Increasing urinary podocyte mRNA excretion and progressive podocyte loss in kidney contribute to the high risk of long-term renal disease caused by preterm birth.

Podocyte abnormalities are common mechanism driving the progression of glomerular diseases, which account for most chronic kidney diseases (CKDs). However, the role of podocyte in the mechanism of high-risk long-term CKD caused by prematurity has not been well clarified. In present study, urine samples of 86 preterm infants and 32 full-term infants were collected, and podocyte-specific podocin mRNA levels in urine pellet were applied to indicate urinary podocyte mRNA excretion. In addition, in a preterm animal rat model, preterm rats were identified by delivery 2 days early. From the age of 3 weeks-12 months, urine samples were collected to examine podocyte mRNA excretion by measuring podocyte-specific podocin mRNA levels. Kidney samples at the age of 3 weeks, 2 months, and 12 months were collected from 8, 5 and 6 preterm rats and 9, 6 and 8 full-term rats, respectively, to examine podocyte density and podocyte area by measuring the podocyte specific nuclear marker WT-1 and the podocyte specific marker synaptopodin. As results, a more than threefold increase of urinary podocyte-specific podocin mRNA excretion rate was found in preterm infants compared with full-term infants. In addition, there was negative correlation between gestational age at birth and urinary podocin mRNA excretion. In preterm rats, a reduction in the total number of differentiated podocytes in glomeruli and an increased podocyte podocin mRNA excretion rate in urine were detected at the end of kidney differentiation. Moreover, long-term follow-up data in preterm rats showed there was an increased the risk of renal disease indicated by persistent podocyte mRNA loss, proteinuria, and enlarged glomeruli. In conclusion, increasing podocyte mRNA excretion in urine and podocyte loss in kidney led by prematurity drive the progression of long-term abnormal kidney function and could potentially explain the high risk of long-term CKD in preterm infants.

Lower urinary α-Klotho is associated with lower angiotensin-(1-7) and higher blood pressure in young adults born preterm with very low birthweight.

Early-life factors including preterm birth and VLBW increase the risk of hypertension, but the mechanisms remain poorly understood. Reductions in the anti-aging protein α-klotho are associated with hypertension, possibly due to angiotensin (Ang) II activation, but the mechanisms are incompletely understood and clinical evidence is lacking. The association of α-klotho with the alternative Ang-(1-7) pathway, which counteracts Ang II to lower BP, is undescribed. We hypothesized that lower urinary α-klotho is associated with higher BP and lower urinary Ang-(1-7) in preterm-born VLBW young adults. In a cross-sectional analysis of data from a prospective cohort of 141 preterm-born VLBW young adults, we assessed the associations among urinary α-klotho/creatinine, Ang II/creatinine, Ang-(1-7)/creatinine, Ang II/Ang-(1-7), and BP using generalized linear models adjusted for age and hypertensive pregnancy and conducted a sensitivity analysis in 32 term-born young adults. Among those born preterm, lower α-klotho/creatinine was associated with higher systolic BP (adjusted ß (aß): -2.58 mm Hg, 95% CI -4.99 to -0.17), lower Ang-(1-7)/creatinine (ln aß: 0.1, 0.04-0.16), and higher Ang II/Ang-(1-7) (ln aß: -0.14, -0.21 to -0.07). In term-born participants, α-klotho/creatinine was inversely associated with Ang II/creatinine (ln aß: -0.15, -0.27 to -0.03) and Ang II/Ang-(1-7) (ln aß: -0.15, -0.27 to -0.03). In preterm-born young adults with VLBW, lower urinary α-klotho/creatinine was associated with higher SBP, lower urinary Ang-(1-7)/creatinine, and higher urinary Ang II/Ang-(1-7). Reduced renal α-klotho expression could lead to renal Ang-(1-7) suppression as a novel mechanism for the development of hypertension among individuals born preterm with VLBW.

Membranous Nephropathy in Pregnancy.

BACKGROUND: Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated. METHODS: We retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded. RESULTS: Of the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates. CONCLUSIONS: Pregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.

Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

BACKGROUND: Preterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor. METHODS: In a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n = 1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28 weeks of gestation) individually and averaged over pregnancy with gestational age at delivery and preterm birth. We additionally assessed differences in associations by study visit and among preterm births with a spontaneous delivery. RESULTS: Compared to women in the general USA population, urinary concentrations of metabolites of di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) were higher among pregnant women in Puerto Rico. Interquartile range (IQR) increases in pregnancy-averages of urinary metabolites of DBP and DiBP were associated with shorter duration of gestation and increased odds of preterm birth. An IQR increase in mono-n-butyl phthalate (MBP), a metabolite of DBP, was associated with 1.55 days shorter gestation (95% confidence interval [CI] = -2.68, -0.42) and an odds ratio (OR) of 1.42 (95% confidence interval [CI]: 1.07, 1.88) for preterm birth. An IQR increase in mono-isobutyl phthalate (MiBP), a metabolite of DiBP, was associated with 1.16 days shorter gestation (95% CI = -2.25, -0.08) and an OR of 1.32 (95% CI: 1.02, 1.71) for preterm birth. Associations were greatest in magnitude for urinary concentrations measured at the second study visit (median 23 weeks gestation). DiBP metabolite associations were greatest in magnitude in models of spontaneous preterm birth. No associations were detected with other phthalate metabolites, including those of di-2-ethylhexyl phthalate. CONCLUSION: Among pregnant women in the PROTECT cohort, DBP and DiBP metabolites were associated with increased odds of preterm birth. These exposures may be contributing to elevated rates of preterm birth observed in Puerto Rico.

Is the Concentration of Cadmium, Lead, Mercury, and Selenium Related to Preterm Birth?

Environmental pollution and exposure of people to heavy metals cause many bad obstetric outcomes. Our aim is to demonstrate the role of cadmium (Cd), lead (Pb), mercury (Hg), and selenium (Se) in preterm labor etiology with a case-control study. In this study, between November 2017 and April 2018, preterm delivery mothers and term delivery mothers were compared in Çorum, Turkey. All deliveries were performed with cesarean sections and there were 30 mothers in the control group and 20 in the study group. The maternal blood, maternal urine, umbilical cord blood, and heavy metal levels in the amnion fluid in both groups were studied. Graphite furnace atomic absorption spectrometry was used to determine the blood concentration of Cd, Pb, Hg, and Se. We found lower levels of selenium in blood and urine of preterm delivery mothers and umbilical cord and amnion fluids of preterm infants (p < 0.01). We found a statistically significant positive correlation at selenium levels between mother's blood and umbilical cord blood (r (50) = 0.896, p < 0.001) and between maternal urine and amniotic fluid (r (50) = 0.841, p < 0.001). We have not found a similar correlation between mother and fetus of other metals (p > 0.05). We found that selenium levels were lower in mothers who were preterm birth in the light of the data in our study. We could not determine the positive or negative correlation of Cd, Pb, and Hg levels in blood, urine, and amniotic fluid samples with preterm birth.

Group B streptococci cultured in urine during pregnancy associated with preterm delivery: a selection problem?

Objective: To investigate an association between Group B streptococci (GBS) in urine culture during pregnancy and preterm delivery. Methods: A population-based cohort consisted of all the pregnant women (n = 36,097) from the catchment area of Lillebaelt Hospital, Denmark, during the period January 2002 -December 2012. The cohort of 34,285 singleton pregnancies used in this study was divided into three groups. Group I (N = 249) included women whose urine culture was positive for GBS; group II (N = 5765) included women whose urine culture was negative for GBS; and group III (N = 28 271) included women whose urine had not been cultured during pregnancy. Primary outcome was preterm delivery before 37 weeks' gestation (PTD). Results: We did not find an association between PTD and GBS bacteriuria in the cultured groups (odds ratios (OR) = 0.89; 95% CI: 0.5-1.4) ( Table 1 ). After controlling for potential confounders, the PTD remained not associated with GBS bacteriuria (adjusted OR = 0.99; 95% CI: 0.6-1.6). Combined, the cultured groups (I and II) were associated with a statistically significant higher risk for PTD, when compared with the group with no urine specimens taken for culture (OR = 1.96; 95% CI: 1.8-2.2 and adjusted or 1.80; 95% CI 1.6-2.0). The cultured group of women differed considerably from the group of women with no urine specimens taken for culture on the vast majority of variables examined. Conclusions: No association between asymptomatic GBS bacteriuria and preterm delivery among women with singleton pregnancy and urine specimens cultured during pregnancy was found. Previous suggestions of such association may have been compromised by a selection problem for testing due to a high-risk profile of pregnancy complications in pregnant women selected for urine culture.

Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery.

BACKGROUND: Oxidative stress has been implicated in numerous birth outcomes, including spontaneous preterm birth. However, the relationship with presentation at delivery has been less well studied. We assessed the relationship between oxidative stress biomarkers and gestational duration with a focus on spontaneous presentation for delivery. METHODS: Our sample included 740 women from a multi-center prospective cohort study, recruited from 2010 to 2012. Resultant measures of oxidative stress in pregnancy prostaglandin F2α (PGF2α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and the primary 8-iso-PGF2α metabolite were measured in third trimester urine samples. Information on presentation for delivery was abstracted from medical records. We examined associations with preterm birth using adjusted logistic models. Time to event (overall delivery and spontaneous delivery) was examined using adjusted accelerated failure time models. RESULTS: The 8-iso-PGF2α metabolite was associated with increased odds of overall preterm birth (OR: 1.44 [95% CI: 1.00, 2.06]), and the association with spontaneous preterm birth was similar in magnitude but not statistically significant (OR: 1.45 [95% CI: 0.96, 2.20]). We did not detect associations between other biomarkers and preterm birth, or between biomarkers and timing of overall or spontaneous delivery in accelerated failure time models. CONCLUSIONS: Our data suggest that increased oxidative stress, as indicated by the 8-iso-PGF2α metabolite, may be associated with preterm birth. In contrast to previous studies, associations were similar among individuals with spontaneous versus non-spontaneous presentation for delivery.

Urinary trace metals individually and in mixtures in association with preterm birth.

One in ten infants born in the United States is born preterm, or prior to 37 weeks gestation. Exposure to elevated levels of metals, such as lead and arsenic, has been linked to higher risk of preterm birth (PTB), but consequences of lower levels of exposure and less studied metals are unclear. We examined the associations between 17 urinary trace metals individually and in mixtures in relation to PTB. The LIFECODES birth cohort enrolled pregnant women at <15 weeks gestation at Brigham and Women's Hospital in Boston. We selected cases of PTB (n = 99) and unmatched controls (n = 291) and analyzed urine samples for a panel of trace metals (median: 26 weeks gestation). We used logistic regression models to calculate the odds ratio (OR) for PTB and subtypes of PTB based on presentation at delivery. Subtypes included spontaneous and placental PTB. We used elastic net (ENET) regularization to identify individual metals or pairwise interactions that had the strongest associations with PTB, and principal components analysis (PCA) to identify classes of exposures associated with the outcome. We observed increased odds of PTB (OR: 1.41, 95% Confidence Interval [CI]: 1.12, 1.78) in association with an interquartile range difference in urinary copper (Cu). We also observed an increased OR for selenium (OR: 1.33, 95% CI: 0.98, 1.81). ENET selected Cu as the most important trace metal associated with PTB. PCA identified 3 principal components (PCs) that roughly reflected exposure to toxic metals, essential metals, and metals with seafood as a common source of exposure. PCs reflecting essential metals were associated with increased odds of overall and spontaneous PTB. Maternal urinary copper in the third trimester was associated with increased risk of PTB, and statistical analyses for mixtures indicated that after accounting for correlation this metal was the most important statistical predictor of the outcome.

THE FEATURES OF THE WOMEN'S SIMPATHOADRENAL SYSTEM FUNCTIONAL STATE WITH RISK OF EARLY PREGNANCY TERMINATION.

