The role of seminal reactive oxygen species assessment in the setting of infertility and early pregnancy loss.

The male contribution to a couple suffering with adverse early pregnancy outcomes is being increasingly investigated. Seminal oxidative stress is considered to cause sperm DNA damage, thus affecting the functional capacity of the sperm. Multiple lines of evidence support an association between elevated seminal reactive oxygen species (ROS) and infertility. In the setting of assisted reproduction various factors in the in vitro environment, differing from the in vivo environment, may exacerbate oxidative stress. Furthermore, seminal ROS levels have been found to be higher in the male partners of couple's affected by both spontaneous and recurrent pregnancy loss. There are several methods by which to assess ROS levels however they are costly, inconsistent and their incorporation into clinical practice is unclear. The value of ROS assessment lies in the ability to plan targeted therapies to improve pregnancy and live birth rates. As such, further robust study is required before firm conclusions can be made to inform clinical practice. We aim to review the available evidence regarding the role of seminal ROS in infertility and pregnancy loss.

A multi-pollutant assessment of preconception persistent endocrine disrupting chemicals and incident pregnancy loss.

BACKGROUND: A few endocrine disrupting chemicals (EDCs) have been associated with pregnancy loss often as reported by women, though there has been no study of EDC mixtures and pregnancy loss in keeping with the nature of human exposure. OBJECTIVES: To investigate preconception exposure to a mixture of EDCs to identify important drivers and inform multi-pollutant models of EDCs in relation to incident human gonadrophin chorionic (hCG) pregnancy loss. METHODS: A cohort of 501 couples were recruited from the general population and prospectively followed until a hCG-confirmed pregnancy or 12 months of trying to become pregnant. Pregnant (n = 344; 69%) women were followed daily through seven weeks post-conception then monthly until delivery. Loss was defined as conversion to negative pregnancy test or a clinical diagnosis. Preconception exposure assessment of EDCs included sixty-three serum chemicals and three blood metals. EDCs were measured using isotope dilution gas chromatography-high resolution mass spectrometry or high-performance liquid chromatography-tandem mass spectrometry, and inductively coupled plasma-mass spectrometry, respectively. Using elastic net variable selection to identify important factors from the exposure mixture, EDC levels and covariates were then included in Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of time-to-pregnancy loss in multi-pollutant models. RESULTS: Incidence of hCG pregnancy loss was 28%. Nine EDCs of the sixty-six chemical mixture were associated with pregnancy loss; HRs were elevated for polychlorinated biphenyl 194, 2-(N-methyl-perfluorooctane sulfonamido) acetate, polybrominated diphenyl ether 28, and cadmium, even in sensitivity models adjusting for male partners' EDC concentrations. In final multivariable multi-pollutant Cox proportional hazard models, female partners'polybrominated diphenyl ether 28 (aHR = 1.16, 95% CI: 1.02, 1.31) and cadmium (aHR = 1.23, 95% CI: 1.07, 1.40) remained associated with hCG pregnancy loss. Female partners' preconception serum polychlorinated biphenyl 194 and 2-(N-methyl-perfluorooctane sulfonamido) acetate concentrations were consistently inversely associated with loss [(aHR = 0.72, 95% CI: 0.56, 0.92) and (aHR = 0.79, 95% CI: 0.65, 0.95), respectively]. CONCLUSION: Assessing exposure to a mixture of 66 persistent EDCs, females' preconception concentrations of polybrominated diphenyl ether 28 and cadmium were positively associated with incident hCG pregnancy loss in a cohort of couples from the general population trying for pregnancy.

Multistate methodology improves risk assessment under time-varying drug intake-a new view on pregnancy outcomes following coumarin exposure.

PURPOSE: Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques. METHODS: We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion. RESULTS: We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians. CONCLUSIONS: An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.

Methods for the assessment of selection bias in drug safety during pregnancy studies using electronic medical data.

