Penelope P. Howards

Timing Clinic Visits to Phases of the Menstrual Cycle by Using a Fertility Monitor: The BioCycle Study

Planning study visits during specific menstrual cycle phases is important if the exposure or outcome is influenced by hormonal variation. However, hormone profiles differ across cycles and across women. The value of using fertility monitors to time clinic visits was evaluated in the BioCycle Study (2005-2007). Women aged 18-44 years (mean, 27.4) with self-reported menstrual cycle lengths of 21-35 days were recruited in Buffalo, New York, for 2 cycles (n = 250). Participants were provided with home fertility monitors that measured urinary estrone-3-glucuronide and luteinizing hormone (LH). The women were instructed to visit the clinic for a blood draw when the monitor indicated an LH surge. The monitor recorded a surge during 76% of the first cycles and 78% of the second cycles. Scheduling visits by using set cycle days or algorithms based on cycle length, such as a midcycle window or a window determined by assuming a fixed luteal phase length, would be simpler. However, even with perfect attendance in a 3-day window, these methods would have performed poorly, capturing the monitor-detected LH surge only 37%-57% of the time. Fertility monitors appear to be useful in timing clinic visits in a compliant population with flexible schedules.

Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study

Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark, 1997-2008. Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.

The association between cadmium, lead and mercury blood levels and reproductive hormones among healthy, premenopausal women

BACKGROUND Cadmium, lead and mercury have been identified in human follicular fluid and ovarian tissue, and have been associated with adverse reproductive outcomes in epidemiologic studies; however, few studies have examined the relationship between blood metal levels and reproductive hormones. METHODS Among 252 premenopausal women aged 18-44 years, we examined the association between blood metal levels (cadmium, lead and mercury), cycle length, and reproductive hormones [FSH, LH, estradiol (E(2)) and progesterone] measured at clinically relevant time points in the menstrual cycle. The association between metal levels (continuous) and hormone levels was assessed using linear regression with hormone levels (natural) log transformed and the results interpreted as the percentage difference in hormone level per unit increase in metal level. RESULTS Median (interquartile range) cadmium, lead and mercury levels were 0.30 µg/l (0.19, 0.43), 0.87 µg/dl (0.68, 1.20) and 1.10 µg/l (0.58, 2.10), respectively. Each 1 µg/l increase in cadmium levels was associated with a 21% [95% confidence interval (CI): -2.9, 49.9] increase in early follicular phase E(2) levels after adjusting for age, race/ethnicity, lead and mercury. This association decreased when restricted to never smokers (10%; 95% CI: -19.5, 51.3). Cadmium was also associated with a non-significant 9% (95% CI: -0.2, 19.9), or 2.7 day, increase in cycle length among never smokers. No associations were observed between lead or mercury and the outcomes in adjusted analyses. CONCLUSIONS Further evaluation of the association between cadmium, E(2) and cycle length is warranted, taking into consideration cigarette smoke and its multiple components.

Spontaneous Abortion and a Diet Drug Containing Caffeine and Ephedrine: A Study within the Danish National Birth Cohort

Background Medications may be consumed periconceptionally before a woman knows she is pregnant. In this study, the authors evaluate the association of a prescription diet drug (Letigen) containing ephedrine (20 mg) and caffeine (200 mg) with spontaneous abortion (SAB) in the Danish National Birth Cohort. Methods Women were recruited during their first prenatal visit from 1996–2002. Pre-conception and early pregnancy medication use was reported on the enrollment form, and pregnancy outcome was determined by linking the mothers Civil Registration Number to the Medical Birth Registry and the National Hospital Discharge Register. Of 97,903 eligible pregnancies, 4,443 ended in SAB between 5 and 20 completed gestational weeks, inclusive. Letigen use was reported for 565 pregnancies. Cox regression models accounting for left truncation were fit to estimate the effect of pre-conception and early pregnancy Letigen use on SAB. Principal Findings The estimated maternal age-adjusted hazard ratio for SAB was 1.1 (95% confidence interval 0.8–1.6) for any periconceptional Letigen use compared to no periconceptional use. Conclusions Although Letigen has high levels of caffeine (the recommended 3 pills/day are approximately equivalent to caffeine from 6 cups of coffee), periconceptional use does not appear to be associated with an appreciably increased hazard of clinically recognized SAB.

