Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14.

Preterm severe preeclampsia in singleton and twin pregnancies.

OBJECTIVE: We aimed to evaluate rates of delivery and clinical manifestations of preterm severe preeclampsia in singleton and twin gestations. STUDY DESIGN: This retrospective cohort study included 86 765 deliveries from 2000 to 2009, including 3244 twins. Rates of delivery for severe preeclampsia among infants born 24 to 31+6, and 32 to 36+6 weeks gestation were calculated, and diagnostic criteria were compared. RESULT: Re-term severe preeclampsia was more common in twin pregnancies (2.4% vs 0.4%, P<0.001, relative risk 5.70 (95% confidence interval 4.47 to 7.26)). This was also true for deliveries from 24 to 31+6 (0.8% vs 0.2%, P<0.001) and 32 to 36+6 weeks (1.7% vs 0.3%, P<0.001). Diagnostic criteria and disease manifestation including hemolysis elevated liver enzymes low platelet count syndrome, abruption and growth restriction were similar between groups. CONCLUSION: Twin pregnancies are significantly more likely than singletons to be delivered preterm for severe preeclampsia. Diagnostic criteria and disease manifestation were similar in singletons and twins, at all gestational ages.

Maternal circulating PlGF concentrations and placenta-related pregnancy complications: First results from the CoLab AngF Study.

INTRODUCTION: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis. OBJECTIVE: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia. METHODS: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared. RESULTS: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility. CONCLUSIONS: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders.