Nonsurgical fertility control for managing free-roaming dog populations: A review of products and criteria for field applications

About 75% of dogs worldwide are free to roam and reproduce, thus creating locally overabundant populations. Problems caused by roaming dogs include diseases transmitted to livestock and humans, predation on livestock, attacks on humans, road traffic accidents, and nuisance behavior. Nonsurgical fertility control is increasingly advocated as more cost-effective than surgical sterilization to manage dog populations and their impact. The aims of this review were to 1) analyze trends in numbers of scientific publications on nonsurgical fertility control for dogs; 2) illustrate the spectrum of fertility inhibitors available for dogs; 3) examine how differences between confined and free-roaming dogs might affect the choice of fertility inhibitors to be used in dog population management; and 4) provide a framework of criteria to guide decisions regarding the use of nonsurgical fertility control for dog population management. The results showed that the 117 articles published between 1982 and 2011 focussed on long-term hormonal contraceptives, such as gonadotropin-releasing hormone agonists, immunocontraceptives, and male chemical sterilants. The number of articles published biennially increased from one to five papers produced in the early 1980s to 10 to 20 in the past decade. Differences between confined dogs and free-roaming dogs include reproduction and survival as well as social expectations regarding the duration of infertility, the costs of sterilization, and the responsibilities for meeting these costs. These differences are likely to dictate which fertility inhibitors will be used for confined or free-roaming dogs. The criteria regarding the use of fertility control for dog population management, presented as a decision tree, covered social acceptance, animal welfare, effectiveness, legal compliance, feasibility, and sustainability. The review concluded that the main challenges for the future are evaluating the feasibility, effectiveness, sustainability, and effects of mass nonsurgical sterilization campaigns on dog population size and impact as well as integrating nonsurgical fertility control with disease vaccination and public education programs.     

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions

Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. Design: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. Setting: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). Subjects: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). Main outcome measure: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. Results: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. Conclusion: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.

Key messages

• The use of oral contraceptives is associated with an increased risk of cerebral venous sinus thrombosis
• This risk of cerebral venous sinus thrombosis in women who use oral contraceptives is larger if there is an additional hereditary prothombotic factor (protein C, S, or antithrombin deficiency, factor V Leiden mutation)
• The association between oral contraceptives, thrombophilia, and deep vein thrombosis is also valid for cerebral sinus thrombosis
• Women do not need to stop using oral contraceptives as the absolute risk of cerebral sinus thrombosis is very small

     

Effectiveness of abortion as birth control.

Several models used to study the effectiveness of abortion in population limitation are examined. The Keyfitz model, based on the probability that an individual woman will conceive in a given month, is extended and public implications of legal abortions are discussed. A model more appropriate for a population of women rather than a single woman can be developed by relating the probability of conception and the sterile intervals to the number of birth and the number of women in the population. The effectiveness of abortion as a birth control method is studied using this model and includes: 1) abortion effectiveness combined with efficient contraception (95% effective); 2) the sensitivity of abortion to gestation when a contraceptive of lower efficiency is used; 3) these effects modified for prolonged lactation; 4) the effect of changing the monthly probability of conception and the monthly efficiency of contraception. Abortion later in pregnancy is advantageous when efficient contraception is absent. The effectiveness of abortion to gestation is approximately the same whether lactation is included or absent, although abortion is more effective at all gestations and for all contraceptives efficiencies in the absence of lactation. The sensitivity of the effectiveness of abortion to the probability of conception decreases as monthly effectiveness of contraception increases. The probability of conception and the monthly effectiveness of contraception are difficult parameters to measure in the population. The effect of abortion averaged over the entire population at risk of pregnancy is different from its effect on certain subgroups. For U.S. females the probability of conception may be between .06 and .16, and from the model it is indicated that the effectiveness of abortion would be from 1 to 1.13 abortions per live birth. The application of the model suggests that the expenditures for abortion services in this population are a reasonable investment, although investment for efficient contraception is also suggested.     

Current Concepts in Conception Control

The progressive increase in world population has become a most urgent global problem in recent years. Man has, however, been interested in controlling his reproductivity at the family level for many centuries. Historical aspects of this saga are reviewed.The modern era of conception control was ushered in by Makepeace et al. in 1937 when ovulation inhibition by progesterone was demonstrated. Confirmation of this by Pincus and associates, and development of the potent oral progestational agents, the 19-norsteroids, have made efficient reliable contraception a reality.Experience with one of these agents (Ortho-Novum, 2 mg.) in 115 patients through 805 cycles is presented. Conception control was 100% effective at this dosage. Side effects were minimal. Only three of the women discontinued the tablets because of these effects. All but five in this group of 115 preferred the oral contraceptives to methods previously employed.     