Electronic health data are routinely used for population drug studies. Due to the ethical dilemma in carrying out experimental drug studies on pregnant women, the effects of medication usage during pregnancy on fetal and maternal outcomes are largely evaluated using this data collection medium. One major limitation in this type of study is the delayed inclusion of pregnancies in the cohort. For example, in the province of Quebec, Canada, a major pregnancy cohort only captured pregnancies after 20 weeks gestation. The purpose of this study was to demonstrate three methods that can be used to assess the extent of selection bias due to the delayed inclusion of pregnancies. We use causal directed acyclic graphs to explain the source of this selection bias. In an example involving a cohort of pregnant asthmatic women reconstructed from the linkage of administrative health databases from the province of Quebec, we use numerical derivations, a simulation study and a sensitivity analysis to investigate the potential for bias and loss of power due to the delayed inclusion. We find that this selection bias can be partially mitigated by controlling for variables related to (spontaneous or therapeutic) abortion and the outcome of interest. The three proposed methods allow for the pre and post hoc ascertainment of the bias. While delayed pregnancy inclusion selection bias (which includes "live birth bias") can produce substantial bias in pregnancy drug studies, all three methods are effective at producing estimates of the size of the bias.

Access to Medication Abortion Among California's Public University Students.

PURPOSE: A proposed California law will require student health centers at public universities to provide medication abortion. To understand its potential impact, we sought to describe current travel time, costs, and wait times to access care at the nearest abortion facilities. METHODS: We projected total medication abortion use based on campus enrollment figures and age- and state-adjusted abortion rates. We calculated distance and public transit time from campuses to the nearest abortion facility. We contacted existing abortion-providing facilities to determine costs, insurance acceptance, and wait times. RESULTS: We estimate 322 to 519 California public university students seek medication abortions each month. As many as 62% of students at these universities were more than 30 minutes from the closest abortion facility via public transportation. Average cost of medication abortion was $604, and average wait time to the first available appointment was one week. CONCLUSIONS: College students face cost, scheduling, and travel barriers to abortion care. Offering medication abortion on campus could reduce these barriers.

The Gulf oil spill, miscarriage, and infertility: the GROWH study.

PURPOSE: To examine whether reported exposure to the Gulf oil spill (2010) was related to reproductive reported miscarriage or infertility. METHODS: 1524 women aged 18-45 recruited through prenatal and Women, Infant, and Children (WIC) clinics, and community events were interviewed about their experience of the oil spill and reproductive history. 1434 women had information on outcomes of at least one pregnancy, and 633 on a pregnancy both before and after the spill. Generalized estimating equations were used to examine the relationship between contact with oil and economic and social consequences of the spill with postponement of pregnancy, miscarriage, and infertility (time to pregnancy >12 months or reported fertility issues), with adjustment for age, race, BMI, smoking, and socioeconomic status. Results were compared for pregnancies occurring prior to and after the oil spill. RESULTS: 77 (5.1%) women reported postponing pregnancy due to the oil spill, which was more common in those with high contact with oil or overall high exposure (aOR 2.92, 95% CI 1.31-6.51). An increased risk of miscarriage was found with any exposure to the oil spill (aOR, 1.54, 95% CI 1.17-2.02). Fertility issues were more common in the overall most highly exposed women (aOR 1.88, 1.19-2.95), when the data were limited to those with pregnancies before and after. However, no particular aspect of oil spill exposure was strongly associated with the outcomes, and effects were almost as strong for pregnancies prior to the oil spill. CONCLUSIONS: The oil spill appears to have affected reproductive decision-making. The evidence is not strong that exposure to the oil spill was associated with miscarriage or infertility.

Exposure to cox-2 inhibitors (coxibs) during the first trimester and pregnancy outcome: a prospective observational cohort study.

