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Diabetes and oral contraception
Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 67–76
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Diabetes and oral contraception Pierre Gourdy, MD, PhD, Professor a, b, * a b
Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU de Toulouse, France INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, France
Keywords: diabetes mellitus estrogens progestins contraception pregnancy cardiovascular risk
The prevalence of diabetes mellitus is increasing dramatically worldwide, resulting in more and more women of reproductive age being affected by either type 1 or type 2 diabetes. Management of contraception is a major issue due to the specific risks associated with pregnancy and those potentially induced by hormonal contraceptives in diabetic women. This review emphasizes the urgent need to improve the use of contraception in women with diabetes. There is no consistent evidence that combined oral contraceptives significantly influence the risk of developing diabetes, even in women with a history of gestational diabetes. Furthermore, although data from specific studies remain sparse, no worsening effect has been reported in diabetic women, either in glycemic control or on the course of microvascular complications. Thus, the use of estroprogestive pills is now recognized as a safe and effective option for preconception care of women with uncomplicated diabetes. According to recent guidelines, these contraceptives must be avoided in case of associated cardiovascular risk factors, cardiovascular disease or severe microvascular complications such as nephropathy with proteinuria or active proliferative retinopathy. Prescription of combined hormonal contraception in type 2 diabetic women must also be considered with caution due to a frequent association with obesity and vascular risk factors which increase both thromboembolic and arterial risks. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives, as well as non-hormonal methods, represent alternatives according to patient wishes. Ó 2012 Elsevier Ltd. All rights reserved.
Abbreviation: COC, combined oral contraception. * Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: þ33 561 323 740; Fax: þ33 561 322 270. E-mail address: [email protected]. 1521-690X/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2012.11.001
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Introduction Contraception is a critical issue in women affected by diabetes mellitus.1 It is crucial to achieve a balance between the specific risks associated with pregnancy and those potentially induced by the contraceptive itself in diabetic women. It is well recognized that unplanned pregnancy can result in severe outcomes in women with diabetes, from the fetal to the neonatal period.2,3 Diabetes with poor metabolic control favors congenital abnormalities, spontaneous abortion, in utero death, fetal overgrowth leading to macrosomia, neonatal hypoglycaemia and hyperbilirubinemia, as well as many other deleterious effects for the fetus or newborn child. Unplanned pregnancy can also lead to dramatic complications for pregnant diabetic women, including an increased risk of hypertension and preeclampsia, as well as the worsening of pre-existing degenerative complications such as retinopathy or nephropathy.2,3 The potential side-effects of certain contraception regimens frequently expose diabetic women to risk factors for cardiovascular events such as thromboembolic and cardiovascular risk. Thus, vascular safety represents a major concern for the orientation of contraception strategy in diabetic women.1 In the present review, we will first summarize recent epidemiological data that emphasize the urgent need to improve the use of contraception in women with diabetes. We will also focus on oral hormonal contraceptives and discuss their specific effects on glucose metabolism and vascular risk, in order to clarify their position in the management of contraception in both type 1 and type 2 diabetic women, according to recent guidelines. Diabetes mellitus: a growing public health problem in women The prevalence of diabetes has dramatically increased in the past two decades, and continues to rise worldwide. Epidemiological projections from the International Diabetes Federation (IDF) indicate that the global number of diabetic subjects among the adult population (20–79 year range) will increase from 285 million in 2010 to 439 million in 2030, with a maximal progression in developing countries.4 It is obvious that this epidemic trend mainly concerns type 2 diabetes, concurrently with the growing prevalence of obesity. However, the incidence of type 1 diabetes has also been reported to have increased worldwide, especially in children and teenagers.5 These worrying epidemiological considerations provide evidence that more women of reproductive age have diabetes, resulting in more pregnancies that place both mother and fetus at higher risk of complications. Consequently, clinicians will have to face a growing number of complex situations, such as adolescents with poorly controlled type 1 diabetes,6 or young women developing type 2 diabetes in association with obesity and concomitant cardiovascular risk factors. A crucial role for contraception in diabetic women It is well established that the specific risks related to diabetes can be minimized through preconception care including specific programs of therapeutic education and optimal glycemic control, both before and during pregnancy. Therefore, women with diabetes are able to improve pregnancy outcomes by delaying conception until optimal glucose levels are reached and/or microvascular complications, such as retinopathy, are stabilized.7 This absolute need for preconceptional care and planning of pregnancy emphasize the conclusion that adequate use of contraception represents a crucial step in the management of diabetes in women during their reproductive lives. Unfortunately, recent data suggest that diabetic women and obese women are less likely to use contraception or to receive preventive health care services.8 Analyzing the responses of 5955 participants aged 20–44 years in the 2002 National Survey for Family Growth in the United States, women with diabetes were more likely to not use contraception than women without diabetes (odds ratio [OR]: 2.61 [95% CI 1.22–5.58]), in unadjusted comparisons among sexually active women who were not sterilized.8 Similar results were reported from a cross sectional study comparing the use of hormonal contraception in 947 type 1 diabetic women, 365 type 2 diabetic women and age-matched women without diabetes, all included in the United Kingdom General Practice Research Database (GPRD).9 Women with diabetes were less likely to use hormonal contraception than women without
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diabetes: OR for type 1 diabetes 0.83 (0.59–0.93), OR for type 2 diabetes 0.60 (0.42–0.83). Furthermore, the data indicate that diabetes status significantly influences the choice of the contraception strategy since women with type 1 diabetes were more likely to be prescribed a combined pill than a progestinonly pill, but were significantly more likely to be prescribed the latter contraception than were women without diabetes: OR 1.65 (1.26–2.13). Compared with non-diabetic subjects, women with type 2 diabetes were also less likely to be prescribed a combined oral contraceptive: OR 0.39 (0.24–0.62).9 Taken together, these observations highlight significant variations in prescribing hormonal contraception to diabetic women compared with those without diabetes. As hormonal contraception is now recognized as a safe and effective option for women with uncomplicated diabetes, we can hypothesize that poor metabolic control, or associated risk factors for cardiovascular disease, have influenced clinicians in avoiding the use of hormonal contraception. However, it is paradoxically these women who are at most risk from unplanned pregnancy. Thus, improving the management of contraceptives in the whole population of diabetic women potentially exposed to pregnancy should be considered as a major health care issue. To this end, it is of utmost importance to consider the respective safety profiles of the different contraceptive modes in diabetic women. Although specific studies in diabetic women remain sparse, we will detail thereafter our current knowledge on the influence of the two types of oral hormonal contraception, namely combined estroprogestive and progestin-only pills, on metabolic and vascular risks in this population. Influence of oral contraception on glucose homeostasis There is no evidence that current combined oral contraception (COC), containing ethinyl-estradiol (EE) doses lower than 35 mg, exerts a significant influence on plasma glucose concentrations and insulin secretion profile.10 In most studies, no significant changes in fasting plasma glucose were observed in women receiving such oral contraception.11–13 Furthermore, following the introduction of a COC, glycemic profiles in response to oral glucose challenge have been shown to remain unchanged,14 or to weakly increase, but without clinical significance in non-diabetic women.12,15,16 In a study by Oeklers et al., COCs induced a slight increase in the area under the curve after a standardized oral glucose tolerance test: 10% increase for the combination of EE 15 mg and drospirenone 3 mg, 14% increase for EE 20 mg and drospirenone 3 mg, 14% increase for 30 mg EE and levonorgestrel, and 19% increase for EE 30 mg and drospirenone 3 mg.15 Fasting insulinemia was also reported to remain unchanged17,18 or to slightly increase12,19 in women using COC. In a transversal study including 559 Finnish women, insulinemia was not modified in women receiving EE combined with either levonorgestrel or desogestrel compared with women not receiving oral contraception.18 Among the 1940 women participating in the CARDIA prospective trial in the United States, fasting insulinemia levels slightly increased in women receiving oral contraception (þ0.12 mU/L), and this trend remained significant after multiple adjustments for confounding factors.19 Finally, although some studies suggested that COC could alter insulin sensitivity,20,21 the data available to date indicate that this mode of contraception does not exert significant influence on glucose metabolism.13 The influence of progestin-only contraceptives on glucose and lipid metabolism also appears weak and, in most cases, non-significant, although it depends on the specific pharmacologic characteristics of the different molecules.22,23 A complete review from the Cochrane Database recently evaluated the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk of diabetes due to overweight.24 This latter analysis confirms that current evidence indicates no major differences in glucose metabolism between different hormonal contraceptives in women without diabetes. Oral contraception and incidence of diabetes in women From epidemiological data, it can be concluded that oral contraception in healthy women is not associated with an increased risk of developing diabetes. As a first demonstration, among the 98,590 women participating in the Nurses’ Health Study, the incidence of diabetes was not increased in current or past users of oral contraceptives.25,26 After a four year follow-up, the OR for diabetes occurrence was 1.6
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(0.9–3.1) in current users, and 1.2 (0.8–1.8) in past users, after adjusting for age, body mass index, familial history of diabetes, tobacco consumption, physical activity, alcohol consumption, hypertension, previous pregnancies and dyslipidemia.25 Accordingly, a case-control study including 57,180 Chinese women (Shanghai Women’s Health Study) did not find any association between the use of oral contraception and the incidence of diabetes.27 Thus, even if some oral contraceptive combinations slightly alter insulin sensitivity, no clinical relevance has been reported in terms of diabetes incidence. Influence of oral contraception on metabolic control in women with diabetes The influence of COC appears to be non-significant in healthy women, but it was important to address their impact on glycemic control in diabetic women. A Cochrane review conducted in 2006 investigated whether progestin-only, combined or non-hormonal contraceptives differ in terms of effectiveness in preventing pregnancy, in their side-effects on carbohydrate and lipid metabolism and in long-term complications such as micro- and macrovascular disease, when used in women with diabetes.28 Although the three randomized controlled trials included in this systematic review were insufficient to provide definite conclusions, no difference was found in daily insulin requirement, glycated hemoglobin (HbA1c) or fasting blood glucose after twelve months of contraception in type 1 diabetic women. In the whole diabetic population, the analysis reported blood glucose levels to remain stable during treatment with most contraception regimens. Only high-dose COC was found to slightly impair glucose homeostasis.28 Although none of them compared the effect of different doses of EE, studies conducted in type 1 diabetic women failed to demonstrate an increase in insulin needs under estroprogestive contraception. In a Russian study including 113 premenopausal women with diabetes, combined oral contraception did not influence HbA1c nor insulin requirements, and the majority of the hormonal combinations did not exert any unfavorable effects on blood lipid profile.29 Oral contraception and microvascular complications in diabetic women In women with diabetes, one