Preterm labor is an urgent medical-social and demographic issue at the present stage. A considerable number of factors affects the course of pregnancy and its outcome, their effect is realized at the level of the central nervous system through numerical metabolic interactions, where monoaminergic systems play an important role. Objective - to study the features of the sympathoadrenal system state by determining the excretion level of DOPHA, dopamine, norepinephrine and epinephrine in women's daily urine with different periods of abortion. 227 pregnant women who were admitted to the Kharkiv perinatal center have been examined, 190 of them had clinical signs of premature delivery in the gestation period of 23-36 weeks. Formation of clinical groups was carried out depending on the pregnancy term in the form of premature and timely delivery. Diagnosis of preterm labor was carried out in the presence of abdominal pain syndrome and structural changes in the cervix. Consequently, pregnancy compensatory and adaptive mechanisms are complex of neurohumoral process, which are realized through monoaminergic systems and a significant factor in its interruption is their destabilization. Reducing of sympathoadrenal system activity and reserve capacity in pregnant women may be a pathogenetic factor in the development of preterm labor. Therefore determination of the imbalance initial manifestations in the catecholamines exchange may possibly prevent the loss of pregnancy in the early stages.

Diagnostic value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for late-onset neonatal sepsis in infected preterm neonates.

Objective Sepsis is a complex clinical condition caused by a dysregulated immune response to an infection resulting in a fatal outcome. This study aimed to investigate the value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for diagnosing culture-proven sepsis in preterm infants. Methods Preterm neonates were evaluated for late-onset sepsis (LOS). Laboratory investigations were performed. Urine sTREM-1 samples and blood cultures were synchronously collected. Using blood culture results, preterm neonates were divided into the culture-proven group and suspected sepsis group. Results A total of preterm 62 infants were included in the study; 31 had culture-proven sepsis and 31 were suspected as having sepsis. There were no significant differences in gestational age, sex, birth weight, and delivery mode between the groups. Neonates in the culture-proven group had significantly higher urine sTREM-1 levels than did those in the suspected sepsis group. Using a cut-off point for a urine sTREM-1 level of 78.5 pg/mL, the sensitivity was 0.90, specificity was 0.78, positive predictive value was 0.68, and negative predictive value was 0.94. Conclusions The present study highlights the role of urine sTREM-1 levels in LOS. Urine sTREM-1 may be a reliable and sensitive marker in detecting sepsis in preterm infants.

Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: A repeated measures study.

BACKGROUND: Maternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy. OBJECTIVES: We aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation. METHODS: Our study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility. RESULTS: In our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: -14.2, -1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4. CONCLUSIONS: Our results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes.

Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy.

BACKGROUND: Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease. OBJECTIVE: We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress. METHODS: This nested case-control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure-mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure-mediator interaction. RESULTS: We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure-mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively. CONCLUSIONS: This demonstrates mediation of the phthalate-preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure-mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494; http://dx.doi.org/10.1289/EHP282.

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study.

This work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.

Maternal iodine insufficiency and adverse pregnancy outcomes.

This study aimed to assess the iodine status of pregnant women in each trimester and to compare the pregnancy outcomes between groups with iodine insufficiency and iodine sufficiency. Longitudinal study on urinary iodine concentration (UIC) in each trimester as well as comparison between women with iodine insufficiency (<150 mcg L(-1) ) and iodine sufficiency was conducted. Pregnant women without thyroid diseases who had not received iodine supplementation were recruited for UIC measurements in each trimester and were followed up for pregnancy outcomes. In the analysis of 384, 325 and 221 samples in the first, second and third trimester, the medians of UICs were 147.39, 157.01 and 153.07 mcg L(-1) , respectively. Of 399 women, 174 (43.6%) had a UIC less than 150 mcg L(-1) (suggesting iodine insufficiency) and 225 (56.4%) had a UIC greater than or equal to 150 mcg L(-1) (suggesting iodine sufficiency). Of 390 women with availability of the final outcomes, 171 and 219 in the insufficiency and sufficiency group, respectively, the rates of preterm birth and low birthweight were significantly higher in the insufficiency group, 17.5% vs. 10.0% (P = 0.031) and 19.9% vs. 12.3% (P = 0.042), respectively. Logistic regression analysis showed that iodine status was an independent risk of preterm birth and low birthweight. Finally, women with a UIC <100 mcg L(-1) had a significantly higher rate of fetal growth restriction, 13/68 vs. 30/322 (P = 0.031). In northern Thailand, a great number of pregnant women had a median UIC less than 150 mcg L(-1) and they had a higher risk of preterm birth and low birthweight. Finally, those with a median UIC of less than 100 mcg L(-1) had a higher risk of fetal growth restriction.