PURPOSE: Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further data on coxibs and their effects on embryogenesis are needed. METHODS: This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January 2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens. RESULTS: The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI 0.34-3.42; OR adjusted 0.96, 95% CI 0.28-3.26). The cumulative incidence of spontaneous abortions was nonsignificantly lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51-1.58; HR adjusted, 0.87; 95% CI, 0.49-1.56). Elective terminations of pregnancies (ETOP), mainly for 'social' reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR, 2.31; 95% CI, 1.26-4.24; HR adjusted 2.12, 95% CI 1.13-3.97). CONCLUSIONS: Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence basis on coxib exposure during pregnancy, well-established alternatives should be preferred.

Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy: a systematic literature review.

BACKGROUND: Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. METHODS: Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). RESULTS: Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. CONCLUSION: Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed.

The health consequences of aerial spraying illicit crops: The case of Colombia.

This paper exploits variations in aerial spraying across time and space in Colombia and employs a panel of individual health records in order to study the causal effects of the aerial spraying of herbicides (glyphosate) on short-term health-related outcomes. Our results show that exposure to the herbicide used in aerial spraying campaigns increases the number of medical consultations related to dermatological and respiratory illnesses, as well as the number of miscarriages. These findings are robust to the inclusion of individual fixed effects, which compare the prevalence of these medical conditions for the same person under different levels of exposure to the herbicide used in the aerial spraying program over a period of 5 years. Also, our results are robust to controlling for the extent of illicit coca cultivation in the municipality of residence.

Assessment of time to pregnancy and spontaneous abortion status following occupational exposure to organic solvents mixture.

PURPOSE: Due to increasing usage of chemicals in various industries, occupational exposure of women with these materials is unavoidable. Nowadays, some studies indicate adverse effects of exposure to these chemicals, especially organic solvents on the reproductive system of females. This study aimed to assess the relationship between spontaneous abortion and occupational exposure to organic solvents mixture in pharmaceutical industry. METHODS: This study was carried out in a pharmaceutical factory located in the suburb of Tehran in 2010. During the study, married women who were working in the factory laboratory units and had exposure to mixed organic solvents were compared with married women who were working in the packing units of the factory without occupational exposure to organic solvents in terms of spontaneous abortion frequency and duration of pregnancy using statistical methods. RESULTS: In this study, the frequency of spontaneous abortion in employees with and without exposure to organic solvents mixture was 10.7 and 2.9% respectively. This study showed that even after adjustment for confounding factors, there was a significant correlation between spontaneous abortion and occupational exposure to organic solvents mixture and this correlation increased with increasing levels of exposure to organic solvents. Also, a significant correlation was observed between occupational exposure to mixed organic solvents and waiting time to become pregnant (TTP). Furthermore, this study showed that even after adjustment for confounding variables, shift workers were significantly more affected by spontaneous abortion compared to daytime workers (P < 0.001). Also, in our study, synergistic effect between shift working and occupational exposure to organic solvents mixture on spontaneous abortion was seen. CONCLUSIONS: According to the results of this study, since there is probability of spontaneous abortion resulting from occupational exposure to various chemicals including organic solvents, recommendation to review the status of occupational exposure of workers can be helpful in improving fertility consultations and reproductive health.

Patterns of medication use during pregnancy in rheumatoid arthritis.