of the most important questions relates to the potential worsening effect of hormonal contraception on the occurrence or the progression of degenerative complications, especially retinopathy and glomerulopathy, through direct deleterious actions on microvascular circulation. However, this specific risk seems to be insignificant except in cases of severe and active complications. Indeed, no increase in the prevalence and/or the severity of microvascular complications, namely retinopathy and nephropathy, was reported in type 1 diabetic women using COC. A prospective study examined the progression of microvascular lesions in 86 women with type 1 diabetes (diabetes duration: 14 years, HbA1c: 12%), and found no influence of combined oral contraceptives one year after the initiation of this mode of contraception.30 In addition, COCs did not exert any worsening effect on the progression of retinopathy or on the incidence of macular edema in women with either younger onset diabetes (type 1) or older-onset diabetes (both type 1 and type 2) after a 10year or a 6-year follow-up, respectively (Table 1).31 Only one observational study reported an association between COC use and a significant increase in proteinuria level, but in a small sample of type 1 diabetic patients.32 Despite these reassuring data, it is crucial to remember that the prescription of combined contraception with estrogens and progestins, whatever their route of administration, should not be proposed, or at least with extreme caution, in diabetic patients with uncontrolled microvascular complications such as severe retinopathy (ischemic or proliferative area), active macular edema, or nephropathy with persistent proteinuria. It cannot be excluded that estroprogestives could exert deleterious effects on microvessels, and robust prospective data regarding the safety of this mode of contraception are still lacking in such pathophysiological contexts. Oral contraception and vascular risk in diabetic women In addition to these considerations on glycemic control and microvascular complications, the safety profile of oral contraceptive methods must be analyzed according to the level of cardiovascular risk, more specially in women with type 2 diabetes. The latter condition is frequently associated with
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Table 1 Influence of combined oral contraceptive (COC) use on retinopathy progression in the Wisconsin Epidemiological study of Diabetic Retinopathy (women with either younger- or older-onset diabetes). Adapted from Ref.31 Changes in complications
Progression of retinopathy Progression to proliferative retinopathy Incidence of macular edema Incidence of hypertension a b
Adjusted OR (95%CI) COC users versus non-users Younger-onset diabetesa 10-Year follow-up
Older-onset diabetesb 6-Year follow-up
1.21 (0.73–2.02) 0.54 (0.27–1.08)
1.19 (0.43–3.24) 0.28 (0.03–2.77)
0.99 (0.46–2.14) 1.05 (0.56–1.94)
0.48 (0.11–2.08) 1.91 (0.50–7.26)
Women diagnosed with diabetes before the age of 30 years (all on insulin therapy). Women diagnosed with diabetes after the age of 30 years (random sample stratified by duration of diabetes, insulin-treated or not).
obesity and multiple cardiovascular risk factors such as hypertension and dyslipidemia. Unfortunately, to date, no study specifically dedicated to diabetic women has been conducted to address the cardiovascular safety of combined oral contraceptives, but data from sub-group analyses are available. For instance, in a WHO study, the influence of combined estroprogestive contraception on the incidence of stroke was higher in diabetic than in non-diabetic women.33 Another study reported a significant increase in the risk of stroke (OR: 7.1 (3.5–16.1)) in diabetic women using a COC.34 In addition, a case-controlled study analyzed the risk of myocardial infarction induced by COCs according to diabetic status. The data confirmed that diabetes represents an independent risk factor, but also show that this mode of contraception is associated with a further increase in the incidence of myocardial infarction risk in the diabetic population: OR ¼ 7.4 (3.1–98.1) in diabetic users and OR ¼ 4.2 (1.6–10.9) in diabetic non-users.35 Importantly, the identification of one or more cardiovascular risk factors associated with diabetes should lead us to reconsider the prescription of combined contraceptives in diabetic women. Illustrating the influence of cumulative cardiovascular risk factors, a WHO case-control study included 1309 women in Europe and developing countries, and found no significant influence of COC on the risk of myocardial infarction in women without tobacco consumption and hypertension: OR 1.1 (0.12–9.69).36 In contrast, this study demonstrated a significant increase in myocardial infarction incidence related to oral contraception use in women with associated cardiovascular risk factors: non-smoking women with hypertension (OR: 16.4 [3.08–87.7]), smoking women without hypertension (OR: 26.6 [7.00– 101]), and smoking women with hypertension (OR: 71.4 [16.5–309]).36 It is also important to consider the potential worsening effect of COC on cardiovascular risk factors in diabetic women. This mode of contraception has been shown to influence plasma lipid profile (increasing triglycerides and HDL cholesterol and slightly decreasing LDL cholesterol), according to both estrogen dosage and to the androgenic action of the progestin.37,38 Since dyslipidemia is a frequent feature of metabolic syndrome and type 2 diabetes, it is crucial to consider the hypertriglyceridemic effects of COCs and to prescribe this type of contraception with caution. In clinical practice, plasma lipid profile must be analyzed before and monitored after the initiation of COC. Furthermore, COCs will be contraindicated in case of persistent hypertriglyceridemia in diabetic women. In the absence of familial dyslipidemia or nephropathy, the situation appears to be quite different in type 1 diabetic patients. No significant changes in insulin sensitivity, lipid profile or coagulation parameters were observed in type 1 diabetic women after the introduction of a COC, compared with non-diabetic women.39 To our knowledge, no specific studies have been performed to evaluate the influence of oral contraception on blood pressure in diabetic women. In the general population, the influence of COCs on blood pressure is modest, although they are able to induce hypertension in less than 5% of women.40 However, the prevalence of hypertension is generally higher in women with type 2 diabetes, and also in the case of nephropathy in type 1 diabetic women. Identification of hypertension history and blood pressure measurement are thus absolutely required before prescribing hormonal contraception in diabetic women, and combined contraceptives will be contraindicated in case of uncontrolled hypertension.
