Comparison of Patients' Ethical Perspectives of Preimplantation Embryo Genetic Testing for Aneuploidy (PGT-A) vs. Monogenic Disorders (PGT-M).

What are the ethical perspectives of preimplantation genetic testing in patients using/considering PGT-A compared to those using/considering PGT-M? A 17-item questionnaire administered online was used to assess ethical perspectives in US patients who recently used/considered PGT-A (n=80) vs. those who used/considered PGT-M (n=72). Kruskal-Wallis, Chi-square, and Fisher exact tests were conducted with STATA. Most PGT-A and PGT-M users/considerers supported using PGT to screen for diseases fatal in childhood (86-89%) and those causing lifelong disabilities (76-79%) and opposed using PGT to screen for non-medical physical (80-87%) or intellectual traits (74-86%). Both groups agreed that PGT aids in parental decision-making, although some expressed concern over its potential to lead to unforeseen consequences for society and the PGT offspring. More PGT-M than PGT-A users/considerers opposed implanting genetically abnormal embryos when requested by parents (29% PGT-A vs. 56% PGT-M, p = 0.007). For embryo disposition, more PGT-A users/considerers favored freezing (95% PGTA vs. 82% PGT-M, p = 0.018) or donating genetically normal embryos to research (73% PGT-A vs. 57% PGT-M, p = 0.044), while more PGT-M users/considerers supported donating embryos with known genetic abnormalities to research (56% PGT-A vs. 81% PGT-M, p = 0.001). Regardless of the reason for using PGT, users generally agreed on the acceptable and unacceptable uses for it, as well as the potential societal impact. PGT-M users/considerers expressed more opposition than PGT-A users/considerers to implanting embryos with a genetic alteration when requested by the parents.

Patients' preimplantation genetic testing decision-making experience: an opinion on related psychological frameworks.

The process of deciding whether to pursue preimplantation genetic testing (PGT) of an embryo is highly stressful for individuals and couples and has adverse emotional consequences (e.g. distress and uncertainty). PGT influences patients' lives in both positive and negative ways and is experienced at an individual level, as a dyadic unit, as a family member and as part of the society. Here, we argue that providing a conceptual framework with which to understand the `experience of decision making' about PGT for monogenic disease (PGT-M) testing specifically, as well as the factors contributing to `decisional distress' and `uncertainty' that patients endure as a result-apart from what decision they make-is crucial to optimizing patient counseling, satisfaction and outcomes in the field of ART. Derived from psychological theory, the framework proposed here identifies three categories of contributing factors to decisional distress and uncertainty in considering PGT-M; namely, 'intraindividual', 'interpersonal' and 'situational' factors. We reviewed evidence from the PGT literature to inform our framework. Well-accepted theories of stress and health decision making were also reviewed for their relevance to PGT-M decision making, focusing on potential distress and uncertainty. Our novel conceptual framework can be used to inform clinical practice, to advance research and to aid the development of interventions for individuals and couples who are deciding whether or not to use PGT-M. Alleviating emotional distress and uncertainty can improve patients' well-being during their reproductive journey.

Review of patient decision-making factors and attitudes regarding preimplantation genetic diagnosis.

The increasing technical complexity and evolving options for repro-genetic testing have direct implications for information processing and decision making, yet the research among patients considering preimplantation genetic diagnosis (PGD) is narrowly focused. This review synthesizes the literature regarding patient PGD decision-making factors, and illuminates gaps for future research and clinical translation. Twenty-five articles met the inclusion criteria for evaluating experiences and attitudes of patients directly involved in PGD as an intervention or considering using PGD. Thirteen reports were focused exclusively on a specific disease or condition. Five themes emerged: (1) patients motivated by prospects of a healthy, genetic-variant-free child, (2) PGD requires a commitment of time, money, energy and emotions, (3) patients concerned about logistics and ethics of discarding embryos, (4) some patients feel sense of responsibility to use available technologies, and (5) PGD decisions are complex for individuals and couples. Patient research on PGD decision-making processes has very infrequently used validated instruments, and the data collected through both quantitative and qualitative designs have been inconsistent. Future research for improving clinical counseling is needed to fill many gaps remaining in the literature regarding this decision-making process, and suggestions are offered.