OBJECTIVE: To characterize therapies prescribed during pregnancy to women with rheumatoid arthritis (RA). METHODS: We conducted a cohort study of women with RA with pregnancies using health care utilization data from 2002-2008. We examined the distribution of RA drugs by therapeutic classes, including nonsteroidal antiinflammatory drugs (NSAIDs)/coxibs, glucocorticoids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs, during 90-day pregnancy trimesters and the 180 days prior to pregnancy. Drugs were characterized according to the Food and Drug Administration risk classification system. Differences in exposure by period were determined by chi-square tests. RESULTS: A total of 393 pregnancies were identified among 34,169 women with RA. Seventy-two percent of pregnancies ended in a delivery. Approximately 24% of women with RA received a DMARD during preconception. At any point during pregnancy, 23% of women with deliveries were dispensed ≥1 DMARD and the proportion of use declined from the first to the third trimester (P = 0.03). Similar to DMARD therapy, use of NSAIDs/coxibs and exposure to category D/X medications were significantly lower compared to prepregnancy use (P < 0.05). In contrast, more women were prescribed glucocorticoids during pregnancy than before pregnancy. Use of biologics occurred in 12.5% of pregnancies. Compared to women with deliveries, women who experienced abortions were more frequently exposed to NSAIDs/coxibs (P < 0.05). Dispensing of category D/X medications was also higher in women with spontaneous abortions and primarily involved methotrexate (P < 0.05). CONCLUSION: Approximately 24% of women with RA received a DMARD in the 180 days before conception, and the proportion dropped during pregnancy. Glucocorticoid use remained high throughout pregnancy. Our results suggest that continued efforts directed at counseling women and their physicians about the potential risks/benefits of RA therapies during pregnancy are warranted.

Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes.

BACKGROUND: A significant number of women of childbearing age have schizophrenia or other psychoses. This means that there is a considerable risk of in utero exposure to risperidone due to maternal use. OBJECTIVE: To determine whether in utero exposure to the atypical antipsychotic risperidone is associated with poor pregnancy and fetal/neonatal outcomes. METHODS: A search of the Benefit Risk Management Worldwide Safety database, using a selection of preferred terms from the Medical Dictionary of Regulatory Activities, was performed to identify all cases of pregnancy or fetal/neonatal outcomes reported in association with risperidone treatment from its first market launch (international birth date, 1 June 1993) to 31 December 2004. The main measures were the patterns and reporting rates of pregnancy (stillbirth and spontaneous and induced abortion) and fetal/neonatal outcomes (congenital abnormalities, perinatal syndromes and withdrawal symptoms) for women administered risperidone during pregnancy. RESULTS: Overall, 713 pregnancies were identified in women who were receiving risperidone. Data were considered prospective in 516 of these, and retrospective in the remaining 197 cases. The majority of the known adverse pregnancy and fetal/neonatal outcomes were retrospectively reported. Of the 68 prospectively reported pregnancies with a known outcome, organ malformations and spontaneous abortions occurred 3.8% and 16.9% (when the 15 induced abortions were excluded from the denominator, as they were predominantly undertaken for nonmedical reasons), respectively, a finding consistent with background rates of the general population. There were 12 retrospectively reported pregnancies involving major organ malformations, the most frequently reported of which affected the heart, brain, lip and/or palate. There were 37 retrospectively reported pregnancies involving perinatal syndromes, of which 21 cases involved behavioural or motor disorders. In particular, there was a cluster of cases reporting tremor, jitteriness, irritability, feeding problems and somnolence, which may represent a withdrawal-emergent syndrome. CONCLUSION: This comprehensive review of the Benefit Risk Management Worldwide Safety database for case reports of risperidone exposure during pregnancy represents the largest ever published dataset documenting pregnancy outcomes for women taking the atypical antipsychotic risperidone. It indicates that in utero exposure to risperidone does not appear to increase the risk of spontaneous abortions, structural malformations and fetal teratogenic risk above that of the general population. Self-limited extrapyramidal effects in neonates were observed after maternal exposure to risperidone during the third trimester of pregnancy. Risperidone should only be used during pregnancy if the benefits outweigh the potential risks.

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature.