Mass spectrometry-based proteomics for pre-eclampsia and preterm birth.

Pregnancy-related complications such as pre-eclampsia and preterm birth now represent a notable burden of adverse health. Pre-eclampsia is a hypertensive disorder unique to pregnancy. It is an important cause of maternal death worldwide and a leading cause of fetal growth restriction and iatrogenic prematurity. Fifteen million infants are born preterm each year globally, but more than one million of those do not survive their first month of life. Currently there are no predictive tests available for diagnosis of these pregnancy-related complications and the biological mechanisms of the diseases have not been fully elucidated. Mass spectrometry-based proteomics have all the necessary attributes to provide the needed breakthrough in understanding the pathophysiology of complex human diseases thorough the discovery of biomarkers. The mass spectrometry methodologies employed in the studies for pregnancy-related complications are evaluated in this article. Top-down proteomic and peptidomic profiling by laser mass spectrometry, liquid chromatography or capillary electrophoresis coupled to mass spectrometry, and bottom-up quantitative proteomics and targeted proteomics by liquid chromatography mass spectrometry have been applied to elucidate protein biomarkers and biological mechanism of pregnancy-related complications. The proteomes of serum, urine, amniotic fluid, cervical-vaginal fluid, placental tissue, and cytotrophoblastic cells have all been investigated. Numerous biomarkers or biomarker candidates that could distinguish complicated pregnancies from healthy controls have been proposed. Nevertheless, questions as to the clinically utility and the capacity to elucidate the pathogenesis of the pre-eclampsia and preterm birth remain to be answered.

Urinary Bisphenol A Levels during Pregnancy and Risk of Preterm Birth.

BACKGROUND: Preterm birth (PTB), a leading cause of infant mortality and morbidity, has a complex etiology with a multitude of interacting causes and risk factors. The role of environmental contaminants, particularly bisphenol A (BPA), is understudied with regard to PTB. OBJECTIVES: In the present study we examined the relationship between longitudinally measured BPA exposure during gestation and PTB. METHODS: A nested case-control study was performed from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston, Massachusetts, during 2006-2008. Urine samples were analyzed for BPA concentrations at a minimum of three time points during pregnancy on 130 cases of PTB and 352 randomly assigned controls. Clinical classifications of PTB were defined as "spontaneous," which was preceded by spontaneous preterm labor or preterm premature rupture of membranes, or "placental," which was preceded by preeclampsia or intrauterine growth restriction. RESULTS: Geometric mean concentrations of BPA did not differ significantly between cases and controls. In adjusted models, urinary BPA averaged across pregnancy was not significantly associated with PTB. When examining clinical classifications of PTB, urinary BPA late in pregnancy was significantly associated with increased odds of delivering a spontaneous PTB. After stratification on infant's sex, averaged BPA exposure during pregnancy was associated with significantly increased odds of being delivered preterm among females, but not males. CONCLUSIONS: These results provide little evidence of a relationship between BPA and prematurity, though further research may be warranted given the generalizability of participant recruitment from a tertiary teaching hospital, limited sample size, and significant associations among females and within the clinical subcategories of PTB. CITATION: Cantonwine DE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. 2015. Urinary bisphenol A levels during pregnancy and risk of preterm birth. Environ Health Perspect 123:895-901; http://dx.doi.org/10.1289/ehp.1408126.

Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth.

BACKGROUND: It is of critical importance to evaluate the role of environmental chemical exposures in premature birth. While a number of studies investigate this relationship, most utilize single exposure measurements during pregnancy in association with the outcome. The studies with repeated measures of exposure during pregnancy employ primarily cross-sectional analyses that may not be fully leveraging the power and additional information that the data provide. METHODS: We examine 9 statistical methods that may be utilized to estimate the relationship between a longitudinal exposure and a binary, non-time-varying outcome. To exemplify these methods we utilized data from a nested case-control study examining repeated measures of urinary phthalate metabolites during pregnancy in association with preterm birth. RESULTS: The methods summarized may be useful for: 1) Examining sensitive windows of exposure in association with an outcome; 2) Summarizing repeated measures to estimate the relationship between average exposure and an outcome; 3) Identifying acute exposures that may be relevant to the outcome; and 4) Understanding the contribution of temporal patterns in exposure levels to the outcome of interest. In the study of phthalates, changes in urinary metabolites over pregnancy did not appear to contribute significantly to preterm birth, making summary of average exposure across gestation optimal given the current design. CONCLUSIONS: The methods exemplified may be of great use in future epidemiologic research projects intended to: 1) Elucidate the complex relationships between environmental chemical exposures and preterm birth; 2) Investigate biological mechanisms in prematurity using repeated measures of maternal factors throughout pregnancy; and 3) More generally, address the relationship between a longitudinal predictor and a binary, non-time-varying outcome.

Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth.

OBJECTIVE: The purpose of this study was to investigate oxidative stress as a mechanism of preterm birth in human subjects; we examined associations between urinary biomarkers of oxidative stress that were measured at multiple time points during pregnancy and preterm birth. STUDY DESIGN: This nested case-control study included 130 mothers who delivered preterm and 352 mothers who delivered term who were originally recruited as part of an ongoing prospective birth cohort at Brigham and Women's Hospital. Two biomarkers that included 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane were measured in urine samples that were collected at up to 4 time points (median 10, 18, 26, and 35 weeks) during gestation. RESULTS: Urinary concentrations of 8-isoprostane and 8-OHdG decreased and increased, respectively, as pregnancy progressed. Average levels of 8-isoprostane across pregnancy were associated with increased odds of spontaneous preterm birth (adjusted odds ratio, 6.25; 95% confidence interval, 2.86-13.7), and associations were strongest with levels measured later in pregnancy. Average levels of 8-OHdG were protective against overall preterm birth (adjusted odds ratio, 0.19; 95% confidence interval, 0.10-0.34), and there were no apparent differences in the protective effect in cases of spontaneous preterm birth compared with cases of placental origin. Odds ratios for overall preterm birth were more protective in association with urinary 8-OHdG concentrations that were measured early in pregnancy. CONCLUSION: Maternal oxidative stress may be an important contributor to preterm birth, regardless of subtype and timing of exposure during pregnancy. The 2 biomarkers that were measured in the present study had opposite associations with preterm birth; an improved understanding of what each represents may help to identify more precisely important mechanisms in the pathway to preterm birth.

Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis.

BACKGROUND: Phthalate exposure occurs readily in the environment and has been associated with an array of health end points, including adverse birth outcomes. Some of these may be mediated by oxidative stress, a proposed mechanism for phthalate action. OBJECTIVES: In the present study, we explored the associations between phthalate metabolites and biomarkers of oxidative stress measured in urine samples from multiple time points during pregnancy. METHODS: Women were participants in a nested case-control study of preterm birth (n = 130 cases, n = 352 controls). Each was recruited early in pregnancy and followed until delivery, providing urine samples at up to four visits. Nine phthalate metabolites were measured to assess exposure, and 8-hydroxydeoxyguanosine and 8-isoprostane were also measured in urine as markers of oxidative stress. Associations were assessed using linear mixed models to account for intraindividual correlation, with inverse selection probability weightings based on case status to allow for greater generalizability. RESULTS: Interquartile range increases in phthalate metabolites were associated with significantly higher concentrations of both biomarkers. Estimated differences were greater in association with monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), and monoisobutyl phthalate (MiBP), compared with di(2-ethylhexyl) phthalate (DEHP) metabolites. CONCLUSIONS: Urinary phthalate metabolites were associated with increased oxidative stress biomarkers in our study population of pregnant women. These relationships may be particularly relevant to the study of birth outcomes linked to phthalate exposure. Although replication is necessary in other populations, these results may also be of great importance for a range of other health outcomes associated with phthalates.

Urinary angiotensinogen level is increased in preterm neonates.

BACKGROUND: All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates and examined the relationship between urinary angiotensinogen levels and gestational age. METHODS: Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. RESULTS: Plasma angiotensinogen concentrations were not increased in preterm neonates compared with that in full-term neonates (P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared with that in full-term neonates (P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age (P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age (P = 0.7814). CONCLUSIONS: These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development.