Acupuncturist perceptions of serving as a clinical trial practitioner.

OBJECTIVE: This article describes the experience of four acupuncturists in terms of what it meant for them to be a practitioner in a recently completed sham-controlled acupuncture randomized control trial (RCT) with a standardized protocol. DESIGN: At the completion of the RCT for women with ovarian dysfunction, study acupuncturists (2 male MD/acupuncturists and 2 female professional acupuncturists) were queried about their perceptions of participating in the RCT using both written responses to 5 open-ended questions and a focus group interview. Data was analyzed to categorize responses and identify themes. SETTING: Virginia, USA. RESULTS: The acupuncturists' experience of participating in a RCT was generally very positive, including: usual practitioner/participant relationships, collegial sharing, and increased patient volume and diversity. There was angst expressed about the unknown RCT results. While there were concerns about standardizing the acupuncture session ("dilutes the power of acupuncture therapeutics"), the acupuncturists' were supportive of the pre-established protocol. The acupuncturists overall did not have concerns with a sham intervention arm because the sham recipients did not know their treatment arm and felt as satisfied with study participation as the true acupuncture recipients. CONCLUSIONS: Despite initial misgivings about both a standardized protocol and a sham arm, all practitioners discovered positive aspects of being a study acupuncturist. The analysis highlights the need for communication before, during and after a clinical trial between the study investigators and the intervention practitioners. As stake holders in the perception of CAM therapies with the public and with conventional medicine practitioners, it would benefit future research on CAM to similarly assess experiences of being a CAM study practitioner in order to enhance provider recruitment and reduce provider drop-out.

Chemoradiation with and without adjuvant extrafascial hysterectomy for IB2 cervical carcinoma.

The optimal treatment strategy for stage IB2 cervical carcinoma that maximizes survival while minimizing toxicity remains controversial. The purpose of this study was to compare survival and toxicity in stage IB2 cervical cancer patients treated with chemoradiation and adjuvant extrafascial hysterectomy (cRT + H) versus definitive chemoradiation (cRT). Data were abstracted from patients with IB2 cervical carcinoma primarily treated at a single institution from January 1994 to December 2004. All patients received chemotherapy concurrent with external beam radiation therapy. Patients were subsequently treated with either a single low-dose rate brachytherapy applicator followed by adjuvant extrafascial hysterectomy (n = 24) or a second brachytherapy application to complete full-dose definitive chemoradiation (n = 30). Analyses were conducted using Kaplan-Meier survival and Chi-square statistics. Groups did not differ demographically with the exception of smoking. Smokers were significantly (P = 0.04) more likely to have been treated with definitive chemoradiation. Median tumor size was similar between groups. There was no difference in overall or disease-free survival between patients who received cRT + H versus cRT (P = 0.82 and 0.75, respectively). All recurrences in the cRT arm were in smokers. There were two grade 3-4 toxicities in each group. No treatment-related deaths occurred. In this small retrospective cohort study, we observed no difference in survival between patients treated with cRT + H versus cRT. These data complement published results of Gynecologic Oncology Group studies in patients with IB2 cervical cancer. Definitive comparison between the two treatment strategies would require a randomized prospective trial with stratification based on smoking.

Predictors of suboptimal surgical cytoreduction in women with advanced epithelial ovarian cancer treated with initial chemotherapy.

The objective of this study was to retrospectively evaluate predictors of suboptimal surgical cytoreduction (SSC) in women with advanced epithelial ovarian cancer (EOC) treated with initial chemotherapy (IC). All women with EOC treated with IC at our hospital between January 1, 1995, and January 1, 2003, were eligible; 128 patients met inclusion criteria and underwent retrospective chart review. Eighty-four patients (66%) had an optimal surgical cytoreduction (OSC), 14 patients (11%) had an SSC, and 30 (23%) patients were treated with chemotherapy only (CO). Patients in the SSC group had more small-bowel mesentery disease on preoperative computed tomography (CT) scan compared to the OSC group (38% SSC vs 6% OSC, P = 0.024). Patients in the SSC group were also more likely to have disease on the liver surface, small-bowel surface, large-bowel mesentery, bladder peritoneum, spleen, and diaphragm that was not reported on preoperative CT but found at surgery. More patients in the SSC group had chemoresistant disease (indicated by stable or progressive disease on CT scan [56% SSC vs 17% OSC, P = 0.05]) and less of a decrease in their CA-125 values (69% SSC vs 93% OSC, P

Bacterial vaginosis and cervical dilation and effacement at 24-29 weeks' gestation.