Postoperative Thromboembolism and the Use of Oral Contraceptives

We have previously reported the results of a retrospective study of the relationship between oral contraceptives and deep vein thrombosis and pulmonary embolism occurring in the absence of an evident predisposing cause. The present paper describes a similar investigation of the relationship between oral contraceptives and thromboembolism following certain surgical procedures.Of 30 patients with thromboembolism, 12 (40%) had been using oral contraceptives during the month preceding surgery, while only 9 of 60 matched controls (15%) had been doing so. From these data it is estimated that the risk of postoperative thromboembolism is increased threefold to fourfold by the use of contraceptive steroids.It is recognized that few of the episodes of deep vein thrombosis and pulmonary embolism that occur postoperatively are detectable clinically, and that not all of these are recorded in discharge summaries or diagnostic indexes. Despite these considerations, we have been unable to detect any important bias in the data which could account for the observed association between oral contraceptives and the development of postoperative thromboembolism.     

The return of the pharmaceutical industry to the market of contraception

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.     

Investigation of Relation between Use of Oral Contraceptives and Thromboembolic Disease. A Further Report

The results of a previous study of the use of oral contraceptives by married women discharged from hospital with a diagnosis of thromboembolic disease in the years 1964–6 were reported by us last year. The present paper adds results relating to patients discharged during 1967 and a few data, that could not be sought previously, for patients discharged with cerebral or coronary thrombosis from three of the hospitals in the earlier period.Of 84 patients with deep-vein thrombosis or pulmonary embolism 42 (50%) had used oral contraceptives during the month preceding the onset of their illness, while only 23 of the 168 controls (14%) had done so. No differences in risk were found either for the types of preparation or for the duration of use. After allowance for age and height, the patients with venous thromboembolism were about 10 lb. (4,535 g.) heavier than the control patients, irrespective of whether they were using oral contraceptives or not. No appreciable difference was found between the smoking habits of patients with and without venous thromboembolism treated during 1967, nor between women who were using oral contraceptives and those who were not. The trend in hospital admissions for venous thromboembolism with time corresponded to the trend in the use of oral contraceptives, and there was no evidence to suggest that the number of admissions was affected by publicity about the risk of using the preparations. Of 19 patients with cerebral thrombosis 11 (58%) had been using oral contraceptives, compared with an expected figure of 3.5 from the experience of the control subjects. All the published data (clinical, angiographic, and post-mortem) show that the thrombosis affects the cerebral arteries rather than the cerebral veins. Of 17 patients with coronary thrombosis 2 (12%) had been using oral contraceptives, compared with an expected figure of 2.1. The patients with coronary thrombosis smoked more than the control patients and were, on average, 8.3 lb. (3,765 g.) heavier than control women of the same age and height.The new evidence strengthens the belief that oral contraceptives are a cause of venous thromboembolism and cerebral thrombosis but does not indicate that they are a cause of coronary thrombosis.     

Five Classic Articles in Public Health

In this brief review, Dr. Jonathan Borak comments on five seminal papers that helped shape the fields of epidemiology and public health. These papers include Hill’s criteria for inferring causality; the first proof of the multistage theory of cancer; the first evidence that subclinical lead exposures can cause neurobehavioral impairment in children; a simple yet robust study that had a major influence on setting current air pollution policies; and a landmark review of the general public’s perception of risk in relation to actual public health hazard.Dr. Jonathan Borak is a Clinical Professor of Epidemiology and Public Health at the Yale School of Public Health, Clinical Professor of Internal Medicine at the Yale School of Medicine, and Director of the Yale Interdisciplinary Risk Assessment Forum. In this article, Dr. Borak provides his perspective on five publications that significantly influenced the study and practice of epidemiology and public health. This article is the first in a series that will identify and provide commentary on the top five seminal papers published in a field related to biology and medicine.A former student, a member of the Yale Journal of Biology and Medicine’s Editorial Board, reminded me of a comment I made in class. I had described a particular assigned reading as “one of those classic articles” that should be read by everyone studying public health. Okay, he challenged me, what other “classic articles” were on my list? And so began the following: my short list of five articles that represent “must reading” for all students in public health.First, note that I do not speak for public health in general, a field of great breadth of interest and activity, but only the narrower slice, including toxicology, risk assessment, and related interests. Also, I was principally concerned to identify articles that provide models of critical thinking, addressed issues of substantial public health importance, and served as stepping stones for subsequent research and the formulation of public health policy. I also wanted to include articles that were observational and opportunistic, i.e., based on real world observations and available data, not complex laboratory models.My five choices below include: 1) a landmark presentation of criteria for inferring causality from observational data (Hill 1965); 2) a thought experiment based on the re-analysis of publicly available cancer mortality data, which shaped the fields of cancer biology and risk assessment (Armitrage & Doll, 1954); 3) an early study of the effects of lead exposure in school children (Needleman, 1979); 4) a study of the impact of air pollution on children’s health, which was enabled by a fortuitous labor dispute that shuttered a polluting steel mill (Ransom & Pope, 1992); and, 5) a critical literature review of cognitive psychology research that shaped our understanding about how public health risks are perceived (Slovic, 1987).     

