Displaying 11-20 letters out of 397 published
Iron and COPD: discretion - yes; inaction - no
We thank Ghio for his interest in our work (1) but are concerned by his suggestion that we are advocating the use of iron as a treatment for COPD. We stated that intravenous iron should be explored as a novel therapeutic option in the condition and we stand by this conclusion. We agree with Ghio that, "Iron metabolism is recognised to participate in the pathogenesis of cancer", but take the view that it is overly simplistic to characterise the relationship as one of iron promoting carcinogenesis. For example, it has been suggested that iron deficiency may contribute to the high rates of recurrence of breast cancer in premenopausal women by upregulating vascular endothelial growth factor signalling (2). There may be a general effect of iron deficiency on angiogenesis - a central process in tumour progression - via an action on the hypoxia-inducible factor (HIF) pathway (3). Epidemiological data suggest that though dietary intake of iron in the form of red meat may be associated with elevated cancer risk, iron stores per se are in fact negatively correlated with cancer incidence (4). It is also noteworthy that intravenous iron supplementation, when used for the treatment of anaemia in individuals with established malignancy, is not associated with harm in terms of disease progression (5).
As we highlighted, the interactions between inflammation, iron and oxygen homeostasis are complex. Moreover, it is not just the oxygen- sensing HIF-hydroxylases discussed in our report that are affected by iron bioavailability; iron is a vital cofactor for a superfamily of enzymes that are involved in a range of diverse processes including DNA methylation, carnitine biosynthesis, histone demethylation and collagen modification (6). All of these processes are relevant to cancer biology.
It should be remembered that three decades ago iron chelation was advocated as a potential treatment for cardiovascular disease - the so- called "iron hypothesis" (7). We now have overwhelming evidence that iron deficiency is both common and extremely harmful in that setting (8-10), and the benefit of treatment with intravenous iron has been established (11,12). The way to determine if this is also the case for the millions of patients suffering from COPD is to conduct well designed clinical trials.
1. Nickol AH, Frise MC, Cheng HY, et al. A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease. BMJ open 2015;5(7):e007911.
2. Huang X. Does iron have a role in breast cancer? The Lancet Oncology 2008;9(8):803-7.
3. Eckard J, Dai J, Wu J, et al. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. Cancer cell international 2010;10:28.
4. Fonseca-Nunes A, Jakszyn P, Agudo A. Iron and cancer risk--a systematic review and meta-analysis of the epidemiological evidence. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014;23(1):12-31.
5. Gafter-Gvili A, Rozen-Zvi B, Vidal L, et al. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials. Acta oncologica (Stockholm, Sweden) 2013;52(1):18-29.
6. Loenarz C, Schofield CJ. Expanding chemical biology of 2- oxoglutarate oxygenases. Nature chemical biology 2008;4(3):152-6.
7. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1(8233):1293-4.
8. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. American heart journal 2013;165(4):575-82.
9. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. European heart journal 2014;35(36):2468- 76.
10. Jankowska EA, Wojtas K, Kasztura M, et al. Bone marrow iron depletion is common in patients with coronary artery disease. International journal of cardiology 2014;182C:517-22.
11. Anker SD, Comin-Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. The New England journal of medicine 2009;361(25):2436-48.
12. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. European heart journal 2015;36(11):657-68.
Conflict of Interest:
Since the publication of the original article, the authors declare no additional competing interests.
Table and contents correctionPage 7, Table 5: There are 6 cells deviated to right for Summary estimate (95% CI) and I2 at delta 12,24,36 months. Page 9, Line 9, Conclusion: "and declining body reserve of vitamin B12" should be deleted. The correct sentence should be "Anemia may occur with declining body reserve of vitamin B12 and deteriorating iron metabolism, which can be identified early by ferritin levels but can also be masked by serum iron."
Conflict of Interest:
These days the Mediterranean diet must be prudent
It is interesting to read the study on the Mediterranean diet and type 2 diabetes. Basically, the Mediterranean diet is a healthier option. It is very important to appreciate that food items with a high-glycemic index like chocolates (as conventional chocolates contain sugar) and white bread (as it has a high- glycemic index) must be avoided. The use of unrefined olive oil (as the process of refinement includes the addition of harmful chemicals) is good. However, olive oil is not suitable for frying any item as the oil tends to break when temperature exceeds 80 degrees centigrade. For frying mustard oil is the best as it is stable up to 300 degrees centigrade.
Any item should not be seasoned with sugar or jaggery (white jaggery is always adulterated with washing powders), though for the sweet taste, sweet items like apples could be used.
Apart from the conventional Mediterranean diet, these days all consumers must be enlightened about the rampant pernicious adulteration in the food items in several countries, e.g. polishing the apples with wax to make them shiny. Salad items must also be thoroughly washed before being served, as in most places excessive insecticides are used and in some places the plants are even irrigated with untreated sewage water (leading to bacterial and parasitic infestations).
It is best to use unprocessed milk after boiling as the processing of the milk leads to break down of macro-fat globules into micro-fat globules (though it improves the texture) leading to increased absorption of this animal fat in the intestine.
Conflict of Interest:
Counseling to increase physical activity should be intelligent and appealing
Physical inactivity and low-level of exercise is highly prevalent. Despite routine counseling and follow-up the compliance with improved physical activity is poor. I have discovered a novel technique in my practice to improve the compliance with much better results. The technique is, we must enquire about his sexual life (as most sedentary males suffer from erectile dysfunction of some degree), and counsel them about the importance of regular physical activities in improving the sexual life, particularly erectile dysfunction.
The improved sexual life with regular physical activities makes the patient much more compliant as compared with other incentives.