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Corroborating data indicate that diabetic women are generally characterized by an increased risk of thromboembolic events. This trend mainly results from the fact that most women with type 2 diabetes are obese or at least overweight, whereas no significant increase in venous risk has been associated to hyperglycemia itself. Although transdermal or vaginal administration of estroprogestive combinations limits their influence on protein synthesis by the liver, the safety of both alternative routes has not been addressed to date and the contraindications remain the same that those of COCs in diabetic women. Similarly, the safety of the recent hormonal contraception formulation containing estradiol–valerate or 17-b-estradiol has not been addressed in diabetic women. Use of oral contraceptives in diabetic women Medical eligibility criteria for contraceptive use were updated in 2009 by the WHO,41 then adapted for the United States in 2010.42 These clinical guidelines include situations potentially associated with high vascular risks, such as diabetes (Table 2). Thereafter, we devised the following recommendations for the management of oral contraceptives in women with either type 1 or type 2 diabetes. Women with type 1 diabetes As previously detailed in this review, it is crucial to take into account the existence of microvascular or cardiovascular complications and/or vascular risk factors (dyslipidemia, hypertension, tobacco consumption, diabetes duration >20 years) before the introduction of any oral contraceptive in type 1 diabetic women. COC can be prescribed for type 1 diabetic women without any macrovascular or active microvascular complications, and in the absence of any cardiovascular risk factors. Poor glycemic control alone does not represent a contraindication for use of combined contraceptives, but great caution must be exercised with associated risk factors, especially tobacco consumption. In our opinion, minor or moderate non-proliferative retinopathy, as well as isolated and moderate microalbuminuria, should not be considered as contraindications to combined contraception use. In contrast, when severe degenerative complications are present, such as nephropathy with proteinuria and/or renal failure, active retinopathy (ischemic and proliferative area), cardiovascular diseases or peripheral/vegetative neuropathy, COC must be contra-indicated. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives represent an alternative, as well as non-hormonal methods, according to patient wishes. Women with type 2 diabetes The situation is quite different for type 2 diabetes since this metabolic condition is frequently associated with obesity, insulin resistance and cardiovascular risk factors. Thus, the use of COC must be
Table 2 Medical eligibility criteria for the use of combined oral contraceptives and progestin-only pills in diabetic women. Adapted from Refs.41,42 Clinical presentation
Combined oral contraceptives
Progestin-only pills
History of gestational diabetes Type 1 diabetes (absence of vascular complications) Type 2 diabetes (absence of vascular complications) Microvascular complications (retinopathy, nephropathy, neuropathy) Other vascular disease or diabetes duration >20 years
No restriction Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Theoretical/proven risks outweigh advantages to unacceptable health riska Theoretical/proven risks outweigh advantages to unacceptable health riska
No restriction Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks
a
According to the severity of the complications.