Oral contraceptives and porphyria cutanea tarda

The clinical and biochemical findings in two cases of porphyria cutanea tarda (PCT) are presented. The cases are unique in their early age of onset (24 and 22 years) and their apparent precipitation by low-dosage oral contraceptives.Review of the literature reveals these to be the two youngest patients with estrogen-induced PCT. Only one other case of PCT induced by low-dosage oral contraceptives has been reported. In most cases of PCT induced by estrogens, high dosages have been taken by patients over age 35.     

Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis

ObjectiveTo compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.DesignCohort and case-control analyses derived from the General Practice Research Database.SettingUK general practices, January 1993 to December 1999.ParticipantsWomen aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.ResultsThe adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.ConclusionsThese findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.     

Studies of Carbohydrate and Lipid Metabolism in Women Developing Hypertension on Oral Contraceptives

Metabolic studies in 100 women developing hypertension on combined oestrogen-progestogen oral contraceptives have been compared with similar studies in normotensive women on oral contraceptives, matched for age and duration of contraceptive use, and in women not taking contraceptives.The metabolic changes known to be induced by oral contraceptives—impaired glucose tolerance, elevated blood pyruvate levels, and raised serum lipid concentrations—were found to be exaggerated in the matched hypertensive group, largely due to pronounced abnormalities in 33 subjects with diastolic blood pressures over 110 mm Hg.Women developing severe hypertension were older, more obese, and of higher parity than those with mild hypertension and there was a high incidence of previous toxaemia of pregnancy in the hypertensive group.The results show that in women on oral contraceptives changes in blood pressure and in metabolic functions tend to be correlated with one another, and are consistent with the hypothesis that oral contraception induces a primary biochemical effect whose expression in the individual is determined by intrinsic factors including genetic constitution, age, weight, and parity.     

Effect of NBS1 gene polymorphism on the risk of cervix carcinoma in a northern Indian population

Cervical cancer is one of the most common neoplastic diseases affecting women, with a worldwide incidence of almost half a million cases. A history of smoking and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. Genetic susceptibility and immune response, especially impaired cellular immune response, may well be related to the development of cervical cancer. NBS1 is one of the key proteins participating in the recognition and repair of double-strand breaks that may lead to genomic instability and cancer if unrepaired. The objective of the present study was therefore to investigate NBS1 Glu185Gln gene polymorphisms and the risk of cervix cancer in a northern Indian population. We found that passive smokers having particular NBS1 genotypes (Glu/Gln, Gln/Gln or Glu/Gln + Gln/Gln)have an increased risk of developing cervix cancer (OR 5.21, p=0.000001; OR 4.60, p=0.001; OR 5.10, p=0.0000009, respectively).The risk was increased 2.4-fold in oral contraceptive users with a Glu/Gln genotype. We conclude that the risk of cervical cancer is increased in passive smokers and in users of oral contraceptives with certain NBS1 genotypes.     

Proceedings: Correlation of various clinical parameters with glucose tolerance test in women using oral contraceptives

A study was carried out to determine whether oral contraceptives affect carbohydrate metabolism as assessed by glucose tolerance curves. Glucose tolerance tests were carried out in seventy-six women. The women were divided into two groups. The first group constituted the control and the second group comprised women taking combination oral contraceptives. The glucose tolerance curves were correlated with: (1) the duration of thereapy; (2) the family history of diabetes; (3) the obstetric history; (4) age: (5) weight gain; (6) parity; and (7) changes in blood pressure. The combination type of oral contraceptives were observed to affect adversely the glucose tolerance test. A significant correlation was recorded between the familial diabetic history, intake of combination contraceptives and abnormal glucose tolerance tests. A history of birth of a large baby was found to be an important indicator of abnormal values of glucose tolerance in women taking a combination type of oral contraceptive. Such women showed an abnormal curve pattern at a much earlier age in life compared with controls. It was also observed that a high percentage of women who had gained excessive weight on combination contraceptives had an altered glucose tolerance test. Parity and blood pressure were two parameters which did not reveal any correlation with abnormal glucose tolerance curves.     

Oral contraceptives,pregnancy, and endogenous oestrogen in gall stone disease--a case-control study.