Conflict of Interest:
Methodologically sound, with perhaps an uncomfortable result: authors' reply
Joyce Arthur, from the Abortion Rights Coalition of Canada, has claimed in a letter that our study, "Abortion legislation, maternal healthcare, fertility, female literacy, sanitation, violence against women, and maternal deaths: a natural experiment in 32 Mexican states," has "fatal flaws." We appreciate the opportunity to respond to the questions and critique raised in the letter and to clarify specific issues. After carefully reviewing the criticisms by Arthur we believe that her concerns are based largely on personal opinions or speculative assumptions and that she misrepresents important methodological issues. The letter does not in fact document "deep flaws"; rather, it seems to perhaps reflect discomfort with the study's findings. It quotes several Op -Ed pieces published in non-peer reviewed sources, including personal or ad-hoc blogs, which focus on political discussions or personal views on the legal status of abortion. In fact, many of her concerns are about issues not directly germane to the data and the analysis. Below, we give a point-by-point response to Arthur's criticisms.
Arthur asserts that our study "purports to show that Mexican states with more restrictive abortion laws have lower maternal mortality rates than states with more permissive laws." This critique oversimplifies and misconstrues our study conclusion focusing only on simple and purely descriptive differences in maternal mortality according to abortion legislation. In fact, as stated in the conclusions of the abstract and the discussion section of the article (first paragraph), our findings support the null hypothesis, namely that differences in abortion legislation do not correlate ultimately with maternal mortality when the influence of other major factors is accounted for. Further, robust and exhaustive multivariate analyses showed that most of the differences (up to 88%) in maternal mortality were largely explained by other factors such as women's literacy, maternal healthcare, emergency obstetric care, individual-level risk factors, clean water, sanitation, fertility rate and intimate-partner violence against women. These findings suggest that reducing disparities in these factors may facilitate an epidemiological transition towards low maternal mortality rates in developing countries, especially in poorer nations. However, Arthur suggests that our study is using such factors as a "smokescreen" to cover up the effect of unsafe or illegal abortion on maternal mortality. We deeply disagree with this unsubstantiated and dissociated assertion from our paper's discussion and results. We wish to emphasize the importance of addressing these factors that strongly impact women's health in developing nations, who continue suffering and dying in childbirth from preventable causes.
PREVIOUS STUDIES ON MATERNAL MORTALITY IN MEXICO
Arthur refers to a previous study of abortion-related mortality in Mexico conducted by Schiavon et al. from Ipas-Mexico  to imply that maternal mortality and abortion-related mortality was grossly underestimated in our study. In an exploratory research on maternal mortality in Mexico, we in fact reanalysed the dataset used by Schiavon et al. In that study, significant overestimation of maternal and abortion-related mortality in the entire Mexican country (up to 35%) was found, mainly due to the consideration of flawed denominators of live births. For example, these authors used indirect estimates of live births as denominator to calculate maternal mortality ratios. Compared with observed live births officially registered in Mexico, these indirect estimates for the period 1990-2010 totalled 46,505,160 while the actual figure of official live births totalled 56,759,478 (the difference is more than10 million live births). It is immediately obvious that using substantially smaller figures of live births as denominator resulted in a significant overestimation of maternal mortality ratios in the study by Schiavon et al. The current study in BMJ Open used vital statistic of corrected live births by residence and occurrence as denominator of mortality ratios in every state (see Tables S2 and S3, Data Supplement 1). Consequently, we are reporting accurate maternal mortality ratios for each state based on the actual official records and not based on indirect estimates of live births; this is a serious deficiency in the study quoted in the letter by Arthur.
RELIABILITY OF MORTALITY DATA
Although the letter criticizes the quality of official statistics in Mexico, we would like to point out that Mexico is a country which has been commended by the WHO as being reliable in terms of completeness of civil registration, integrity of vital records, use of international standards for coding of disease, and maternal death audit [3, 4]. While maternal deaths occur most often in settings with poor or non-existent national vital registration systems, this is not the case for countries such as Mexico [2, 5, 6] Chile  and at least other six countries with reliable and virtually complete vital records in the American continent. Accurate Mexican mortality records allowed us to distinguish maternal deaths by place of occurrence and place of residence. For instance, the Federal District showed the highest difference in maternal mortality outcomes for those residing outside versus inside the Federal District (61.9 vs 48.7 for MMR per 100,000 live births, respectively) suggesting that inter-state mobility into the Federal District is associated with an increased risk of maternal death for pregnant women arriving from other states. Although errors such as misreported deaths are still possible, in the case of Mexico, minimal errors are expected since 2002 because of the strengthening of the epidemiological surveillance system in that year, incorporating maternal death audits to identify miscoding and minimising under-reporting. In addition the data allowed us to segregate deaths by different abortive outcomes. For instance, in a 2009 audit of maternal deaths in Mexico during the influenza A H1N1 epidemic, researchers were able to distinguish subcategories of causes of maternal deaths, including complications of spontaneous abortion, induced abortion and unspecified abortion. In other words, the results exposed in the BMJ Open article are based on the best mortality data available for every Mexican state at the present, making unlikely that the differences among states are explained by errors in the death registry.
IDENTIFYING AND SEGREGATING ABORTION-RELATED DEATHS
Arthur asserts that there may be widespread misclassification of maternal deaths suspected to be the result of an illegally induced abortion in Mexico. As reviewed elsewhere,[2, 7] however, this has become much less likely in view of ICD-10 codes for death due to other abortion (O05), unspecified abortion (O06), and failed attempted abortion (O07), especially in countries with adequate civil registration of vital data and active epidemiological surveillance of maternal deaths. Usage of these ICD codes, especially O06, allows safeguarding of both professional and patient confidentiality when physicians suspect a self-provoked abortion or when the primary cause is poorly defined in clinical history. Otherwise, the code O04 is used to classify complications for legal medical abortions.