OBJECTIVE: A systematic review and meta-analysis was conducted to test the hypothesis that oncology health care workers are at an increased risk of cancer, reproductive complications and acute toxic events. DESIGN: A structured literature search of Index Medicus/ MEDLINE, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews and Healthstar was performed from 1966 to December 2004 for human epidemiological studies evaluating the risk of toxic events in health care workers exposed to cytotoxic drugs. Raw data and adjusted odds ratios (OR) reported in eligible studies were combined using a random effects model to calculate point estimates and 95% confidence intervals (CI) for each potential risk outcome. MAIN OUTCOME MEASURES: Adjusted OR for congenital malformations, stillbirths and spontaneous abortions among health care workers exposure to cytotoxic agents compared to a nonexposed control group. RESULTS: The systematic review identified 14 studies evaluating the outcomes of interest, seven of which were suitable for statistical pooling. Due to lack of evidence, we were unable to estimate a pooled OR for the risk of cancer and acute toxic events. However, no significant association was detected between exposure to cytotoxic drugs and; congenital malformations (OR = 1.64; 95% CI: 0.91-2.94) and stillbirths (OR = 1.16; 95% CI: 0.73-1.82). In contrast, an association was identified between exposure to chemotherapy and spontaneous abortions (OR = 1.46; 95% CI: 1.11-1.92). CONCLUSIONS: The results of this systematic review identified a small incremental risk for spontaneous abortions in female staff working with cytotoxic agents. Health policy decision makers should effectively communicate the magnitude of this risk to their staff and implement cost effective interventions for its reduction or elimination.

Assessment and treatment of depression during pregnancy: an update.

Depression occurs commonly during pregnancy, and women with recurrent depression are at particularly high risk for depressive illness in this setting. Though the use of psychotropic medications during pregnancy raises concerns, there are data to support the use of certain antidepressants, including fluoxetine and the tricyclic antidepressants. Data on the newer SSRI antidepressants is gradually accumulating and is encouraging. None of the SSRIS or TCAs have been associated with an increased risk of congenital malformation. However, information on the long-term neurobehavioral effects of these medications still remains limited. As depression during pregnancy carries risk for both the mother and child, it is crucial to diagnose depression in this setting and to provide appropriate treatment strategies. Further data on nonpharmacologic and pharmacologic strategies is needed to aid in the treatment of this challenging clinical population. The clinician must weigh the relative risks of various treatment options and take into account individual patient wishes. Such a process will lead to thoughtful treatment choices, which with close clinical follow-up can minimize the risk for maternal morbidity.

Evidence-based assessment of pregnancy outcome after sumatriptan exposure.

OBJECTIVE: Assessment of best available evidence for tolerability of sumatriptan after inadvertent exposure during pregnancy. BACKGROUND: Migraine's demography suggests that inadvertent exposure to acute therapies is likely during the earliest undiagnosed stages of pregnancy. The tolerability of such therapies under these conditions is not amenable to clinical trial for ethical reasons. In the United States, sumatriptan is currently labeled pregnancy category C (ie, not recommended for use during pregnancy unless the potential benefit justifies the potential risk to the fetus). METHODS: Three types of adverse events were studied: spontaneous abortion, fetal abnormality, and obstetric complications. Traditional evidence-based criteria were used to assess a search-protocol product of four clinical studies and two case reports. RESULTS: The single positive finding ("preterm delivery" without low birth weight) was in the smallest study; this study was retrospective and the finding was externally inconsistent with the other three larger studies, all of which were prospective. No study followed children for more than 4 years, which is the period needed to identify the maximum number of congenital anomalies. Rigorous teratological technique was generally not employed. Post hoc power calculations were used to provide parameters of the hazard detectable by these studies in aggregate. CONCLUSIONS: Pregnancy categories B and C both seem feasible for sumatriptan. Within the limits of the examined studies, there is no evidence for any specific effect of sumatriptan on pregnancy outcome. Patients inadvertently exposed to sumatriptan during an early stage of pregnancy should be reassured by these data.

Assessment of fetal risk associated with exposure to cancer chemotherapy during pregnancy: a multicenter study.