Advantages outweigh theoretical/proven risks
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restricted in type 2 diabetic women and the choice of an alternative contraception, such as progestinonly or non-hormonal contraceptives, should be systematically considered. However, the incidence of type 2 diabetes rapidly increases in women in association with overweight or obesity but in the absence of additional vascular risk factors, even in the youngest age ranges. COCs can be proposed in these cases, but only in women without obesity (Body Mass Index <30 kg/m2), additional cardiovascular risk factors or microvascular or cardiovascular complications. Choosing this contraceptive strategy systematically implies a strict monitoring of weight, glycemic control, plasma lipid profile and blood pressure. At the population level, there is no evidence that COC induces body weight gain in obese women.43 Obesity must be considered as an additional factor of complexity in women with type 2 diabetes. A recent French study demonstrated a 4-fold increase in the number of undesired pregnancies in obese women, compared with those in the normal weight range.44 Less efficient modes of contraception were used by obese women with poorer medical management. Whether obesity is associated with a decrease in the efficiency of hormonal contraception, due to an increase in distribution volume, remains a matter of debate.45,46 Two case-control studies reported an increase in undesired pregnancy in obese women.47,48 Conversely, other studies did not find any association between the failure of hormonal contraception and obesity.43 Altogether, the data available do not allow us to conclude that optimal use of oral contraceptives leads to lesser protection in obese women than in women with weight in the normal range, although no results have been provided for women with BMI values exceeding 35 kg/m2. However, COC must be avoided in obese women with type 2 diabetes. No specific studies have been conducted to address the metabolic and vascular safety of progestin-only contraception in this context. Oral contraception in women with a history of gestational diabetes Contraceptive options in women who experienced gestational diabetes also represent an important matter of discussion according to the high risk of developing type 2 diabetes in this particular population. Indeed, numerous studies reported a 7-fold increase in diabetes incidence in the 5–10 years following gestational diabetes.49 After gestational diabetes, it is crucial to systematically check the glucose tolerance status in the immediate post-partum period and to organize a systematic screening for alteration of glucose metabolism in the follow-up. Recent data indicated that a history of gestational diabetes is not associated with the use of numerous contraceptives.50 However, only a few studies addressed the question of whether oral contraception alters glucose homeostasis after gestational diabetes. No changes in glucose tolerance, and only a slight alteration of insulin sensitivity, were reported in the short-term following the prescription of oral hormonal contraception in women with a recent history of gestational diabetes.51 Accordingly, after a 7year follow-up, no increase in type 2 diabetes incidence was observed in a cohort of Hispanic women with a history of gestational diabetes who received COCs.52 Recording the data from 14 studies, BaptisteRoberts et al. further demonstrated that combined contraception does not influence the risk of developing type 2 diabetes in women who previously experienced a gestational diabetes.53 Furthermore, a single retrospective study led to discordant results, reporting that COCs led to a worsened glycemic profile compared with non-hormonal contraceptives in 590 Hispanic women followed during 2 years.54 The relationship between microprogestive contraception and type 2 diabetes incidence has been also examined, but in only one study.52 Latino–American women who experienced gestational diabetes were found to have an increased risk of developing type 2 diabetes during the post-partum period with breastfeeding: the OR was 2.87 (1.57–5.27) in the whole population, 2.96 (1.35–6.52) when women were exposed to microprogestins for 4–8 months, and 4.92 (1.76–13.73) for an exposition to this contraceptive mode exceeding 8 months.52 However, these data have not been confirmed to date, and it is important to emphasize that only breastfeeding women were considered, limiting the extrapolation for all post-partum situations. According to current knowledge, the influence of oral contraceptives on the risk of developing type 2 diabetes seems to be non-significant in women with a history of gestational diabetes. The use of combined or progestin-only oral contraception can be proposed in this clinical situation without specific restriction. In the absence of contraindications related to a significant risk of cardiovascular or thromboembolic disease, COCs are thus an excellent option according to patient wishes. However, in relation to the high risk of thromboembolism in the immediate post-partum, COCs are contraindicated
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during the 6 weeks following the delivery, as recommended in the general population. At this time, the only hormonal contraceptive option is progestin-only pills. As highlighted above, women who have had gestational diabetes mellitus must be monitored in the immediate postpartum period to ensure that blood glucose levels return to normal without further treatment. However, the choice of the contraceptive mode must also take into consideration the associated vascular risk factors, more frequent in this specific population. Indeed, the presence of obesity, hypertension, or dyslipidaemia must influence the choice of contraception towards one without cardiovascular consequences, such as progestin-only contraceptives. Conclusion Although exposed to numerous risks of complications during pregnancy, diabetic women are less likely to use contraception than non-diabetic women. As an explanation, oral hormonal contraceptives, mainly estroprogestive pills, are prescribed less in diabetic women, probably as a result of the fear of vascular side effects. However, available data strongly suggest that COCs represent a safe and effective option for preconception care in diabetic women, at least in those with uncomplicated diabetes. Recent guidelines underline the need to avoid the use of estroprogestive pills in case of associated cardiovascular risk factors, cardiovascular diseases or severe microvascular complications, such as nephropathy with proteinuria or active proliferative retinopathy. Furthermore, the number of type 2 diabetic women in the reproductive age range is dramatically higher nowadays, and COCs must be used with caution in this population due to the frequent association with obesity and vascular risk factors which increases both thromboembolic and arterial risks. Facing these high-risk profiles, progestin-only contraceptives represent an interesting alternative thanks to their metabolic and vascular safety profile, as well as non-hormonal methods, according to patient wishes. Importantly, the poor tolerance of microprogestins, particularly due to frequent uterine bleeding, must also be kept in account to guide the choice of contraception, aiming to an optimal adherence and efficiency. Improving the management of contraception will be a crucial step to limit the burden of unplanned pregnancy in women suffering from diabetes mellitus. To this aim, it is crucial that endocrinologists and gynecologists, as well as general practitioners, join forces, firstly to immediately reinforce educative messages about contraception in diabetes, and secondly to conduct specific prospective studies in the diabetic population, including new formulations without EE. Practice points - Diabetic women are exposed to numerous complications during pregnancy. - Diabetic women are less likely to use contraception, especially combined hormonal contraceptives, than non-diabetic women. - Combined oral contraception represents a safe and effective option in diabetic women, at least in those with uncomplicated diabetes. - Progestin-only contraceptives represent an interesting alternative in case of associated cardiovascular risk factors, cardiovascular diseases or severe microvascular complications.