At present in most of Latin American countries (including Mexico) where maternal mortality audit is routinely performed, physicians are exposed to legal and administrative sanctions if they are found guilty of intentionally distorting or misclassifying actual causes of death.[2, 7] This suggests a higher quality of registry data in these countries.[2, 5] For instance, in a recent 10-year times series study of complete hospital discharges for different abortive outcomes in Chile from 2002 to 2011 using the nine ICD-10 codes, over 70% of these discharges are related to ectopic pregnancy (O00), molar pregnancy and other abnormal products of conception (O01, O02 and O08), and spontaneous abortion (O03). It is a prevalent error to consider codes O00, O01, O02, O03 and O08 to be an estimate of illegal, clandestine, or unsafe abortions, an assumption that would mistakenly inflate the numbers.[1, 8, 9] As highlighted by a recent review of the use of ICD-10 codes for the documentation of abortion- related outcomes, none of these codes is likely to be related frequently to illegal procedures. For example, code O02 is used (among others) to classify an anembryonic pregnancy  terminated with curettage, which has become an early diagnosis increasingly frequent in territories exhibiting high rates of echography and surgical obstetrical services. The same may be expected for molar pregnancies and miscarriages in settings with high rates of such services. Therefore, it remains highly speculative to assume that most of hospital discharges from abortive outcomes classified using the codes O00, O01, O02, O03 and O08 reflect complications of unsafe or illegal abortions, and consequently we segregate the specific codes O04, O05, O06 and O07 for the construction of induced abortion mortality ratio (iAMR) in the Mexican study. Arthur did apparently not note this important methodological refinement.
Another matter for concern is the possibility of misreporting or misclassification of deaths from induced abortion as deaths for other causes such as haemorrhage or sepsis. Nevertheless, in Mexico, this seems unlikely because of the maternal mortality audit [5, 6] discussed above and the parallel decreasing trend in maternal mortality overall and due to these causes. For instance, deaths from haemorrhage have decreased by 17% between 2002 (10.6 deaths per 100,000 live births) and 2011 (8.8 per 100,000 live births) and deaths from sepsis have decreased over 25% in the same period (from 3.38 to 2.52 per 100,000 live births). Therefore, the iAMR is a proxy that provides a reasonable method to address the problem of under-reporting of maternal deaths from complications of illegal procedures in countries with reasonably reliable records, such as Mexico.
SEGREGATING MEXICAN STATES BY ABORTION LEGISLATION
Arthur uses the term "data dredging" for the exploratory analyses used to segregate the states in two groups according abortion laws of each state. Our pragmatic approach, completely described in the article, was to assess a spectrum of differences of law across the 32 states summarized in Table 1 of the BMJ Open article, and from these to define an operational binary term for subsequent statistical analysis, meaning 1 = less permissive and 0 = more permissive. Arthur misconstrues the reason for the choice of this term, which makes her criticism of this issue largely misguided. Firstly, this variable is a proxy of legal permissiveness, not an indicator for abortion accessibility. In other words, between states, legal permissiveness may be the same, but accessibility may differ by multiple unmeasured factors. We do not say nor have we stated that we are using this term as a proxy for greater or less accessibility to pregnancy termination in our study. Secondly, as a parsimonious approach, exploratory analyses are valid and valuable tools to avoid an arbitrary categorisation, assessing the initial correlation between a set of categorical variables (in this case, the presence or absence of different types of criminal exemptions for pregnancy terminations in each state) and the primary outcome of interest (i.e., maternal mortality ratio in our study). Thirdly, the single legal characteristic with the greatest discrimination in terms of mortality rates between the states was whether or not there was an exemption for genetic or congenital malformation combined with any other exemption. Finally, this was the criminal exemption that resulted in the most balanced distribution of states in each comparison group: 14 of Mexican states formally allow criminal exemptions in cases of genetic or congenital malformations and 18 states do not allow such exceptions. Other alternative combination of laws were not significantly associated with maternal mortality, supporting the final conclusion of the paper, namely that differences in abortion legislation do not correlate ultimately with maternal mortality in Mexico.
EXEMPTION FOR GENETIC AND CONGENITAL FOETAL CONDITIONS
Similarly, Arthur asserts that the criminal exemption for pregnancy termination in cases of non-lethal conditions such as genetic or congenital foetal anomalies is not a good proxy to study the relationship between abortion legislation and different health outcomes, including maternal mortality. However, there is good evidence from other countries that this particular exemption has a substantial impact on how abortion is utilized, which makes it a likely indicator of both the legal and cultural climate related to abortion. For instance, prenatal screening and more permissive laws of abortion appear to have a strong impact on Down syndrome (trisomy 21), decreasing the prevalence of this condition at birth to less than 1 per 1,000 in Europe [11-14]. Conversely, the prevalence of Down syndrome at birth is higher in settings with less permissive laws: Chile (2.47 per 1,000), Argentina (2.01 per 1,000) and Ireland (2.1 per 1,000 in Dublin) and over 1.7 per 1,000 live births in most other Latin American countries.[8, 13, 14] Thus, it is reasonable to think that the presence or absence of this exemption actually changes some of the utilization of abortion and may reflect the predominance of different cultural factors and attitudes toward abortion in general.
