Associations between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery

Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance.

The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies

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

Is maternal obesity associated with sustained inflammation in extremely low gestational age newborns?

Background: The offspring of obese women are at increased risk for systemic inflammation. Blood concentrations of inflammatory proteins in preterm newborns of obese women have not been reported. Aim: To compare blood concentrations in the highest quartile for gestational age of inflammatory proteins and day of blood specimen collection on two days at least one week apart of newborns of overweight (i.e., BMI 25-29) and obese women (i.e., BMI. ≥. 30) with newborns of women with lower BMIs. Because deliveries for spontaneous indications are more likely than those for other indications to be associated with inflammation, we evaluated spontaneous indication deliveries separately from maternal or fetal indications. Study design: Prospective cohort study. Subjects and outcome measures: We measured from 939 children born before the 28th week of gestation 25 inflammation-related proteins in blood obtained on postnatal day 1 (range 1-3), day 7 (range 5-8) and day 14 (range 12-15). Results: Among infants delivered for spontaneous indications, maternal BMI was not related to elevated concentrations of any protein. Among infants delivered for maternal (i.e., preeclampsia) or fetal indications, those whose mother was overweight or obese were more likely than others to have elevated concentrations of inflammation proteins. Conclusions: Maternal pre-pregnancy overweight and obesity appear to contribute to a pro-inflammatory state in very preterm newborns delivered for maternal or fetal indications. Our failure to see a similar pattern among newborns delivered for spontaneous indications, which often have inflammatory characteristics, might reflect competing risks. © 2013 Elsevier Ltd

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