The objective of the present study was to evaluate and quantify fetal risks involved in the administration of cancer chemotherapy during gestation, as well as to assess the long-term effects on the exposed children. In this retrospective, cohort study, we reviewed the records of women aged 15 to 45 years with a diagnosis of malignancy or benign tumors with malignant behavior at three reference services in the State of Rio Grande do Sul, Brazil, from 1990 to 1997. All patients with a diagnosis of pregnancy at any time during the course of the disease were selected, regardless of whether or not they received specific medication. Fetal outcomes of 14 pregnancies with chemotherapy exposure were compared to that of 15 control pregnancies in which these drugs were not used. Long-term follow-up of the exposed children was carried out. Fisher's exact test was used to compare the groups. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. We found an increased rate of prematurity (6/8 vs 2/10; RR: 3.75; CI: 1.02-13.8; P = 0.03) in the exposed group. There was a trend to an increased fetal death rate (4/12 vs 0/10; P = 0.07) in the group exposed to chemotherapy. No malformations were detected in any child, which can be related to our small sample size as well as to the fact that most exposures occurred after the first trimester of pregnancy. Other larger, controlled studies are needed to establish the actual risk related to cancer chemotherapy during pregnancy.

Final report on the safety assessment of Juniperus communis Extract, Juniperus oxycedrus Extract, Juniperus oxycedrus Tar, Juniperus phoenicea extract, and Juniperus virginiana Extract.

The common juniper is a tree that grows in Europe, Asia, and North America. The ripe fruit of Juniperus communis and Juniperus oxycedrus is alcohol extracted to produce Juniperus Communis Extract and Juniperus Oxycedrus Extract, respectively. Juniperus Oxycedrus Tar is the volatile oil from the wood of J. oxycedrus. Juniperus Phoenicea Extract comes from the gum of Juniperus phoenicea, and Juniperus Virginiana Extract is extracted from the wood of Juniperus virginiana. Although Juniperus Oxycedrus Tar is produced as a by-product of distillation, no information was available on the manufacturing process for any of the Extracts. Oils derived from these varieties of juniper are used solely as fragrance ingredients; they are commonly produced using steam distillation of the source material, but it is not known if that procedure is used to produce extracts. One report does state that the chemical composition of Juniper Communis Oil and Juniperus Communis Extract is similar, each containing a wide variety of terpenoids and aromatic compounds, with the occasional aliphatic alcohols and aldehydes, and, more rarely, alkanes. The principle component of Juniperus Oxycedrus Tar is cadinene, a sesquiterpene, but cresol and guaiacol are also found. No data were available, however, indicating the extent to which there would be variations in composition that may occur as a result of extraction differences or any other factor such as plant growth conditions. Information on the composition of the other ingredients was not available. All of the Extracts function as biological additives in cosmetic formulations, and Juniperus Oxycedrus Tar is used as a hair-conditioning agent and a fragrance component. Most of the available safety test data are from studies using oils derived from the various varieties of juniper. Because of the expected similarity in composition to the extract, these data were considered. Acute studies using animals show little toxicity of the oil or tar. The oils derived from J. communis and J. virginiana and Juniperus Oxycedrus Tar were not skin irritants in animals. The oil from J. virginiana was not a sensitizer, and the oil from J. communis was not phototoxic in animal tests. Juniperus Oxycedrus Tar was genotoxic in several assays. No genotoxicity data were available for any of the extracts. Juniperus Communis Extract did affect fertility and was abortifacient in studies using albino rats. Clinical tests showed no evidence of irritation or sensitization with any of the tested oils, but some evidence of sensitization to the tar. These data were not considered sufficient to assess the safety of these ingredients. Additional data needs include current concentration of use data; function in cosmetics; methods of manufacturing and impurities data, especially pesticides; ultraviolet (UV) absorption data; if absorption occurs in the UVA or UVB range, photosensitization data are needed; dermal reproductive/developmental toxicity data (to include determination of a no-effect level); two genotoxicity assays (one in a mammalian system) for each extract; if positive, a 2-year dermal carcinogenicity assay performed using National Toxicology Program (NTP) methods is needed; a 2-year dermal carcinogenicity assay performed using NTP methods on Juniperus Oxycedrus Tar; and irritation and sensitization data on each extract and the tar (these data are needed because the available data on the oils cannot be extrapolated). Until these data are available, it is concluded that the available data are insufficient to support the safety of these ingredients in cosmetic formulations.