LAWS AS AN INDICATOR OF CULTURAL FACTORS, ATTITUDES AND BEHAVIOURS
Along this line, as we have noted, there is consensus that diversity of abortion legislation in different regions, countries, and territories may partially reflect the predominance of different cultural factors, behaviours, and attitudes in the population towards abortion itself.[15- 23] In our view, Arthur neglects this point. For example, Kilck et al. assessed gonorrhoea incidence rates as a proxy of high-risk sexual behaviour in a panel of 41 countries for which consistent gonorrhoea data were available for a 20-year study period. Compared with less permissive laws allowing abortion only for lethal conditions, the switch to more permissive abortion laws for non-lethal maternal conditions was associated with large increases in reported gonorrhoea incidence. According to the authors, modern economic theory predicts that abortion laws affect sexual behaviour since they change the marginal cost of having high-risk sex (i.e., sexual activity during which barrier contraception is not used, which by definition is associated with higher risk for both STD acquisition and unintended pregnancy). In another study conducted in Spain between 1997 and 2007, Due?as et al. reported that an increasing trend in the use of effective contraceptive methods (49.1% to 79.9%), was paradoxically also associated with an increasing trend in the utilization of pregnancy termination (5.52 to 11.49 per 1,000 women), especially in young women, who reported engaging in high-risk sex more frequently and more precociously. Interestingly, in the Russia Longitudinal Monitoring Survey the availability of abortion was one of the reasons cited for non-use of contraception for the female population. The change in the marginal cost of unprotected or risky sex vis a vis different abortion laws proposed by Klick et al. well may be a plausible mechanism that influences the global efficacy of family planning programs to decrease unintended pregnancies and abortion rates. Altogether, these studies support the need to investigate the relationship between different abortion laws and cultural patterns, attitudes and behaviours that ultimately influence sexual and reproductive health outcomes in different populations. The diversity of abortion laws in Mexico represents a valuable natural laboratory at the population level. Thus, although we did not find an independent association of differences in legal exemptions with maternal mortality, it would be worthwhile for future studies to assess possible associations with other reproductive health outcomes.
OTHER FACTORS IMPACTING MATERNAL MORTALITY
Arthur's letter states that "it's already well established -- practically self-evident-- that maternal mortality can be significantly reduced by educating women, upgrading health systems, and improving access to contraception, skilled birth attendants, clean water, sanitation, and so on". We note that science is not "self-evident" as stated in the letter; our study is consistent with previous research and also adds important original scientific evidence on this subject. Although some previous studies have documented the impact of factors such as women's education level, fertility rate, clean water, sanitation and delivery by skilled attendants, relatively few studies have tested the impact of these variables in a simultaneous fashion, as our study has. In addition, we provide an exhaustive literature review for each factor in the BMJ Open article. We would like to emphasize that simple epidemiologic correlations do not necessarily mean causation. Therefore, we have used multivariate regression models to test the independent contribution of each factor. Furthermore, our study addressed the problem of multicollinearity in providing estimates of unbiased effect sizes for each variable in different panels of multiple regression models (a panel of 24 multivariate regression models, 12 unrefined models and 12 refined models). In the case of Mexico, we detected important disparities among states on different independent predictors, and these disparities appear to explain differences in maternal and abortion-related mortality. Again, we object to Arthur's dismissive statements towards the importance of these positive findings of the study, because addressing these factors could have a major impact to improve the survival and health of women and families worldwide.
On the other hand, the impact of some variables has been scarcely evaluated in the epidemiologic literature. For instance, this is the first study assessing directly the relationship between prevalence of intimate- partner violence against women and maternal mortality rates at the population level in 32 Mexican territories. The Mexican study is also the first study to assess the possible impact of constitutional amendments protecting the unborn on maternal mortality rates. It is noteworthy that the results of the Mexican natural experiment are remarkably consistent with other natural experiment recently conducted in Chile. Arthur's letter fails to provide direct evidence supporting the statement that differences in abortion legislation have a significant association with maternal death rates independent of other factors known to influence maternal mortality at the population level. At present, research on this subject in Mexico and Chile, provisionally supports the null hypothesis, namely that differences in abortion legislation do not correlate ultimately with maternal mortality in these countries when the influence of other major factors is taken into account.
RISK OF COMPLICATIONS FOR LATE-TERM ABORTIONS
Arthur acknowledges that almost all abortion for foetal abnormality occurs later in pregnancy "because the anomaly cannot usually be detected until then". We agree on this point. However, she also claims that the selected exemption for foetal anomaly cannot possibly by itself show any trends or differences in abortion mortality rates "because abortions due to foetal abnormality are always a tiny minority of abortions in any country." This ignores the fact that the risk of complications from second -trimester or late-term abortions is much higher than from terminations conducted during the first trimester. In the classic study by Bartlett et al. "Risk factors for legal induced abortion-related mortality in the United States", the relative risk of abortion-related mortality was 14.7 at 13-15 weeks of gestation, 29.5 at 16-20 weeks, and 76.6 at or after 21 weeks (95% CI 32.5, 180.8).  Hence, the small number of late terminations will contribute significantly to related maternal mortality. This has been suggested empirically in a study using hospital discharge data in the U.S. to assess the rates of major abortion complications from 2001 to 2008 and their relationship to more and less permissive abortion legislation in 23 states with reasonably reliable records. After controlling for socio-economic characteristics and the pregnancy complication rate, less permissive laws were associated to lower complication rates (odds ratio of 0.79 for mandatory delays and 0.74 for Medicaid funding restrictions). According to the authors, this result may reflect the fact that states without restrictions perform a higher percentage of late term abortions, including terminations for genetic or congenital foetal diseases.