The purpose of this study was to investigate the association between bacterial vaginosis (BV) and cervical dilation and effacement, as measures of impending preterm delivery. The Pregnancy, Infection, and Nutrition Study collected genital tract specimens and documented cervical change from 807 eligible women between 24 and 29 weeks' gestation. BV was assessed with Nugent-scored vaginal smears, and analyzed in relation to cervical measurements. At 24-29 weeks' gestation, <7% of women had a dilated cervix, 31% had a cervix < or =2 cm, and 17.3% had BV. Unadjusted analyses found no associations between BV and cervical measurements. Adjusted logistic regression suggested an association between BV and cervical effacement among women with a sexually transmitted disease (STD) earlier in pregnancy (odds ratio = 1.9, 95% CI 0.8-4.3). Stratified analyses for BV/dilation also suggested interaction with STDs. Overall, BV was not association with cervical dilation or effacement at 24-29 weeks' gestation.

Actin coating of secretory granules during regulated exocytosis correlates with the release of rab3D.

The present study describes a novel phenomenon in pancreatic acinar cells undergoing regulated exocytosis. When acinar cell preparations were challenged with the secretagogue carbamylcholine, a subpopulation of zymogen granules became coated with filamentous actin. These zymogen granules were always in proximity of the acinar cell apical membrane (the site of exocytosis) but did not appear to have fused yet. They were distinct from regular zymogen granules not only because of their association with filamentous actin, but also because the majority of them lacked the zymogen granule marker rab3D, a small GTPase implicated in regulated exocytosis. The apparent loss of rab3D, presumed to result from the release of rab3D from the granule membranes, could be prevented by agents that modulate the actomyosin system as well as by GTP[gammaS]. These data suggest that zymogen granules engaging in exocytosis become coated with actin before fusion and that this actin coating is tightly coupled to the release of rab3D. We propose that rab3D is involved in the regulation of actin polymerization around secretory granules and that actin coating might facilitate the movement of granules across the subapical actin network and toward their fusion site.

Risk of stillbirth from medications, illnesses and medical procedures.

Associations between stillbirth and 14 medical exposures during pregnancy were examined using deliveries in 1984 in 10 California counties. Cases (n = 332) were stillbirths and infant deaths within 24 h of birth. Randomly selected live births served as controls (n = 357) and were frequency matched by maternal age and county. Using questionnaire and vital statistics data, logistic regression and proportional hazards modelling were performed with adjustment for potential confounders. The most prevalent exposures were ultrasound (65% of cases, 58% of controls) and acetaminophen (45% of cases, 54% of controls). Prescription pain medication, when taken in the first 2 gestational months, was strongly associated with stillbirths due to congenital anomalies (odds ratio = 7.5, 95% confidence interval [CI] 2.3, 24.1). First and second trimester use of prescription pain or migraine medication was positively associated with all stillbirths (rate ratio [RR] range 1.3-1.6). Fertility drugs were positively associated with stillbirths in total and stillbirths due to complications of the placenta, cord and membranes (RR = 1.8, 95% CI 0.8, 4.1; and RR = 2.5, 95% CI 0.9, 7.2 respectively). No associations were found for aspirin, amniocentesis, diagnostic X-rays or fever, consistent with previous studies. This report is among the few studies of specific causes of stillbirth and medical exposures by gestational time window.

Predictors of urinary tract infection at the first prenatal visit.

We identified maternal demographic, behavioral, and medical history factors that predict bacteriuria (that is, symptomatic and asymptomatic urinary tract infection) at prenatal care initiation. We applied logistic regression modeling to data from all prenatal care recipients who delivered during 1990-1993 and resided in selected North Carolina counties (N = 8037), omitting those with diabetes mellitus, human immunodeficiency virus, or structural urologic abnormalities. The two strongest predictors of bacteriuria at prenatal care initiation were an antepartum urinary tract infection prior to prenatal care initiation (for whites, adjusted prevalence odds ratio (POR) = 2.5, 95% CI 0.6-9.8; for blacks, POR = 8.8, 95% CI 3.8-20.3) and a pre-pregnancy history of urinary tract infection (POR = 2.1, 95% CI 1.4-3.2). For white women only, education beyond high school and age > or =30 years were inversely associated (POR < or = 0.6). Sickle cell hemoglobin nearly doubled the prevalence odds for bacteriuria among African-Americans (POR = 1.9, 95% CI 1.0-3.5), whereas African-Americans with normal hemoglobin had reduced prevalence odds compared with whites (POR = 0.6, 95% CI 0.4-0.9). This study suggests predictors not considered before, including race controlling for sickle cell disease or trait and antepartum urinary tract infections prior to prenatal care.

Race/ethnicity, vaginal flora patterns, and pH during pregnancy.

OBJECTIVES: To investigate the relationship between bacterial vaginosis during pregnancy and black race/ethnicity. STUDY DESIGN: Gram staining was used to evaluate vaginal flora in 842 women at 24 to 29 weeks' gestation. RESULTS: Overall, 22.3% of blacks and 8.5% of whites had bacterial vaginosis. Vaginal pH and flora differed significantly by race/ethnicity; blacks were more likely to have pH > or = 4.5, no lactobacilli, small gram-variable and -negative rods, and Mobiluncus compared with whites (odds ratios 1.6, 1.5, 1.4, and 10.6, respectively). Quantity of morphotypes also differed, especially for Mobiluncus. Among women with Mobiluncus present (12.0% of blacks and 1.3% of whites), 73.3% of blacks compared with 40.0% of whites had the highest level. Adjustment for sociodemographics, sexual activity, sexually transmitted diseases, health behavior, and sexual hygiene did not explain these differences. CONCLUSION: We observed race/ethnicity differences in vaginal flora ecology. These differences may ultimately play a role in the larger proportion of preterm deliveries among black women compared with white women.

Association between bacterial vaginosis and fetal fibronectin at 24-29 weeks' gestation.

OBJECTIVE: To investigate the relationship between fetal fibronectin and bacterial vaginosis, which are associated with an increased risk for preterm delivery. METHODS: Researchers for the Pregnancy, Infection and Nutrition Study, a cohort study of pregnant women at three central North Carolina sites, collected genital tract specimens from all enrolled women between 24 and 29 weeks' gestation. Among women with last menstrual periods between March 10, 1995, and August 15, 1996, 868 pregnancies were eligible for this analysis. Fetal fibronectin was assessed by a dipstick immunoassay kit. Bacterial vaginosis was evaluated by Nugent-scored, Gram-stained vaginal smears (scores of 7-10 considered positive). RESULTS: Overall, 6.3% of women had positive fetal fibronectin test results, and 18.8% had bacterial vaginosis. The unadjusted relative risk (RR) of fetal fibronectin-positivity comparing women with bacterial vaginosis to those without bacterial vaginosis was 1.6 (95% confidence interval [CI] 1.1, 2.5). Using multiple logistic regression to adjust for race, maternal age, parity, and location of care, women who had bacterial vaginosis and smoked at the time of recruitment were at substantially increased risk of fetal fibronectin-positivity (RR 7.8, 95% CI 2.2, 27.8) compared with smokers without bacterial vaginosis. Among nonsmokers, bacterial vaginosis was not associated with fetal fibronectin-positivity (RR 1.0, 95% CI 0.4, 2.4). These results were essentially unchanged after adding the requirement of vaginal pH exceeding 4.5 to the bacterial vaginosis definition. CONCLUSION: Fetal fibronectin was associated positively with bacterial vaginosis, but only among women who smoked. These results might provide clues as to the biologic relationship between smoking, infection, and preterm delivery.

