The impact of maternal age on fetal death: Does length of gestation matter? Am J Obstet Gynecol. 2010 Aug 26. [Epub ahead of print]

Objective: The objective of the investigation was to study the association of fetal death with maternal age by length of gestation.

Study Design: This was a population study including all ongoing pregnancies after 16 weeks of gestation in Norway during the period 1967–2006 (n = 2,182,756).

Results: The risk of fetal death was 1.4 times higher in women 40–44 years old than in women aged 20–24 years in mid pregnancy but 2.8 times higher at term. In term pregnancies the relative importance of maternal age increased by additional pregnancy weeks. In gestational weeks 42–43, the crude risk was 5.1 times higher in mothers 40 years old or older. In the recent period, the elevated risk of fetal death in elderly mothers at term has been attenuated.

Conclusion: Women 40 years old or older had the highest risk of fetal death throughout pregnancy, particularly in term and postterm pregnancies. Improved obstetric care may explain the attenuation of risk associated with age in recent time.

Delivery outcome of women with epilepsy: A population-based cohort study. BJOG. 2010 Aug 18. [Epub ahead of print] DOI:10.1111/j.1471-0528.2010.02694.x

Objective: To investigate whether women with epilepsy have increased risks of complications during labour, and to explore the impact of antiepileptic drug use.

Design: Population-based cohort study.

Setting: Data from the Medical Birth Registry of Norway 1999–2005.

Population: All births (n = 372 128) delivered in Norway, ensured through linkage with the National Population Registry run by Statistics Norway. All singleton births and the first child in multiple pregnancies were included, leaving 365,107 pregnancies for analysis.

Methods: Data from the Medical Birth Registry of Norway 1999–2005 were analysed.

Main Outcome Measures: Induction, caesarean section, use of forceps and vacuum, abnormal presentation, placental abruption, mechanical disproportion, postpartum haemorrhage, atony and Apgar score < 7 after 5 minutes.

Results: We compared 2805 pregnancies in women with a current or past history of epilepsy (0.8%) and 362 302 pregnancies in women without a history of epilepsy. Antiepileptic drugs were used in 33.6% (n = 942) of pregnant women with epilepsy. Women with epilepsy had an increased risk of induction [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.1–1.4], caesarean section (OR, 1.4; 95% CI, 1.3–1.6) and postpartum haemorrhage (OR, 1.2; 95% CI, 1.1–1.4) compared with women without epilepsy. These rates were even higher for women with epilepsy and antiepileptic drug use, with ORs (95% CIs) of 1.6 (1.4–1.9), 1.6 (1.4–1.9) and 1.5 (1.3–1.9), respectively. In addition, the risk of an Apgar score < 7 was higher (OR, 1.6; 95% CI, 1.1–2.4). For women with epilepsy without antiepileptic drug use, only a slightly increased risk of caesarean delivery was observed and no increased risk for any other complications studied.

Conclusions: Pregnant women with epilepsy have a low complication rate; however, they have a slightly increased risk of induction, caesarean section and postpartum haemorrhage. It is not possible to ascertain on the basis of this study whether this is a result of more severe epilepsy or antiepileptic drug use.

Migraine and risk of haemorrhagic stroke in women: Prospective cohort study. BMJ. 2010 Aug 24;341:c3659. doi: 10.1136/bmj.c3659.

Objectives: To examine the association between migraine and migraine aura status with risk of haemorrhagic stroke.

Design: Prospective cohort study.

Setting: Women's Health Study, United States.

Participants: 27,860 women aged > or = 45 who were free from stroke or other major disease at baseline and had provided information on self-reported migraine, aura status, and lipid values.

Main Outcome Measures: Time to first haemorrhagic stroke and subtypes of haemorrhagic stroke.

Results: At baseline, 5130 (18%) women reported any history of migraine; of the 3612 with active migraine (migraine in the previous year), 1435 (40%) described having aura. During a mean of 13.6 years of follow-up, 85 haemorrhagic strokes were confirmed after review of medical records. Compared with women without a history of migraine, there was no increased risk of haemorrhagic stroke in those who reported any history of migraine (adjusted hazard ratio 0.98, 95% confidence interval 0.56 to 1.71, p = 0.93). In contrast, risk was increased in women with active migraine with aura (2.25, 1.11 to 4.54, p = 0.024). The age adjusted increased risk was stronger for intracerebral haemorrhage (2.78, 1.09 to 7.07, p = 0.032) and for fatal events (3.56, 1.23 to 10.31, p = 0.02). Four additional haemorrhagic stroke events were attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura had no increased risk for haemorrhagic stroke.