ILLEGAL USE OF MISOPROSTOL AND ABORTION COMPLICATION RATES
We agree with Arthur that the illegal use of drugs with abortive effects, especially misoprostol, probably has become the most prevalent method to conduct unsafe abortions in Mexico and other countries.[7, 8, 29 -32] However, approximately half of the women that use this drug could experience bleeding and pelvic pain greater than that of a regular menstrual cycle and may consequently seek medical assistance. In addition, the rate of complications and failures can reach 30% or more with the use of self-administered misoprostol when taken in inadequate dosages or after more than nine weeks of gestation.[33, 34] Thus, one might predict that any significant increase in the illegal use of misoprostol at the population level at least would translate into an increase in less severe cases of abortion-related complications in hospital discharges, particularly in code O06 (unspecified abortion). However, to the best of our knowledge, no epidemiologic study has provided evidence that the illicit distribution or illegal use of misoprostol decreases maternal mortality rates from clandestine, illegal, or unsafe abortion, independently of other major factors such as access to emergency obstetric care.
THE IMPORTANCE OF EMERGENCY OBSTETRIC CARE
An independent inverse association between all-abortion hospitalization ratios and maternal mortality ratios was found in our study. The unadjusted coefficient represented a reduction of 1.71 maternal deaths per 100,000 live births for each unit of all-abortion hospitalisation ratio (see Table 6 of the BMJ open article). After full adjustment, for each incremental unit in this variable, a decrease of 0.8 maternal deaths per 100,000 live births was estimated among states (see Table 7). The result was remarkably consistent through different panels of regression models (see Table 8). Mexican states classified as having less permissive abortion legislation exhibited higher all-abortion hospitalisation ratios than more permissive states (see Table 9). This indicator of all-abortion hospitalization ratio serves as proxy for access to opportune or immediate emergency obstetric care in women experiencing complications from any kind of abortion. In other words, we found evidence that improved access to emergency obstetric care is likely a key factor decreasing maternal deaths in women resorting to illegal, clandestine, or unsafe abortions in settings with less permissive abortion laws regardless of the procedures utilised to conduct abortions. Arthur neglects this important finding of our study.
ESTIMATES OF ILLEGAL ABORTIONS IN MEXICO
Arthur makes a number of assertions about the practice of illegal abortion in Mexico and other countries that do not directly relate to the findings of our paper in BMJ Open. We do assume that legislation will have some influence on the practice of abortion (an assumption that we suspect Arthur shares, or there would be no concern about abortion laws). We do not dispute the existence of illegal, clandestine, or unsafe abortion. For the record, we do not advocate imprisoning women who have received illegal abortions, and as this idea is nowhere stated or implied in our paper. We are not making any recommendation in our paper regarding the legal status of abortion at the population level. However, we are interested in the prevention of abortion and its deleterious consequences for women's health. Furthermore, we acknowledge the importance of estimating empirically plausible figures of abortion.
Elsewhere, we have reviewed the methodological problems that produce inconsistent figures of illegal abortions in M?xico and other Latin American countries.[2, 8, 35, 36] For instance, a study conducted in 1990 that was based on opinion surveys with expansion factors reported controversial figures for Chile, suggesting that approximately 160,000 illegal abortions were performed every year in this country. However, a review of the methodology found it lacking reproducibility and subject to selection bias, recall bias, and possibly ideological bias of the interviewed individuals, especially in the calculation of an expansion factor that multiplies the number of discharges by abortion complications surveyed in health institutions. There is no study validating the utilization of expansion factors based on the mere opinion of subjects arbitrarily selected. In contrast, three major global reports have detected important reductions in maternal and abortion-related mortality in Latin American countries.[38-40] It is self-contradictory to say that unsafe abortions have increased substantially over the last decades while observing substantial reductions in deaths from this cause.
Other examples from countries that have modified their abortion legislation also suggest large estimation errors. For example, in the Federal District of Mexico, Juarez et al estimated that more than 194,875 abortions were performed every year before liberalizing changes in legislation. After more than 5 years following the new law allowing first trimester terminations on demand, the number of pregnancy terminations in the public health sector has not reached 20,000 per year. In Mexico, most of the population utilise the public health system, however, even assuming some degree of underreporting for legal abortions in the private sector of the Federal District, the numbers presented by Juarez et al appear to be overestimates. Similarly, in Uruguay, 33,000 illegal abortions per year were estimated pre- legislation, but after the first full year of complete statistics post -legislation allowing first-trimester abortion on demand, the total number of terminations was 6,676. The second year post-legislation, the number of pregnancy terminations increased about 20% (8,500 procedures, an increment from 9 to 12 per 1,000 women at 15-45 years old, according the Ministry of Public Health).
CAUSES OF MATERNAL DEATH IN MEXICO
Arthur claims that an estimated 13% of maternal mortality globally is due to unsafe abortion without providing the source of such estimate. The 2014 global analysis carried out by Say et al. reported an estimated 7.9% of deaths from abortion. The WHO report during 2008 reported an estimated 13%. Previously in 2006, Khan et al. reported 12% for Latin America in a systematic review published by The Lancet. Regardless of these global reports, a detailed analysis in Mexico  shows the following proportions for different maternal mortality causes during 2009, in decreasing order: 33.9% for Indirect Obstetric Causes (O98-O99); 21.5% for Hypertension and Eclampsia (O10-O16); 19.9% for Haemorrhage (O20, O43- O46, O67, O72, O73); 13.7% for Other Direct Obstetric Causes (O01-O02, O21, O24-O26, O28-O36, O40-O42, O47-O48, O60-O66, O68-O71, O74-O75, O80); 5.7% for Sepsis (O22, O23, O85-O88); 2.5% for Ectopic Pregnancy (O00); 2.1% for Medical Abortion, Other Abortion, Unspecified Abortion, and Failed Attempted Abortion (O04-O07); and 0.9% for Spontaneous Abortion (O03). According this analysis, nearly 98% of maternal death causes in Mexico are unrelated to pregnancy termination, regardless of whether if it is legal or illegal. Therefore, the global estimate of 13% quoted by Arthur does not apply in the case of Mexico.