Serum polybrominated diphenyl ether concentrations and thyroid function in young children

Thyroid hormones are essential for proper neurodevelopment in early life. There is evidence that exposure to polybrominated diphenyl ethers (PBDEs) affects thyroid function, but previous studies have been inconsistent, and no studies among children have been conducted in the United States where PBDE levels are particularly high. Serum levels of seven PBDE congeners and thyroid hormones and other thyroid parameters were measured in 80 children aged 1-5 years from the southeastern United States between 2011 and 2012. Parents of the children completed questionnaires with details on demographics and behaviors. Multivariate linear regression models were used to estimate the associations between serum PBDE levels, expressed as quartiles and as log-transformed continuous variables, and markers of thyroid function. BDE-47, 99, 100 and 153 were detected in >60% of samples, and were summed (∑PBDE). PBDE congeners and ∑PBDE were positively associated with thyroid-stimulating hormone (TSH). A log-unit increase in ∑PBDE was associated with a 22.1% increase in TSH (95% CI: 2.0%, 47.7%). Compared with children in the lowest quartile of ∑PBDE exposure, children in higher quartiles had greater TSH concentrations as modeled on the log-scale (second quartile: β=0.32, 95% confidence interval (CI): -0.09, 0.74; third quartile: β=0.44, 95% CI: 0.04, 0.85; and fourth quartile: β=0.49, 95% CI: 0.09, 0.89). There was also a tendency toward lower total T4 and higher free T3 with increasing PBDE exposure. Results suggest that exposure to PBDEs during childhood subclinically disrupts thyroid hormone function, with impacts in the direction of hypothyroidism.

Diabetes mellitus is associated with cavities, smear grade, and multidrug-resistant tuberculosis in Georgia.

SETTING National tuberculosis (TB) treatment facility in the country of Georgia. OBJECTIVE To determine the prevalence of diabetes mellitus (DM) and pre-DM among patients with TB using glycosylated-hemoglobin (HbA1c), and to estimate the association between DM and clinical characteristics and response to anti-tuberculosis treatment. DESIGN A cohort study was conducted from 2011 to 2014 at the National Centre for TB and Lung Disease in Tbilisi. Patients aged ⩾ 35 years with pulmonary TB were included. HbA1c was used to define DM (⩾ 6.5%), pre-DM (⩾ 5.7-6.4%), and no DM (<5.7%). Interviews and medical chart abstraction were performed. Regression analyses estimated associations between DM and 1) baseline TB characteristics and 2) anti-tuberculosis treatment outcomes. RESULTS A total of 318 newly diagnosed patients with TB were enrolled. The prevalence of DM and pre-DM was 11.6% and 16.4%, respectively. In multivariable analyses, patients with TB-DM had more cavitation (adjusted OR [aOR] 2.26), higher smear grade (aOR 2.37), and more multidrug-resistant TB (MDR-TB) (aOR 2.27) than patients without DM. The risk of poor anti-tuberculosis treatment outcomes was similar among patients with and those without DM (28.1% vs. 23.6%). CONCLUSION DM and pre-DM were common among adults with newly diagnosed pulmonary TB in Tbilisi, Georgia, and DM was associated with more clinical symptoms, and MDR-TB, at presentation.

Diabetes Mellitus, Smoking Status, and Rate of Sputum Culture Conversion in Patients with Multidrug-Resistant Tuberculosis: A Cohort Study from the Country of Georgia

Introduction Diabetes mellitus (DM) is a risk factor for active tuberculosis (TB) but little is known about the effect of DM on culture conversion among patients with multidrug-resistant (MDR)-TB. The primary aim was to estimate the association between DM and rate of TB sputum culture conversion. A secondary objective was to estimate the association between DM and the risk of poor treatment outcomes among patients with MDR-TB. Materials and Methods A cohort of all adult patients starting MDR-TB treatment in the country of Georgia between 2009–2011 was followed during second-line TB therapy. Cox proportional models were used to estimate the adjusted hazard rate of sputum culture conversion. Log-binomial regression models were used to estimate the cumulative risk of poor TB treatment outcome. Results Among 1,366 patients with sputum culture conversion information, 966 (70.7%) had culture conversion and the median time to conversion was 68 days (interquartile range 50–120). The rate of conversion was similar among patients with MDR-TB and DM (adjusted hazard ratio [aHR] 0.95, 95%CI 0.71–1.28) compared to patients with MDR-TB only. The rate of culture conversion was significantly less in patients that currently smoked (aHR 0.82, 95%CI 0.71–0.95), had low body mass index (aHR 0.71, 95%CI 0.59–0.84), second-line resistance (aHR 0.56, 95%CI 0.43–0.73), lung cavities (aHR 0.70, 95%CI 0.59–0.83) and with disseminated TB (aHR 0.75, 95%CI 0.62–0.90). The cumulative risk of poor treatment outcome was also similar among TB patients with and without DM (adjusted risk ratio [aRR] 1.03, 95%CI 0.93–1.14). Conclusions In adjusted analyses, DM did not impact culture conversion rates in a clinically meaningful way but smoking did.