Predictors of symptomatic urinary tract infection after 20 weeks' gestation.

OBJECTIVE: To identify predictors of symptomatic urinary tract infection (UTI) after 20 weeks' gestation. STUDY DESIGN: A retrospective cohort analysis was conducted of all deliveries at three North Carolina hospitals between 1990 and 1993. A total of 7403 deliveries remained after exclusions (pre-pregnancy diabetes, HIV-positive, structural urologic abnormalities, no prenatal care) and restrictions (black or white race, county of residence). Cystitis and pyelonephritis were identified by clinician diagnosis. Multiple logistic regression was conducted. RESULTS: Prior UTIs (both before and earlier in pregnancy), nonprivate clinics, and a history of chlamydia (white women only) doubled the risk of symptomatic UTIs after 20 weeks' gestation. The strongest predictor of pyelonephritis was prior antenatal UTIs (adjusted incidence odds ratio = 5.3, 95% confidence interval of 2.6-11.0), followed by less education (< 12 years), a history of chlamydia, nonprivate clinics, illicit drug use, sickle cell hemoglobinopathy, and being unmarried. CONCLUSION: Medical history and demographic factors predict cystitis and pyelonephritis after 20 weeks' gestation. Prospective studies of pyelonephritis predictors and screening strategies are warranted.

Risk of stillbirth from occupational and residential exposures.

OBJECTIVES: To analyse the risk of stillbirth from 12 residential and occupational maternal exposures during pregnancy. METHODS: Stillbirths and neonatal deaths in 1984 within 24 hours of birth from 10 California counties were identified from death certificates. Controls were randomly selected from live births born in 1984 and frequency matched to cases by maternal age and county. Data sources included vital statistics and a self-administered postal questionnaire. Logistic regression and proportional hazards modelling were performed; the proportional hazards considered the truncated opportunity for exposure among cases. Special focus was given to two cause of deaths groups: congenital anomalies (12% of deaths) and complications of the placenta, cord, and membranes (37% of deaths). RESULTS: Occupational exposure to pesticides during the first two months of gestation was positively associated with stillbirths due to congenital anomalies (odds ratio (OR) 2.4, 95% confidence interval (95% CI) 1.0 to 5.9), and during the first and second trimesters with stillbirths due to all causes of death (risk ratios (RR) 1.3-1.4, 95% CI 1.0 to 1.7) and stillbirths due to complications of the placenta, cord, and membranes (RR 1.6-1.7, 95% CI 1.1 to 2.3). Occupational exposure to video display terminals in the third trimester was found to have a modest inverse association with stillbirths (RR 0.7, 95% CI 0.6, 0.9). Home pesticide exposure was positively associated with stillbirths due to congenital anomalies (OR 1.7, 95% CI 1.0 to 2.9). CONCLUSIONS: Occupational exposure to pesticides, especially during early pregnancy, had a clear positive association with stillbirths regardless of cause of death. Methodologically, this study of stillbirths is unique in its analysis of specific causes of death and use of time specific exposure windows.

Timing and patterns of exposures during pregnancy and their implications for study methods.

Patterns of exposure variability across pregnancy were examined for medical, lifestyle, residential, and occupational exposures in a population-based sample of 357 livebirths from 10 rural California counties. A new measure of variability, the ratio of overall prevalence to time-window-specific prevalence, is introduced. The higher the overall : time window (OTW) ratio, the greater the potential for misclassification when using anytime-during-pregnancy prevalence for an agent that exerts its effect in a smaller time window. Exposures to cigarettes, marijuana, saunas/hot tubs, factors related to location of residence, and some workplace substances tended to be of longer duration. Intertrimester concordance was high (kappa's > 0.8) for smoking, residential proximity to crops, and use of video display terminals; moderately high (kappa's between 0.4 and 0.8) for many occupational exposures; and low (kappa's < 0.4) for illnesses, which tended to be of short duration. The lowest OTW ratios were for smoking and some residential exposures (1.1-1.3), while OTW ratios were much higher for paint applications, influenza, vaginal infections, and ultrasound (reaching, e.g., 4-6). Use of anytime-during-pregnancy exposure indices can bias measures of association between risk factors and adverse pregnancy outcomes, particularly if the OTW ratio is high. Misclassification bias occurs if there is a vulnerable time window during which the exposure exerts its effect. The misclassification can be differential when the average length of gestation of cases is shorter than that of controls. For exposures that vary, investigations of pregnancy outcome should collect as much detail as feasible regarding timing.