In our study, we present all-abortion hospitalisation ratios segregated for each state (Table 5 of the BMJ Open article). Arthur's letter quotes about 159,000 hospital discharges for abortion complications in public institutions in Mexico for 2009, an estimate of 1,026,000 unsafe abortions, and a complication rate of 36% for these abortions. The letter further states that approximately 25% of women with complications by unsafe abortions do not seek treatment. Arthur fails to provide any verifiable sources for these figures. In addition, a simple analysis reveals that these numbers apparently do not add up. According Mexican official data for 2012, from the total of 189,694 hospital discharges for any kind of abortion, 68,715 were related to ectopic pregnancy, mole, other abnormal products of conception and miscarriage (ICD codes O00-O03 and O08) and 112,979 associated to induced abortion, including medical abortion, other abortion, unspecified abortion, and failed attempted abortion (codes O04-O07). Subtracting the number of cases for legal terminations of pregnancies (codes O04 and O07) the hospital discharges associated with complications of other induced abortions comprise 112,564 cases and we estimate that at least 50% or more of these cases are probably the result of complications from illegal or unsafe abortions. If we assume the rate of complications claimed by Arthur: 36% for 1,026,000 unsafe abortions, the result is 369,360 cases; after subtracting 25% of women that do not seek treatment, the expected number of hospital discharges related to unsafe abortions will be 277,020 cases. However, the official figure of 112,564 cases of hospital discharges probably related to unsafe abortion in public health institutions roughly represents 40% of the estimates from Arthur's letter. The overestimate suggested in the Arthur's letter is unlikely because most of the Mexican population attends public health facilities  and does not appear to be consistent with available data.
OTHER UNWARRANTED COMMENTS
Arthur makes unwarranted comments that are not scientifically based. For example, in reference to our studies, it is claimed that by "rendering those women invisible, such studies become dangerous weapons that threaten to slow down the global decrease in maternal mortality and continue allowing women to suffer and die unnecessarily" and that "the BMJ Open study is the latest contribution to this ideological battle disguised as science". It is further asserted that our "studies appear professional and are published in reputable journals." Although we value some criticisms in the letter, which have facilitated the contrast and free exchange of scientific ideas, we feel that such comments as the above are not germane inasmuch as they do not focus on science or the results of our research. Instead, these comments reflect the discomfort and personal beliefs of the writer. Science is not a question of authority, prejudices or subjective opinions, but a question of objective data, falsifiable hypotheses, rigorous methodology, testability and reproducibility.
THE USE OF THE WORDS "PROGRESSIVE CHANGES" AND "UNBORN"
Arthur states that we characterize the Mexican states' constitutional amendments protecting the "unborn" from conception as "progressive changes." Arthur considers these expressions as "anti-abortion language". This is a distortion, which takes these terms out of context. The term "progressive changes" refers to legal changes that have steadily added Mexican states over time (Figure S1, Supplementary Material). The word "unborn" is a common legal term utilised in constitutional amendments.
UNSUBTANTIATED CRITICISM TO BMJ OPEN
Arthur states that BMJ Open accepted our study without subjecting it to sufficient scrutiny. As detailed in this point-by-point rebuttal letter, we consider this criticism unsubstantiated and inappropriate. Although our times-series study on determinants of maternal mortality in 32 Mexican states had some inherent limitations - as any observational study - all of our data come from reliable sources that can be checked independently. Following current rules of scientific transparency, BMJ Open conducted an open peer-review and the entire pre-publication history has been published. The database is publicly available, published as supplementary data at BMJ Open and also available via the Dryad data repository. Consequently, statistical analyses can be fully reproduced or re-analysed by any research group interested in corroborating or refuting our findings. Finally, BMJ Open offered a valuable opportunity to Arthur to express her ideas and criticisms of our study in an e-letter. Undoubtedly, this is another proof of scientific transparency from BMJ Open.
While some of the issues raised in Arthur's letter represent areas of legitimate scientific discussion, we believe she has relied on several highly questionable assumptions, overstated some concerns and neglected other important methodological strengths. The epidemiologic methods used in our study are robust, valid, reproducible, and based on reliable data from a country that has met high standards in improving and auditing their ascertainment of maternal mortality and its components, including abortion -related mortality. Additionally, many of the comments in the Arthur's letter appear to reflect a lack of understanding or difficulty accepting the conclusions of our study. We find it remarkable that maternal mortality was unrelated to differences in abortion legislation, but was largely explained by other factors such as women's literacy, maternal healthcare, emergency obstetric care, individual-level risk factors, clean water, sanitation, fertility rate and intimate-partner violence against women. Again, we wish to emphasize the importance of addressing promptly these factors that strongly impact women's health in developing nations.
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Conflict of Interest:
Better choices are always better options
I read with interest the protocol of this interesting study.
Data is rapidly accumulating that not all diuretics are the same in the contemporary management of hypertension (HT). It is very important to appreciate, HT (largely asymptomatic disease) is treated to prevent adverse cardiovascular outcomes and therefore only antihypertensives with proven reduction in cardiovascular outcomes should be used/further studied.
In a comprehensive review  no evidence of reduction in cardiovascular outcomes (heart attacks, stroke, and death) was reported with hydrochlorothiazide (HCTZ) 12.5 to 25 mg/day. It is worth pointing out that higher doses of HCTZ have been shown to increase the risk of cardiac arrest dose-dependently. Compared to HCTZ 25 mg/day, 50 mg /day has been reported to increase the risk of primary cardiac arrest (odd ratio 1.7) and 100 mg was associated with even larger increase in risk (OR 3.6) . The authors of the review concluded that whenever a diuretic is needed in HT, it should be either indapamide or chlorthalidone.