Conclusion: Migraine with aura might, in addition to ischaemic events, also be a risk factor for haemorrhagic stroke. The relatively low number of events and attributable risk should caution against definitive conclusions and call for further confirmation of these observations.

Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: Systematic review and meta-analysis of data from individual patients. BMJ. 2010 Aug 16;341:c3929. doi: 10.1136/bmj.c3929.

Objective: To evaluate the relative effectiveness of hysterectomy, endometrial destruction (both "first generation" hysteroscopic and "second generation" non-hysteroscopic techniques), and the levonorgestrel releasing intrauterine system (Mirena) in the treatment of heavy menstrual bleeding.

Design: Meta-analysis of data from individual patients, with direct and indirect comparisons made on the primary outcome measure of patients' dissatisfaction.

Data Sources: Data were sought from the 30 randomised controlled trials identified after a comprehensive search of the Cochrane Library, Medline, Embase, and CINAHL databases, reference lists, and contact with experts. Raw data were available from 2814 women randomised into 17 trials (seven trials including 1359 women for first v second generation endometrial destruction; six trials including 1042 women for hysterectomy v first generation endometrial destruction; one trial including 236 women for hysterectomy v Mirena; three trials including 177 women for second generation endometrial destruction v Mirena).

Eligibility Criteria for Selecting Studies: Randomised controlled trials comparing hysterectomy, first and second generation endometrial destruction, and Mirena for women with heavy menstrual bleeding unresponsive to other medical treatment.

Results: At around 12 months, more women were dissatisfied with outcome with first generation hysteroscopic techniques than with hysterectomy (13% v 5%; odds ratio 2.46, 95% confidence interval 1.54 to 3.9, p < 0.001), but hospital stay (weighted mean difference 3.0 days, 2.9 to 3.1 days, p < 0.001) and time to resumption of normal activities (5.2 days, 4.7 to 5.7 days, p < 0.001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (odds ratio 1.2, 0.9 to 1.6, p = 0.2), although second generation techniques were quicker (weighted mean difference 14.5 minutes, 13.7 to 15.3 minutes, p < 0.001) and women recovered sooner (0.48 days, 0.20 to 0.75 days, p < 0.001), with fewer procedural complications. Indirect comparison suggested more unsatisfactory outcomes with second generation techniques than with hysterectomy (11% v 5%; odds ratio 2.3, 1.3 to 4.2, p = 0.006). Similar estimates were seen when Mirena was indirectly compared with hysterectomy (17% v 5%; odds ratio 2.2, 0.9 to 5.3, p = 0.07), although this comparison lacked power because of the limited amount of data available for analysis.

Conclusions: More women are dissatisfied after endometrial destruction than after hysterectomy. Dissatisfaction rates are low after all treatments, and hysterectomy is associated with increased length of stay in hospital and a longer recovery period. Definitive evidence on effectiveness of Mirena compared with more invasive procedures is lacking.

Disparities in breast cancer mortality trends between 30 European countries: Retrospective trend analysis of WHO mortality database. BMJ. 2010 Aug 11;341:c3620. doi: 10.1136/bmj.c3620.

Objective: To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries.

Design: Retrospective trend analysis. Data source WHO mortality database on causes of deaths.

Subjects Reviewed: Female deaths from breast cancer from 1989 to 2006.

Main Outcome Measures: Changes in breast cancer mortality for all women and by age group (<50, 50–69, and > or = 70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change.

Results: From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by > or  = 20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987–9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were −37% (range −76% to −14%) in women aged <50, −21% (−40% to 14%) in 50–69 year olds, and −2% (−42% to 80%) in > or = 70 year olds.

Conclusions: Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality.

Major Dietary Protein Sources and Risk of Coronary Heart Disease in Women. Circulation. 2010 Aug 16. [Epub ahead of print]

Background: With the exception of fish, few major dietary protein sources have been studied in relation to the development of coronary heart disease (CHD). Our objective was to examine the relation between foods that are major dietary protein sources and incident CHD.

Methods and Results: We prospectively followed 84 136 women aged 30 to 55 years in the Nurses' Health Study with no known cancer, diabetes mellitus, angina, myocardial infarction, stroke, or other cardiovascular disease. Diet was assessed by a standardized and validated questionnaire and updated every 4 years. During 26 years of follow-up, we documented 2210 incident nonfatal infarctions and 952 deaths from CHD. In multivariable analyses including age, smoking, and other risk factors, higher intakes of red meat, red meat excluding processed meat, and high-fat dairy were significantly associated with elevated risk of CHD. Higher intakes of poultry, fish, and nuts were significantly associated with lower risk. In a model controlling statistically for energy intake, 1 serving per day of nuts was associated with a 30% (95% confidence interval, 17% to 42%) lower risk of CHD compared with 1 serving per day of red meat. Similarly, compared with 1 serving per day of red meat, a lower risk was associated with 1 serving per day of low-fat dairy (13%; 95% confidence interval, 6% to 19%), poultry (19%; 95% confidence interval, 3% to 33%), and fish (24%; 95% confidence interval, 6% to 39%).