Drinking water and pregnancy outcome in central North Carolina: source, amount, and trihalomethane levels.

In spite of the recognition of potentially toxic chemicals in chlorinated drinking water, few studies have evaluated reproductive health consequences of such exposure. Using data from a case-control study of miscarriage, preterm delivery, and low birth weight in central North Carolina, we evaluated risk associated with water source, amount, and trihalomethane (THM) concentration. Water source was not related to any of those pregnancy outcomes, but an increasing amount of ingested water was associated with decreased risks of all three outcomes (odds ratios around 1.5 for 0 glasses per day relative to 1-3 glasses per day, falling to 0.8 for 4+ glasses per day). THM concentration and dose (concentration x amount) were not related to pregnancy outcome, with the possible exception of an increased risk of miscarriage in the highest sextile of THM concentration (adjusted odds ratio = 2.8, 95% confidence interval = 1.1-2.7), which was not part of an overall dose-response gradient. These data do not indicate a strong association between chlorination by-products and adverse pregnancy outcome, but given the limited quality of our exposure assessment and the increased miscarriage risk in the highest exposure group, more refined evaluation is warranted.

Case-control study of caffeinated beverages and preterm delivery.

Although many women reduce their caffeine consumption once they known they are pregnant, 70-80% of pregnant women still consume caffeine. To evaluate the relation between caffeine consumption and preterm delivery, a case-control study was conducted to identify all preterm (< 37 weeks gestation) infants born to women in selected North Carolina counties from September 1988 through April 1991. Randomly selected full-term, normal-weight livebirths (matched by race and hospital) served as controls. The study population consisted of 408 cases and 490 controls. Telephone interviews with participants assessed the consumption of caffeinated coffee, tea, cola soft drinks, and noncola caffeinated soft drinks, with caffeine consumption measured by the number of daily servings of each beverage and the total milligrams of caffeine. Third-trimester caffeine consumption from all beverages combined showed a nonsignificant inverse association with preterm delivery. Both first- and second-trimester consumption of 1-150 mg/day were associated with a modestly increased risk of preterm delivery, while no association was found at higher consumption levels. Overall, these results do not support an association between caffeinated beverage consumption and preterm delivery, as is true in most previous studies.

Infant mortality by Hispanic origin of mother: 20 States, 1985-87 birth cohorts.

This report examines the mortality experience of infants born between 1985 and 1987 to mothers of Hispanic origin who resided in a study area of 20 States and the District of Columbia and compares it with that of non-Hispanic white infants. Maternal characteristics are also compared. For all Hispanic-origin mothers combined, the infant mortality rate (8.5) was very close to the non-Hispanic white rate (8.3). Among the Hispanic-origin subgroups, the rate for Puerto Rican mothers was higher (10.9) and the rate for Central and South American mothers lower (7.8) than the non-Hispanic white rate. The infant mortality rates of 8.2 for Mexicans and 7.6 for Cubans were not significantly different from the non-Hispanic white rate. The infant mortality experience of the Hispanic-origin population has been termed an ''epidemiological paradox,'' because of their generally favorable birth outcomes despite a higher prevalence of socioeconomic and demographic risk factors. In general, a higher proportion of Hispanic than non-Hispanic white infants were born to mothers traditionally considered to be at elevated risk for infant mortality-teenagers, unmarried mothers, those who have not completed high school, and those beginning prenatal care after the first trimester or not at all. In general, infant mortality rates were higher for these high-risk groups among Hispanic as well as non-Hispanic white mothers. However, the difference in infant mortality rates between high-risk and low-risk groups for each of these maternal characteristics was less for some Hispanic origin subgroups than for non-Hispanic whites.