1. Messerli FH, Makani H, Benjo A, et al. Anti-hypertensive efficacy of Hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol. 2011;57(5) :590-600
2. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994;330(26):1852-7
Conflict of Interest:
The choice of drugs should be contemporary and well-proven
I read with interest the protocol. The idea of comparing initial monotherapy vs dual-drug therapy is timely.
However, the choice of antihypertensive drugs could have been better. Losartan is an angiotensin receptor blocker (ARB). Recently the use of ARB as an antihypertensive drug is seriously questioned. Despite lowering blood pressure, it is not shown to improve cardiovascular outcomes (heart attack, stroke and death) . Likewise, hydrochlorothiazide (HCTZ 12.5-25 mg/d) has not shown to improve cardiovascular outcomes .
Therefore, before investing time, money and efforts with the trial, it is timely to make prudent choices of antihypertensive drugs with well-proven reduction in the cardiovascular outcomes.
1.Flavio Danni Fuchs, James J Di Nicolantonio. Review: Angiotensin receptor blockers for prevention of cardiovascular disease; Where does evidence stand?. Open Heart 2015;2:e000236 doi:10:1136/openhrt-2014-000236
2. Messarli FH,Makani H,Benjo A, et al. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol. 2011;57(5):590-600
Conflict of Interest:
Are DPP-4 inhibitors free from risk of hospitalization for heart failure?
The case-control study  on administrative data did not find increased risk of hospitalization for heart failure (HF) associated with the use of DPP-4 inhibitors (DPP-4is), versus any other antidiabetic treatment. In DPP-4is users the OR for admission for HF was 1.00 (0.94 to 1.07), with a non-significant 1.01 and 1.02 for incident and recurrent HF, respectively. All-cause mortality was 6% lower in DPP-4i users, whereas insulin users showed an excess of risk for any type of hospital admission (19%) and death (20%). The authors admit that the favourable impact of DPP-4is on all-cause mortality should be viewed with caution, because their use can represent a marker of better specialty care, and this could be the real factor linked to a reduction in all-cause mortality. Likewise, the authors hypothesize that the mortality excess of insulin users could be the so called clinical inertia: insulin would be administered too late, in patients whose health is already too compromised. The authors do not seem to consider that the same arguments can be used to explain the apparently neutral result of DPP-4is on HF. Indeed: - if DPP-4is can be a marker of specialty care, and if this care is better, then this generally better care could offset a moderately unfavorable effect of DPP-4is on HF - if the DPP-4is OR for HF versus "any other" antidiabetic drug is only very slightly increased (1.00-1.02), and since the other drugs include insulin, which is associated with a significantly increased risk of hospitalization and mortality, then the HF risk of DPP-4is should be greater if compared with other oral antidiabetic drugs without insulin. To calculate the adjusted OR we asked the corresponding author the access to the data set, but so far we have not received this. Meanwhile, it seems more appropriate to refer to the results of randomized clinical trials (RCTs), less prone to unmeasured confounding factors. In a meta-analysis of ninety-four RCTs , therapy with DPP4is versus other comparators or placebo for ?29 weeks insignificantly increased all- cause mortality (RR 1.012, 95% CI 0.909-1.126), and significantly increased the new onset of HF (RR 1.158, 1.011-1.326). Another meta-analysis  found a high excess of HF risk with thiazolidinediones and an intermediate excess with DPP-4is. A further systematic review  with meta-analysis showed an increase in HF with DPP-4is, with a tendency to increase in cohort studies and a significant increase in the RCTs. The RCT TECOS with sitagliptin , not yet included in the aforementioned meta-analyses, do not show an increase (nor a decrease) of HF, but in the sitagliptin group 10 more patients died. Until now the very expensive DPP- 4is were unable to show overall patient-oriented outcomes better than placebo. The frustrating results of DPP-4is are shared by other antidiabetic drugs. To stay on the subject of HF, also the thiazolidinediones, and at least many of the sulfonylureas, increase the HF risk compared to metformin. To take account of an overall risk-benefit balance, we should reconsider the glycemic targets. A comprehensive Cochrane meta-analysis  included RCTs which randomized intensive versus conventional glycemic thresholds (mean achieved HbA1c 6.6% versus 7.6%). Intensive targets seemed to reduce the risk of microvascular complications (-12%), "if we disregard the risks of bias" , that affected 26 of 28 RCTs. But they caused strong increases in the risks of severe hypoglycaemia (+118%), and a significant increase of serious adverse events (+6%). The quality of life was unchanged, but the intensive therapy group increased the interruptions for adverse effects (+50%). Stratifying the RCTs according to source of funding (and coherently relocating one or two trials  between the RCTs without commercial sponsors), industry funded RCTs show a tendency to protection against all- cause mortality with intensive targets: RR 0.95 (0.88-1.02); conversely, those without commercial sponsors find a significant increase of mortality: RR 1.15 (1.02-1.31) . For CV mortality, with intensive targets industry funded RCTs notice a RR 1.01 (0.85-1.21), whereas non-commercial funded RCTs find a significant increase in mortality: RR 1.23 (1.02-1.48) . Therefore it may be useful (although not entirely evidence based) to maintain an HbA1c ?7% through lifestyle (with the well proven option to prescribe a vegetarian diet ) and metformin. When is deemed appropriate to intensify the treatment with other drugs, the HbA1c target should be between 7% and 8%, and even higher for frail or elderly patients.