A case-control study of gall stone disease in women in relation to use of contraceptives, reproductive history, and concentrations of endogenous hormones was undertaken. The study population comprised 200 hospital patients with newly diagnosed gall stone disease, 182 individually matched controls selected from the community, and 234 controls who were patients in hospital. Use of oral contraceptives was associated with an increased risk of developing gall stones among young subjects but a decreased risk among older subjects. The risk of developing gall stone disease increased in association with increasing parity, particularly among younger women. The risk fell with increasing age at first pregnancy, independent of parity. Mean urinary excretion over 24 hours of oestrone, but not of pregnanediol, was significantly (p less than 0.05) greater for postmenopausal patients than controls. The age dependence of the relative risk associated with exposure to oral contraceptives and pregnancy suggests that there are subpopulations of women susceptible to early formation of gall stones after exposure to either oral contraceptives or pregnancy.     

Oral Contraceptives,Depression, and Libido

Depression, headaches, and libido were rated in 272 women before starting a contraceptive method and at intervals during the first year of use—54 were fitted with an intrauterine device (I.U.D.) and 218 used one of three oral contraceptives. Side effects caused 25% of the oral contraceptive group and 13% of the I.U.D. group to stop the method. Depression, headaches, and loss of libido were the most common reasons for stopping oral contraceptives and breakthrough bleeding was the most common reason for stopping the I.U.D.The group of women who stopped or changed their oral contraceptives during the survey were compared with the group who remained on the same oral contraceptive throughout. The former had higher mean depression and neuroticism scores at the first clinic visit and contained more women with a history of premenstrual weepiness, depression during pregnancy, outpatient psychiatric treatment, and treatment with antidepressants. Changes in the depression, headache, and libido ratings throughout the survey are presented.     

Side effects and discontinuation of oral contraceptive use in southern Brazil

Oral contraceptives have many advantages, but sometimes also have side effects which can cause users to switch appropriately or inappropriately to less effective methods or abandon contraception. In Brazil, 2/3 of married women of childbearing age were using contraception in 1981, and 1/2 of these were using orals. Contraceptive behavior following reported side effects in users of oral contraceptives in Southern Brazil is examined in this study, in relation to diverse factors. Among 2904 currently-married women, aged 15-44, almost 75% reported that they had used the pill at some time, and of these, 45.6% were still doing so. Data on perceived side effects were gathered for all women. There was no independent medical evaluation of the effects, so the data did not necessarily represent actual prevalence of pill related problems. Women who reported problems with the pill were less likely to be current users (25%) than women who did not (65%). However, overall contraceptive prevalence was about the same in both groups (66.2% and 67.0% respectively), indicating that women who stop using oral contraceptives usually switch to another method. However, they are more likely to be using traditional methods than women in the general population, especially if they want more children. Termination of pill use varies little according to the type of problem reported. Women with problems who sought medical attention were more likely to stop using the pill, and 82.4% of women advised to stop by their physician did so, but the major factor affecting discontinuation was the reported experience of a problem. The most frequently reported problems were headaches (38.1%), nausea (34.1%), nervousness (27.9%), and vertigo (18.3%). Physician intervention should help to avoid women's abandoning oral contraceptives unnecessarily.     

The statistical basis of public policy: a paradigm shift is overdue.

The recent controversy over the increased risk of venous thrombosis with third generation oral contraceptives illustrates the public policy dilemma that can be created by relying on conventional statistical tests and estimates: case-control studies showed a significant increase in risk and forced a decision either to warn or not to warn. Conventional statistical tests are an improper basis for such decisions because they dichotomise results according to whether they are or are not significant and do not allow decision makers to take explicit account of additional evidence--for example, of biological plausibility or of biases in the studies. A Bayesian approach overcomes both these problems. A Bayesian analysis starts with a "prior" probability distribution for the value of interest (for example, a true relative risk)--based on previous knowledge--and adds the new evidence (via a model) to produce a "posterior" probability distribution. Because different experts will have different prior beliefs sensitivity analyses are important to assess the effects on the posterior distributions of these differences. Sensitivity analyses should also examine the effects of different assumptions about biases and about the model which links the data with the value of interest. One advantage of this method is that it allows such assumptions to be handled openly and explicitly. Data presented as a series of posterior probability distributions would be a much better guide to policy, reflecting the reality that degrees of belief are often continuous, not dichotomous, and often vary from one person to another in the face of inconclusive evidence.     

Vitamin A,Pregnancy, and Oral Contraceptives

It has been shown that women receiving oral contraceptives have increased levels of serum vitamin A. High vitamin A levels may constitute a teratogenic hazard and it has been suggested that women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard.We have confirmed a significant increase in vitamin A levels in women taking oral contraceptives. During early pregnancy there is no significant difference in vitamin A levels between women who have recently been taking oral contraceptives and those who have not. We have been unable to show that either taking oral contraceptives shortly before pregnancy or a high vitamin A level during the first trimester of pregnancy, comparable to that of a woman taking oral contraceptives, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women who conceive soon after discontinuing oral contraception run any teratogenic risk from increased vitamin A levels.