Research agenda - Specific prospective studies are needed in obese women with uncomplicated type 2 diabetes to assess the efficiency and the safety of oral contraceptives. - The influence of the more recent combined oral contraceptives (low EE dosage, estradiol– valerate, 17b-estradiol) has to be investigated in the diabetic population. - Long-term prospective trials would provide definitive conclusions regarding the safety of oral contraceptives in terms of degenerative complications associated with diabetes.
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A randomized double-blind study of the effects of two low-dose combined oral contraceptives on biochemical aspects. Report from a seven-centred study. WHO Special Programme of Research, Development and Research Training in Human Reproduction. Task force on Oral Contraceptives. Contraception 1985; 32: 223–236. 17. Yu AF, Wu SX, Liu JL et al. Metabolic changes in women using a long-acting monthly oral contraceptive and return of ovulation on discontinuation. Contraception 1988; 37: 517–528. 18. Porkka KV, Erkkola R, Taimela S et al. Influence of oral contraceptive use on lipoprotein (a) and other coronary heart disease risk factors. Annals of Medicine 1995; 27: 193–198. 19. Kim C, Siscovick DS, Sidney S et al. Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA Study. Coronary Artery Risk Development in Young Adults. Diabetes Care 2002; 25: 1027–1032. 20. Crook D & Godsland I. Safety evaluation of modern oral contraceptives. Effects on lipoprotein and carbohydrate metabolism. Contraception 1998; 57: 189–201. 21. Cagnacci A, Ferrari S, Tirelli A et al. Route of administration of contraceptives containing desogestrel/etonorgestrel and insulin sensitivity: a prospective randomized study. Contraception 2009; 80: 34–39. 22. Sitruk-Ware R. New progestagens for contraceptive use. Human Reproduction Update 2006; 12: 169–178. 23. Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2008; 61: 151–157. *24. Lopez LM, Grimes DA & Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database of Systematic Reviews 2012; 4: CD006133. 25. Rimm EB, Manson JE, Stampfer MJ et al. Oral contraceptive use and the risk of type 2 (non-insulin-dependent) diabetes mellitus in a large prospective study of women. Diabetologia 1992; 35: 967–972. 26. Chasan-Taber L, Willett WC, Stampfer MJ et al. A prospective study of oral contraceptives and NIDDM among U.S. women. Diabetes Care 1997; 20: 330–335. 27. Rosenthal AD, Shu XO, Jin F et al. Oral contraceptive use and risk of diabetes among Chinese women. Contraception 2004; 69: 251–257. *28. Visser J, Snel M & Van Vliet HA. Hormonal versus non-hormonal contraceptives in women with diabetes mellitus type 1 and 2. Cochrane Database of Systematic Reviews 2006: CD003990. 29. Grigoryan OR, Grodnitskaya EE, Andreeva EN et al. Contraception in perimenopausal women with diabetes mellitus. Gynecological Endocrinology 2006; 22: 198–206. 30. Garg SK, Chase HP, Marshall G et al. Oral contraceptives and renal and retinal complications in young women with insulindependent diabetes mellitus. The Journal of the American Medical Association 1994; 271: 1099–1102. *31. Klein BE, Klein R & Moss SE. Exogenous estrogen exposures and changes in diabetic retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 1999; 22: 1984–1987. 32. Ahmed SB, Hovind P, Parving HH et al. Oral contraceptives, angiotensin-dependent renal vasoconstriction, and risk of diabetic nephropathy. Diabetes Care 2005; 28: 1988–1994. *33. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996; 348: 498–505. 34. Petitti DB, Sidney S, Bernstein A et al. Stroke in users of low-dose oral contraceptives. New England Journal of Medicine 1996; 335: 8–15. *35. Tanis BC, van den Bosch MA, Kemmeren JM et al. Oral contraceptives and the risk of myocardial infarction. New England Journal of Medicine 2001; 345: 1787–1793.