Conclusions: These data suggest that high red meat intake increases risk of CHD and that CHD risk may be reduced importantly by shifting sources of protein in the US diet.

Hypertension in pregnancy and later cardiovascular risk: Common antecedents? Circulation. 2010;122:579–584. Epub 2010 Jul 26.

Background: Preeclampsia and gestational hypertension are associated with increased risk for cardiovascular disease later in life. We have assessed whether the effect can be attributed to factors that operate in pregnancy or to pre-pregnancy risk factors that are shared by both disorders.

Methods and Results: Longitudinal data from 2 consecutive waves of a Norwegian population-based study (the Nord-Trøndelag Health Study [HUNT]) were combined with data from the Medical Birth Registry of Norway. Among 24 865 women who had participated in both HUNT 1 and 2, we identified 3225 women with a singleton birth between the 2 studies who had standardized measurements of blood pressure, serum lipids, and body mass index. The crude results showed that women who experienced preeclampsia or gestational hypertension in pregnancy had substantially higher levels of body mass index and systolic and diastolic blood pressures and unfavorable lipids compared with other women. However, after adjustment for pre pregnancy measurements, the difference in body mass index was attenuated by >65%, and the difference in blood pressure was attenuated by approximately 50%. In relation to high-density lipoprotein cholesterol and triglycerides, differences between the groups were attenuated by 40% and 72%, respectively.

Conclusions: These results suggest that the positive association of preeclampsia and gestational hypertension with post pregnancy cardiovascular risk factors may be due largely to shared prepregnancy risk factors rather than reflecting a direct influence of the hypertensive disorder in pregnancy.

DHEA-S Levels and Cardiovascular Disease Mortality in Postmenopausal Women: Results from the National Institutes of Health—National Heart, Lung, and Blood Institute (NHLBI)-Sponsored Women's Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab. 2010 Aug 25. [Epub ahead of print]

Context: Dehydroepiandrosterone sulfate (DHEA-S), a major circulating sex steroid prohormone, declines with age. Low levels have been associated with increased cardiovascular disease (CVD) risk and all-cause mortality, although these results have not been consistently replicated, particularly in women.

Objective: Our objective was to examine the association of circulating DHEA-S levels, CVD, and mortality risk among postmenopausal women with suspected myocardial ischemia.

Design: In the Women's Ischemia Syndrome Evaluation, 270 postmenopausal women underwent coronary angiography and blood hormone levels for suspected ischemia and were followed annually. The primary outcome of interest was CVD mortality; secondary analyses included all-cause mortality and nonfatal CVD events (myocardial infarction, stroke, and congestive heart failure) and angiographic obstructive coronary artery disease (CAD).

Results: Women in the lowest DHEA-S tertile had higher CVD mortality (17% 6-yr mortality rate vs. 8%; log-rank p = 0.011), and all-cause mortality (21 vs. 10%; p = 0.011) compared with women with higher DHEA-S levels. The increased CVD mortality risk [hazard ratio (HR) = 2.55; 95% confidence interval (CI) = 1.19–5.45] remained unchanged after adjustment for multiple CVD risk factors (HR = 2.43; 95% CI = 1.06–5.56) but became nonsignificant when further adjusting for the presence or severity of angiographic obstructive CAD (HR = 1.99; 95% CI = 0.87–4.59). Results were similar for all-cause mortality. Lower DHEA-S levels were only marginally but not independently associated with obstructive CAD.

Conclusions: Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher CVD mortality and all-cause mortality. Our study provides valuable feasibility data useful for future investigations and possible mechanistic pathways.

The Polycystic Ovary Post-Rotterdam: A Common, Age-Dependent Finding in Ovulatory Women without Metabolic Significance. J Clin Endocrinol Metab. 2010 Aug 18. [Epub ahead of print]

Introduction: The age-specific prevalence of polycystic ovaries (PCO), as defined by the Rotterdam criteria, among normal ovulatory women, has not yet been reported. It is also uncertain whether these women differ from their peers in the hormonal or metabolic profile.