Menses resumption after cancer treatment–induced amenorrhea occurs early or not at all

OBJECTIVE To identify factors associated with cancer treatment-induced amenorrhea and time to return of menses. DESIGN Population-based cohort study. SETTING Not applicable. PATIENT(S) Female cancer survivors who were diagnosed with cancer between the ages of 20 and 35 and were at least 2 years postdiagnosis at the time of recruitment (median = 7 years; interquartile range, 5-11). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Amenorrhea (≥6 months without menses) and resumption of menses. RESULT(S) After excluding women with hysterectomies before cancer diagnosis, 1,043 women were eligible for analysis. Amenorrhea occurred in 31.6% of women. Among women treated with chemotherapy (n = 596), older age at diagnosis (30-35 vs. 20-24 years: adjusted odds ratio [aOR] = 2.37; 95% confidence interval [CI], 1.30, 4.30) and nulligravidity (vs. gravid: aOR = 1.50; 95% CI, 1.02, 2.21) were risk factors for amenorrhea. Among amenorrheic women, menses resumed in most (70.0%), and resumption occurred within 2 years of treatment for 90.0% of women. Survivors of breast cancer were more likely to resume menses at times greater than 1 year compared with lymphoma and pelvic-area cancers. Women diagnosed at older ages, those exposed to chemotherapy, and those exposed to any radiation experienced longer times to return of menses. Women who were older at diagnosis were more likely to have irregular cycles when menses returned. CONCLUSION(S) Treatment-induced amenorrhea is common in cancer survivors, although most women resume menses within 2 years. However, once resumed, older women are more likely to have irregular cycles. Age at diagnosis and pregnancy history affect the risk of amenorrhea.

PFOA and PFOS serum levels and miscarriage risk.

Background: Serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were assessed in relation to miscarriage in a population of mid-Ohio River Valley residents highly exposed to PFOA through contaminated drinking water. Methods: Serum PFOA and PFOS concentrations were measured in 1129 women in 2005–2006 who reported pregnancy outcomes in follow-up interviews between 2008 and 2011. In the analysis, we included 1438 reported live births, stillbirths, and miscarriages with estimated conception dates after the serum measurements. Preconception serum levels of PFOA and PFOS were analyzed in relation to miscarriage using logistic regression and generalized estimating equations. Results: There was little evidence of association between PFOA and miscarriage. For PFOS, when including all reported prospective pregnancies, the odds ratio of miscarriage per log ng/ml increase was 1.21 (95% confidence interval = 0.94–1.55); in subanalyses restricted to each woman’s first pregnancy conceived after the serum measurement, the odds ratio was 1.34 (1.02–1.76). Categorical analyses showed elevated odds ratios for the top 4 quintiles relative to the first quintile, without a monotonic trend. Positive associations between PFOS and miscarriage were strongest among nulligravid pregnancies. Conclusions: In this prospective study of miscarriage in a population exposed to high levels of PFOA and background levels of PFOS, we found little evidence of association with serum levels of PFOA and limited evidence of association with serum levels of PFOS.

Potential sensitivity of bias analysis results to incorrect assumptions of nondifferential or differential binary exposure misclassification.

Background: Results of bias analyses for exposure misclassification are dependent on assumptions made during analysis. We describe how adjustment for misclassification is affected by incorrect assumptions about whether sensitivity and specificity are the same (nondifferential) or different (differential) for cases and noncases. Methods: We adjusted for exposure misclassification using probabilistic bias analysis, under correct and incorrect assumptions about whether exposure misclassification was differential or not. First, we used simulated data sets in which nondifferential and differential misclassification were introduced. Then, we used data on obesity and diabetes from the National Health and Nutrition Examination Survey (NHANES) in which both self-reported (misclassified) and measured (true) obesity were available, using literature estimates of sensitivity and specificity to adjust for bias. The ratio of odds ratio (ROR; observed odds ratio divided by true odds ratio) was used to quantify magnitude of bias, with ROR = 1 signifying no bias. Results: In the simulated data sets, under incorrect assumptions (eg, assuming nondifferential misclassification when it was truly differential), results were biased, with RORs ranging from 0.18 to 2.46. In NHANES, results adjusted based on incorrect assumptions also produced biased results, with RORs ranging from 1.26 to 1.55; results were more biased when making these adjustments than when using the misclassified exposure values (ROR = 0.91). Conclusions: Making an incorrect assumption about nondifferential or differential exposure misclassification in bias analyses can lead to more biased results than if no adjustment is performed. In our analyses, incorporating uncertainty using probabilistic bias analysis was not sufficient to overcome this problem.