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36. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1997; 349: 1202–1209. 37. Lobo RA, Skinner JB, Lippman JS et al. Plasma lipids and desogestrel and ethinyl estradiol: a meta-analysis. Fertility and Sterility 1996; 65: 1100–1109. 38. LaRosa JC. Effects of oral contraceptives on circulating lipids and lipoproteins: maximizing benefit, minimizing risk. International Journal of Fertility 1989; 34(Suppl. 71–84). 39. Petersen KR. Pharmacodynamic effects of oral contraceptive steroids on biochemical markers for arterial thrombosis. Studies in non-diabetic women and in women with insulin-dependent diabetes mellitus. Danish Medical Bulletin 2002; 49: 43–60. 40. Chasan-Taber L, Willett WC, Manson JE et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996; 94: 483–489. *41. WHO. Medical eligibility criteria for contraceptive use. A WHO family planning cornerstone. WHO Library Cataloguing-inPublication Data edn.. 4th ed. Geneva: World Health Organization, 2009 42. U.S. medical eligibility criteria for contraceptive use, 2010. Adapted from the World Health Organization medical eligibility criteria for contraceptive use, 4th ed. MMWR Recommendations and Reports 2010: 1–86 *43. Lopez LM, Grimes DA, Chen-Mok M et al. Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database of Systematic Reviews 2010: CD008452. 44. Bajos N, Wellings K, Laborde C et al. Sexuality and obesity, a gender perspective: results from French national random probability survey of sexual behaviours. British Medical Journal 2010; 340: c2573. 45. Grimes DA & Shields WC. Family planning for obese women: challenges and opportunities. Contraception 2005; 72: 1–4. 46. Trussell J, Schwarz EB & Guthrie K. Obesity and oral contraceptive pill failure. Contraception 2009; 79: 334–338. 47. Holt VL, Cushing-Haugen KL & Daling JR. Body weight and risk of oral contraceptive failure. Obstetrics & Gynecology 2002; 99: 820–827. 48. Holt VL, Scholes D, Wicklund KG et al. Body mass index, weight, and oral contraceptive failure risk. Obstetrics & Gynecology 2005; 105: 46–52. 49. Bellamy L, Casas JP, Hingorani AD et al. Type 2 diabetes mellitus after gestational diabetes: a systematic review and metaanalysis. Lancet 2009; 373: 1773–1779. 50. Beydoun HA, Beydoun MA & Tamim H. How does gestational diabetes affect postpartum contraception in nondiabetic primiparous women? Contraception 2009; 79: 290–296. 51. Skouby SO, Kuhl C, Molsted-Pedersen L et al. Triphasic oral contraception: metabolic effects in normal women and those with previous gestational diabetes. American Journal of Obstetrics and Gynecology 1985; 153: 495–500. 52. Kjos SL, Peters RK, Xiang A et al. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. The Journal of the American Medical Association 1998; 280: 533–538. *53. Baptiste-Roberts K, Barone BB, Gary TL et al. Risk factors for type 2 diabetes among women with gestational diabetes: a systematic review. American Journal of Medicine 2009; 122: 207–214. e204. 54. Nelson AL, Le MH, Musherraf Z et al. Intermediate-term glucose tolerance in women with a history of gestational diabetes: natural history and potential associations with breastfeeding and contraception. American Journal of Obstetrics and Gynecology 2008; 198: 699.e691–699.e697 [discussion 699.e697–698].
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7
Diabetes and oral contraception Pierre Gourdy, MD, PhD, Professor a, b, * a b
Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU de Toulouse, France INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, France
Keywords: diabetes mellitus estrogens progestins contraception pregnancy cardiovascular risk
The prevalence of diabetes mellitus is increasing dramatically worldwide, resulting in more and more women of reproductive age being affected by either type 1 or type 2 diabetes. Management of contraception is a major issue due to the specific risks associated with pregnancy and those potentially induced by hormonal contraceptives in diabetic women. This review emphasizes the urgent need to improve the use of contraception in women with diabetes. There is no consistent evidence that combined oral contraceptives significantly influence the risk of developing diabetes, even in women with a history of gestational diabetes. Furthermore, although data from specific studies remain sparse, no worsening effect has been reported in diabetic women, either in glycemic control or on the course of microvascular complications. Thus, the use of estroprogestive pills is now recognized as a safe and effective option for preconception care of women with uncomplicated diabetes. According to recent guidelines, these contraceptives must be avoided in case of associated cardiovascular risk factors, cardiovascular disease or severe microvascular complications such as nephropathy with proteinuria or active proliferative retinopathy. Prescription of combined hormonal contraception in type 2 diabetic women must also be considered with caution due to a frequent association with obesity and vascular risk factors which increase both thromboembolic and arterial risks. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives, as well as non-hormonal methods, represent alternatives according to patient wishes. Ó 2012 Elsevier Ltd. All rights reserved.