Methods: A total of 262 ovulatory Caucasian women aged 25–45 yr, enrolled in a community-based ovarian aging study (OVA), underwent transvaginal ultrasound assessment of ovarian volume and antral follicle count (AFC) in the early follicular phase and were categorized as to whether they met the Rotterdam definition of PCO by AFC (>/ = 12 in one ovary) and/or by volume (>10 cm(3) for one ovary). The effect of age on prevalence of PCO was assessed. Serum hormones and metabolic measures were compared between women meeting each element of the Rotterdam criterion and those without PCO using age-adjusted linear regressions.

Results: The prevalence of PCO by AFC was 32% and decreased with age. Those with PCO by AFC had lower FSH; higher anti-Mullerian hormone, estrone, dehydroepiandrostenedione sulfate, and free androgen index; and slightly higher total testosterone than those without PCO. However, slightly higher body mass index and waist circumference were the only metabolic differences. Women with PCO by volume had higher anti-Mullerian hormone and free androgen index but did not differ in any other hormonal or metabolic parameter.

Discussion: PCO is a common, age-dependent finding among ovulatory women. These women lack the metabolic abnormalities seen in PCO syndrome. Isolated PCO in an ovulatory woman is not an indication for metabolic evaluation.

The 25(OH)D/PTH Threshold in Black Women. J Clin Endocrinol Metab. 2010 Aug 4. [Epub ahead of print]

Context: Black women have lower 25-hydroxyvitamin D [25(OH)D] and higher PTH than white women. Recent evidence implicates PTH in adverse cardiovascular outcomes.

Objective: The objective of the study was to determine whether PTH increases at lower 25(OH)D levels (the threshold) in black compared with white women.

Design: Healthy black and white women, aged 20–80 yr were recruited to participate in a cross-sectional study of body-composition in black and white women. Measurement of serum 25(OH) D and PTH were carried out.

Setting: The study was a convenience sample recruited from a community setting.

Patients: Healthy black and white women were recruited by advertising and a direct mail campaign in a comparative study of body composition. Age ranged from 20 to 80 yr. There were 148 black and 129 white premenopausal participants and 87 black and 139 white postmenopausal participants.

Main Outcome: The main outcome was to determine whether the threshold for 25(OH)D/PTH differs in black and white women.

Results: A threshold of 37 nmol/liter (95% confidence interval 35–40) was found for black and 59 nmol/liter (95% confidence interval 56–63) for white women. These two values were significantly different (p < 0.001).

Conclusions: Black women have an increase in serum PTH at a lower 25(OH) D level than white women. Negative health outcomes of higher PTH should be investigated in black women.

Lung Cancer Among Postmenopausal Women Treated With Estrogen Alone in the Women's Health Initiative Randomized Trial. J Natl Cancer Inst. 2010 Aug 13. [Epub ahead of print]

Background: In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.

Methods: The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50–79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.

Results: After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, p = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, p = .79).

Conclusion: Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA. 2010;304:859–866.

Context: Herpes simplex and herpes zoster infections are common and often treated with antiviral drugs including acyclovir, valacyclovir, and famciclovir. Safety of these antivirals when used in the first trimester of pregnancy is insufficiently documented.

Objective: To investigate associations between exposure to acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and risk of major birth defects.

Design, Setting, and Participants: Population-based historical cohort study of 837,795 live-born infants in Denmark from January 1, 1996, to September 30, 2008. Participants had no diagnoses of chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, or congenital viral infections. Nationwide registries were used to ascertain individual-level information on dispensed antiviral drugs, birth defect diagnoses (categorized according to a standardized classification scheme), and potential confounders.

Main Outcome Measure: Prevalence odds ratios (PORs) of any major birth defect diagnosed within the first year of life by exposure to antiviral drugs.

Results: Among 1804 pregnancies exposed to acyclovir, valacyclovir, or famciclovir in the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) among the unexposed (adjusted POR, 0.89; 95% confidence interval [CI], 0.65–1.22). For individual antivirals, a major birth defect was diagnosed in 32 of 1561 infants (2.0%) with first-trimester exposure to acyclovir (adjusted POR, 0.82; 95% CI, 0.57–1.17) and in 7 of 229 infants (3.1%) with first-trimester exposure to valacyclovir (adjusted POR, 1.21; 95% CI, 0.56–2.62). Famciclovir exposure was uncommon (n = 26), with 1 infant (3.8%) diagnosed with a birth defect. Exploratory analyses revealed no associations between antiviral drug exposure and 13 different subgroups of birth defects, but the number of exposed cases in each subgroup was small.

Conclusion: In this large nationwide cohort, exposure to acyclovir or valacyclovir in the first trimester of pregnancy was not associated with an increased risk of major birth defects.