1. Giorda CB, Picariello R, Tartaglino B, et al. Hospitalisation for heart failure and mortality associated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected population of subjects with type 2 diabetes: a nested case-control study. BMJ Open 2015;5:e007959.
2. Savarese G, Perrone-Filardi P, D'Amore C, et al. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta- analysis. Int J Cardiol 2015;181:239-244.
3. Udell JA, Cavender MA, Bhatt DP, et al. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2015;3:356-66.
4. Clifton P. Do DPP-IV inhibitors cause Heart Failure? Clinical Therapeutics 2014;36:2072-9.
5. Green JB, Bethel A, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. New Engl J Med 2015.
6. Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011;343:d6898.
7. Donzelli A, Battaggia A, Mariani G. Algoritmo AIFA AMD SID per la terapia del diabete Target di glicata e rischi di sovratrattamento. InfoFarma 2015;2:1-8.
8. Donzelli A, Sironi S. Diabetologists' attitudes against vegetarian and vegan options are not evidence based. J Hum Nutr Food Sci 2015, in press.
Alberto Donzelli, MD Area of Education for Appropriateness and Evidence Based Medicine, Local Health Unit, ASL of Milan, Italy email@example.com
Alessandro Battaggia, MD MMG - Infofarma Unit? Locale Socio Sanitaria 20, Verona, Italy firstname.lastname@example.org
Ilenia De Carlo, PH Regional Center of Pharmacovigilance, Regional Health Agency, ARS of Marche, Italy email@example.com
Giulio Mariani, MD Direttore ff Medicina 1, responsabile Diabetologia AO San Carlo Borromeo - Milano, Italy firstname.lastname@example.org
Conflict of Interest:
A Canadian continued care prescription
The paper by Morecraft et al. on the emergency supply of prescription medications provides a number of important insights into issues with continuity of prescribed medication in an ambulatory population. The legislative framework in England appears to allow the provision of prescription only medications in an emergency but seems to stop short of a truly satisfactory solution to this important public health issue. In Manitoba, Canada we have created a legislative framework that slightly extends the provisions allowed in England and solves many, but not all, of the problems raised in the paper. In 2002 Manitoba was the first jurisdiction in Canada to formally address the issue of prescriber inaccessibility by establishing a collaborative agreement between the regulatory bodies for pharmacy and medicine to allow pharmacists to refill these prescriptions. These "continued care" provisions were expanded to include nurse prescribers in 2006  and further entrenched in the Pharmaceutical Act (2006) and the Manitoba Pharmaceutical Regulations (2013).[2,3] These regulations now authorize pharmacists to continue chronic prescriptions by acting as prescriber in urgent situations to meet the care and medication needs of the patient. The prescription can then be filled in an amount that is not in excess of the original fill. To ensure appropriate feedback, the original prescriber must be notified of this action. Manitoba has a universal insurance program for prescription medication and all pharmacies have access to the complete prescribing history of all prescriptions filled in the province. Even broader provisions are also in place in true emergencies such as when natural disasters occur. Unfortunately, compensation for all these services is limited to the normal product based fees for providing prescriptions but does avoid the "loaning" situation described by Morecraft et al. We watch with interest for further developments and approaches to ensuring that the pharmacotherapeutic health needs of patients are met in the most seamless and efficient way possible. Clearly on both sides of the ocean, community pharmacists have a key role in achieving this goal.
1. The College of Physicians and Surgeons of Manitoba, The College of Registered Nurses of Manitoba and The Manitoba Pharmaceutical Association Joint Statement: Continued Care Prescriptions from Practitioners. April 2006. Available online at: http://mpha.in1touch.org/uploaded/web/Legislation/Continued-Care- Joint-Statement-April-2006-09.pdf (accessed 30th July 2015).
2. The Pharmaceutical Act. December 2006. Available online at: http://web2.gov.mb.ca/laws/statutes/2006/c03706e.php (accessed 30th July 2015)
3. Manitoba Pharmaceutical Regulations. July 2013. Available online at: http://mpha.in1touch.org/uploaded/web/New%20Pharmaceutical%20Act/July%203,%202013%20Pharmaceutical%20Regulations.pdf (accessed 30th July 2015)
Conflict of Interest:
Harmful consumption of alcohol among people aged 50 or over in England
I read with interest the paper on socioeconomic determinants of risk of harmful alcohol drinking among people aged 50 or over in England . The study found that "harmful drinking in later life is more prevalent among people who exhibit a lifestyle associated with affluence" and suggests that harmful drinking may constitute a hidden problem. It should be noted that harmful drinking was defined only in terms of alcohol consumption above a certain threshold .
Coincidentally, another study using the same dataset was also published recently . This study followed a cohort over a 10 year period and did not find an association between any pattern of current alcohol consumption and poor self-rated health. Drinking above recommended guidelines is more prevalent among affluent people aged 50 or over but this does not predict poor self-rated health 10 years later.
Martin Frisher, Reader in Health Services Research, School of Pharmacy, Keele University, Staffs ST5 5BG Email:email@example.com
1 Iparraguirre J. Socioeconomic determinants of risk of harmful alcohol drinking among people aged 50 or over in England. BMJ Open 2015;5:e007684. doi:10.1136/bmjopen-2015-007684
2. Department of Health. Sensible drinking: report of an inter- departmental working group. London, UK, 1995.
3. Frisher M, Mendonca M, Shelton N, Pikhart H, de Oliveira C, Holdsworth C. Is alcohol consumption in older adults associated with poor self-rated health? Cross-sectional and longitudinal analyses from the English longitudinal study of ageing. BMC Public Health BMC Public Health (2015) 15:703 DOI 10.1186/s12889-015-1993-x
Conflict of Interest: