Rajeshwari Sundaram

Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development--the LIFE Study.

The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e., fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424,423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ∼ 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time.

The natural history of the normal first stage of labor.

OBJECTIVE: To examine labor patterns in a large population and to explore an alternative approach for diagnosing abnormal labor progression. METHODS: Data from the National Collaborative Perinatal Project were used. A total of 26,838 parturients were selected who had a singleton term gestation, spontaneous onset of labor, vertex presentation, and a normal perinatal outcome. A repeated-measures analysis was used to construct average labor curves by parity. An interval-censored regression was used to estimate duration of labor stratified by cervical dilation at admission and centimeter by centimeter. RESULTS: The median time needed to progress from one centimeter to the next became shorter as labor advanced (eg, from 1.2 hours at 3–4 cm to 0.4 hours at 7–8 cm in nulliparas). Nulliparous women had the longest and most gradual labor curve; multiparous women of different parities had very similar curves. Nulliparas may start the active phase after 5 cm of cervical dilation and may not necessarily have a clear active phase characterized by precipitous dilation. The deceleration phase in the late active phase of labor may be an artifact in many cases. CONCLUSION: The active phase of labor may not start until 5 cm of cervical dilation in multiparas and even later in nulliparas. A 2-hour threshold for diagnosing labor arrest may be too short before 6 cm of dilation, whereas a 4-hour limit may be too long after 6 cm. Given that cervical dilation accelerates as labor advances, a graduated approach based on levels of cervical dilation to diagnose labor protraction and arrest is proposed. LEVEL OF EVIDENCE: III

The relationship between male BMI and waist circumference on semen quality: data from the LIFE study

Michael L. Eisenberg1,*, Sungduk Kim2, Zhen Chen2, Rajeshwari Sundaram2, Enrique F. Schisterman2, and Germaine M. Buck Louis2 Departments of Urology, Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5118, USA Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6100 Executive Blvd., Room 7B03, Rockville, MD 20852, USA

Persistent Environmental Pollutants and Couple Fecundity: The LIFE Study

Background: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured. Objectives: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy. Methods: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner’s concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment. Results: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males. Conclusions: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.

Validity of self-reported time to pregnancy.

Background: The reliability of retrospective time to pregnancy (TTP) has been established, but its validity has been assessed in only 1 study, which had a short follow-up. Methods: Ninety-nine women enrolled a decade earlier in a prospective TTP study were queried by means of mailed questionnaires about the duration of time they had required to become pregnant. Their responses were compared with their earlier data from daily diaries (gold standard). Results: One-third of women could not recall their earlier TTP either in menstrual cycles or calendar months. Only 17%–19% of women recalled their TTP exactly. Agreement increased to 41%–51%, 65%–72%, and 72%–77% when defined as ±1, ±2, and ±3 months, respectively. Women with longer observed TTPs or previous pregnancies were more likely to under-report their TTP. Conclusions: The findings raise questions about the commonly assumed validity of self-reported TTP. Recalled TTP may introduce error when estimating fecundability or classifying couples’ fecundity status.

Neonatal and maternal outcomes with prolonged second stage of labor.

OBJECTIVE: To assess neonatal and maternal outcomes when the second stage of labor was prolonged according to American College of Obstetricians and Gynecologists guidelines. METHODS: Electronic medical record data from a retrospective cohort (2002–2008) from 12 U.S. clinical centers (19 hospitals), including 43,810 nulliparous and 59,605 multiparous singleton deliveries at 36 weeks of gestation or greater, vertex presentation, who reached 10-cm cervical dilation were analyzed. Prolonged second stage was defined as: nulliparous women with epidural greater than 3 hours and without greater than 2 hours and multiparous women with epidural greater than 2 hours and without greater than 1 hour. Maternal and neonatal outcomes were compared and adjusted odds ratios calculated controlling for maternal race, body mass index, insurance, and region. RESULTS: Prolonged second stage occurred in 9.9% and 13.9% of nulliparous and 3.1% and 5.9% of multiparous women with and without an epidural, respectively. Vaginal delivery rates with prolonged second stage compared with within guidelines were 79.9% compared with 97.9% and 87.0% compared with 99.4% for nulliparous women with and without epidural, respectively, and 88.7% compared with 99.7% and 96.2% compared with 99.9% for multiparous women with and without epidural, respectively (P<.001 for all comparisons). Prolonged second stage was associated with increased chorioamnionitis and third-degree or fourth-degree perineal lacerations. Neonatal morbidity with prolonged second stage included sepsis in nulliparous women (with epidural: 2.6% compared with 1.2% [adjusted odds ratio (OR) 2.08, 95% confidence interval (CI) 1.60–2.70]; without epidural: 1.8% compared with 1.1% [adjusted OR 2.34, 95% CI 1.28–4.27]); asphyxia in nulliparous women with epidural (0.3% compared with 0.1% [adjusted OR 2.39, 95% CI 1.22–4.66]) and perinatal mortality without epidural (0.18% compared with 0.04% for nulliparous women [adjusted OR 5.92, 95% CI 1.43–24.51]); and 0.21% compared with 0.03% for multiparous women (adjusted OR 6.34, 95% CI 1.32–30.34). However, among the offspring of women with epidurals whose second stage was prolonged (3,533 nulliparous and 1,348 multiparous women), there were no cases of hypoxic–ischemic encephalopathy or perinatal death. CONCLUSIONS: Benefits of increased vaginal delivery should be weighed against potential small increases in maternal and neonatal risks with prolonged second stage. LEVEL OF EVIDENCE: II

Induction of Labor in a Contemporary Obstetric Cohort

OBJECTIVE We sought to describe details of labor induction, including precursors and methods, and associated vaginal delivery rates. STUDY DESIGN This was a retrospective cohort study of 208,695 electronic medical records from 19 hospitals across the United States, 2002 through 2008. RESULTS Induction occurred in 42.9% of nulliparas and 31.8% of multiparas and elective or no recorded indication for induction at term occurred in 35.5% and 44.1%, respectively. Elective induction at term in multiparas was highly successful (vaginal delivery 97%) compared to nulliparas (76.2%). For all precursors, cesarean delivery was more common in nulliparas in the latent compared to active phase of labor. Regardless of method, vaginal delivery rates were higher with a ripe vs unripe cervix, particularly for multiparas (86.6-100%). CONCLUSION Induction of labor was a common obstetric intervention. Selecting appropriate candidates and waiting longer for labor to progress into the active phase would make an impact on decreasing the national cesarean delivery rate.

Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study—the LIFE study

STUDY QUESTION Are womens stress levels prospectively associated with fecundity and infertility? SUMMARY ANSWER Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility. WHAT IS KNOWN ALREADY Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear. STUDY DESIGN, SIZE, DURATION In 2005-2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Enrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals. MAIN RESULTS AND THE ROLE OF CHANCE Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability. LIMITATIONS, REASONS FOR CAUTION Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding. WIDER IMPLICATIONS OF THE FINDINGS This is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

Exposome: time for transformative research

Life expectancy is an overall measure of population health, and has reflected a positive trajectory for several decades in the United States when estimated either at birth or 65 years of age [1]. Despite such improvements, life expectancy varies by socio-demographic characteristics and the availability of adequate medical care. Concerns about the continual sustainability for improving life expectancy have grown in light of the obesity epidemic currently occurring in the United States and in other countries across the globe [2, 3]. For example in 2010, all 50 States comprising the United States reported an obesity prevalence of 20% or more, with 12 states reporting a prevalence of 30% or more [2]. Overall, approximately 33% of adults and 17% of children in the United States are currently estimated to be obese [4]. Other notable changes in population health include the marked reduction in fertility rates over time [5], which has partially but not entirely been attributed to changes in cultural norms and behaviors regarding childbearing practices. In fact, an evolving body of evidence is suggestive of temporal declines in human fecundity, which is defined as the biologic capacity of men and women for reproduction irrespective of pregnancy intentions [6]. The body of evidence supporting a decline in male fecundity over the past few decades includes diminished semen quality and increasing rates of genital-urinary malformations and testicular cancer, all of which are hypothesized to originate in utero or the so-called TDS or testicular dysgenesis syndrome [7]. This conceptual framework has recently been extended to women. Specifically, the ovarian dysgenesis syndrome (ODS) posits that female fecundity is established at conception or in utero with early impairments arising during prepubertal or reproductive years as manifested by alterations in the onset or progression of puberty or gynecologic and gravid disorders, respectively [8]. Assuming that human fecundity may be positively associated with survival as recently reported for semen quality [9], its decline may be at a ‘critical tipping point’ for human health as recently suggested [10] underscoring the importance of new research pardigms such as the exposome for assessing the early origins of fecundity and its implications for health across the lifespan. How might researchers further impact the health and well being of populations across the globe? Certainly, new research paradigms are needed for transforming how we think about health and disease and design research, acordingly. Novel paradigm changes are already underway (e.g., genome and epigenome), though noticeably absent is a paradigm that captures the multitude of environmental exposures that impact human health and disease. This data gap prompted the development of the exposome paradigm, which compliments the (epi)genome while providing a multitude of opportunities for intervention if exposures can be eliminated or minimized. The exposome paradigm focuses on the simultaneous measurement of a multitude of biomarkers including those that originate from external and internal sources. External environmental exposures may include chemicals or physical agents such as radiation among many other types of exposures, while internal environmental exposures arise from bodily functions and processes that govern homeostasis. Internal exposures may include chemicals or biomarkers generated via inflammation or stress along with various other pathways. Of note is the absence of biomarkers for some external environmental exposures (e.g., noise or vibration) resulting in missing data or the need for proxy biomarkers. These issues are further discussed below along with the unique aspects of the exposome such as the longitudinal and high dimensional nature of biomarkers across the lifespan. This paper provides a brief overview of the exposome paradigm along with the resources needed for getting started, research hurdles and challenges to overcome and opportunities for discovery. The overview is organized as responses to five questions: 1) What is the exposome? 2) Why is the timing right for exposome research? 3) What resources are needed for moving forward? 4) What research hurdles and challenges need to be overcome? and 5) What impact might the exposome have for transforming population health? We use human fecundity to illustrate how the exposome might be implemented, though the issues pertain to most (non-Mendelian) health outcomes.

Maternal Serum Preconception Polychlorinated Biphenyl Concentrations and Infant Birth Weight

Background Prenatal and postnatal polychlorinated biphenyl (PCBs) exposure has been associated with decrements in fetal and infant growth and development, although exposures during the preconception window have not been examined despite recent evidence suggesting that this window may correspond with the highest serum concentrations. Objectives We assessed maternal serum PCB concentrations at two sensitive developmental windows in relation to birth weight. Methods Serum samples were collected from 99 women as they began trying to become pregnant (preconception) and after a positive pregnancy test (prenatal); 52 (53%) women gave birth and represent the study cohort. Using daily diaries, women recorded sexual intercourse, menstruation, and home pregnancy test results until pregnant or up to 12 menstrual cycles with intercourse during the estimated fertile window. With gas chromatography with electron capture, 76 PCB congeners were quantified (nanograms per gram serum) and subsequently categorized by purported biologic activity. Serum PCBs were log-transformed and entered both as continuous and categorized exposures along with birth weight (grams) and covariates [smoking (yes/no), height (inches), and infant sex (male/female)] into linear regression. Results A substantial reduction in birth weight (grams) was observed for women in the highest versus the lowest tertile of preconception antiestrogenic PCB concentration (β = −429.3 g, p = 0.038) even after adjusting for covariates (β = −470.8, p = 0.04). Conclusions These data reflect the potential developmental toxicity of antiestrogenic PCBs, particularly during the sensitive preconception critical window among women with environmentally relevant chemical exposures, and underscore the importance of PCB congener–specific investigation.