Impact of chemical warfare with agent orange on women's reproductive lives in Vietnam: a pilot study.

During the American war in Vietnam, huge quantities of the highly toxic herbicide dioxin ('Agent Orange'), were sprayed over large areas of central and south Vietnam. In addition to polluting the environment and causing cancers and other diseases in those directly exposed to it, dioxin has caused high rates of pregnancy loss, congenital birth defects and other health problems in their children. This paper reports the findings of a pilot study in the year 2000 among 30 Vietnamese women whose husbands and/or who themselves were exposed to Agent Orange. The aim was to develop research in order to explore the impact of chemical warfare on people's lives. Using the reproductive lifeline and semi-structured interviews, information was gathered on both partners' periods of exposure to Agent Orange, pregnancy outcomes, perceived health problems of children and experiences of living with handicapped children. The women had had a high number of miscarriages and premature births. About two-thirds of their children had congenital malformations or developed disabilities within the first years of life. Most of the families were poor, aggravated by impaired health in the men, the burden of caring for disabled children, and feelings of guilt and inferiority. The plight of 'Agent Orange families' is special and should be placed in its historical and political context.

Influence of exposure assessment methods on risk estimates in an epidemiologic study of total trihalomethane exposure and spontaneous abortion.

Trihalomethanes are common contaminants of chlorinated drinking water. Studies of their health effects have been hampered by exposure misclassification, due in part to limitations inherent in using utility sampling records. We used two exposure assessment methods, one based on utility-wide sampling averages, and one based on measurements from the utility sampling site closest to the subject's residence, to reestimate total trihalomethane (TTHM) exposure for 4212 participants in a preexisting study of risk factors for spontaneous abortion (SAB). For both approaches we performed unweighted, weighted, and subset analyses. The weighted and subset analyses were intended to reduce exposure misclassification, and were based on within-utility variance in TTHM measurements for the utility-wide average approach, and the distance between the subject's residence and sampling site for the closest-site approach. In general, the utility-wide average methods produced odds ratios equivalent to or slightly higher than the closest-site methods. Odds ratios obtained using the utility-wide average, but not the closest-site, approach also became progressively stronger in the weighted and subset analyses. A dose-response was seen between SAB and an exposure metric incorporating both TTHM concentration (utility-wide average approach) and personal ingestion, with SAB rates ranging from 8.3% to 13.7% (unweighted), 7.9% to 16.6% (variance weighted), and 6.6% to 23.1% (low-variance subset). Utility-wide average TTHM exposure assessment methods together with variance-based weights and subsets are relatively simple exposure assessment techniques, which may increase the epidemiologic usefulness of utility sampling records.

Assessing overall risk in reproductive experiments.

Toxicologists are often interested in assessing the joint effect of an exposure on multiple reproductive endpoints, including early loss, fetal death, and malformation. Exposures that occur prior to mating or extremely early in development can adversely affect the number of implantation sites or fetuses that form within each dam and may even prevent pregnancy. A simple approach for assessing overall adverse effects in such studies is to consider fetuses or implants that fail to develop due to exposure as missing data. The missing data can be imputed, and standard methods for the analysis of quantal response data can then be used for quantitative risk assessment or testing. In this article, a new bias-corrected imputation procedure is proposed and evaluated. The procedure is straightforward to implement in standard statistical packages and has excellent operating characteristics when used in combination with a marginal model fit with generalized estimating equations. The methods are applied to data from a reproductive toxicity study of Nitrofurazone conducted by the National Toxicology Program.