Abbreviation: COC, combined oral contraception. * Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: þ33 561 323 740; Fax: þ33 561 322 270. E-mail address: [email protected]. 1521-690X/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2012.11.001
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Introduction Contraception is a critical issue in women affected by diabetes mellitus.1 It is crucial to achieve a balance between the specific risks associated with pregnancy and those potentially induced by the contraceptive itself in diabetic women. It is well recognized that unplanned pregnancy can result in severe outcomes in women with diabetes, from the fetal to the neonatal period.2,3 Diabetes with poor metabolic control favors congenital abnormalities, spontaneous abortion, in utero death, fetal overgrowth leading to macrosomia, neonatal hypoglycaemia and hyperbilirubinemia, as well as many other deleterious effects for the fetus or newborn child. Unplanned pregnancy can also lead to dramatic complications for pregnant diabetic women, including an increased risk of hypertension and preeclampsia, as well as the worsening of pre-existing degenerative complications such as retinopathy or nephropathy.2,3 The potential side-effects of certain contraception regimens frequently expose diabetic women to risk factors for cardiovascular events such as thromboembolic and cardiovascular risk. Thus, vascular safety represents a major concern for the orientation of contraception strategy in diabetic women.1 In the present review, we will first summarize recent epidemiological data that emphasize the urgent need to improve the use of contraception in women with diabetes. We will also focus on oral hormonal contraceptives and discuss their specific effects on glucose metabolism and vascular risk, in order to clarify their position in the management of contraception in both type 1 and type 2 diabetic women, according to recent guidelines. Diabetes mellitus: a growing public health problem in women The prevalence of diabetes has dramatically increased in the past two decades, and continues to rise worldwide. Epidemiological projections from the International Diabetes Federation (IDF) indicate that the global number of diabetic subjects among the adult population (20–79 year range) will increase from 285 million in 2010 to 439 million in 2030, with a maximal progression in developing countries.4 It is obvious that this epidemic trend mainly concerns type 2 diabetes, concurrently with the growing prevalence of obesity. However, the incidence of type 1 diabetes has also been reported to have increased worldwide, especially in children and teenagers.5 These worrying epidemiological considerations provide evidence that more women of reproductive age have diabetes, resulting in more pregnancies that place both mother and fetus at higher risk of complications. Consequently, clinicians will have to face a growing number of complex situations, such as adolescents with poorly controlled type 1 diabetes,6 or young women developing type 2 diabetes in association with obesity and concomitant cardiovascular risk factors. A crucial role for contraception in diabetic women It is well established that the specific risks related to diabetes can be minimized through preconception care including specific programs of therapeutic education and optimal glycemic control, both before and during pregnancy. Therefore, women with diabetes are able to improve pregnancy outcomes by delaying conception until optimal glucose levels are reached and/or microvascular complications, such as retinopathy, are stabilized.7 This absolute need for preconceptional care and planning of pregnancy emphasize the conclusion that adequate use of contraception represents a crucial step in the management of diabetes in women during their reproductive lives. Unfortunately, recent data suggest that diabetic women and obese women are less likely to use contraception or to receive preventive health care services.8 Analyzing the responses of 5955 participants aged 20–44 years in the 2002 National Survey for Family Growth in the United States, women with diabetes were more likely to not use contraception than women without diabetes (odds ratio [OR]: 2.61 [95% CI 1.22–5.58]), in unadjusted comparisons among sexually active women who were not sterilized.8 Similar results were reported from a cross sectional study comparing the use of hormonal contraception in 947 type 1 diabetic women, 365 type 2 diabetic women and age-matched women without diabetes, all included in the United Kingdom General Practice Research Database (GPRD).9 Women with diabetes were less likely to use hormonal contraception than women without
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diabetes: OR for type 1 diabetes 0.83 (0.59–0.93), OR for type 2 diabetes 0.60 (0.42–0.83). Furthermore, the data indicate that diabetes status significantly influences the choice of the contraception strategy since women with type 1 diabetes were more likely to be prescribed a combined pill than a progestinonly pill, but were significantly more likely to be prescribed the latter contraception than were women without diabetes: OR 1.65 (1.26–2.13). Compared with non-diabetic subjects, women with type 2 diabetes were also less likely to be prescribed a combined oral contraceptive: OR 0.39 (0.24–0.62).9 Taken together, these observations highlight significant variations in prescribing hormonal contraception to diabetic women compared with those without diabetes. As hormonal contraception is now recognized as a safe and effective option for women with uncomplicated diabetes, we can hypothesize that poor metabolic control, or associated risk factors for cardiovascular disease, have influenced clinicians in avoiding the use of hormonal contraception. However, it is paradoxically these women who are at most risk from unplanned pregnancy. Thus, improving the management of contraceptives in the whole population of diabetic women potentially exposed to pregnancy should be considered as a major health care issue. To this end, it is of utmost importance to consider the respective safety profiles of the different contraceptive modes in diabetic women. Although specific studies in diabetic women remain sparse, we will detail thereafter our current knowledge on the influence of the two types of oral hormonal contraception, namely combined estroprogestive and progestin-only pills, on metabolic and vascular risks in this population. Influence of oral contraception on glucose homeostasis There is no evidence that current combined oral contraception (COC), containing ethinyl-estradiol (EE) doses lower than 35 mg, exerts a significant influence on plasma glucose concentrations and insulin secretion profile.10 In most studies, no significant changes in fasting plasma glucose were observed in women receiving such oral contraception.11–13 Furthermore, following the introduction of a COC, glycemic profiles in response to oral glucose challenge have been shown to remain unchanged,14 or to weakly increase, but without clinical significance in non-diabetic women.12,15,16 In a study by Oeklers et al., COCs induced a slight increase in the area under the curve after a standardized oral glucose tolerance test: 10% increase for the combination of EE 15 mg and drospirenone 3 mg, 14% increase for EE 20 mg and drospirenone 3 mg, 14% increase for 30 mg EE and levonorgestrel, and 19% increase for EE 30 mg and drospirenone 3 mg.15 Fasting insulinemia was also reported to remain unchanged17,18 or to slightly increase12,19 in women using COC. In a transversal study including 559 Finnish women, insulinemia was not modified in women receiving EE combined with either levonorgestrel or desogestrel compared with women not receiving oral contraception.18 Among the 1940 women participating in the CARDIA prospective trial in the United States, fasting insulinemia levels slightly increased in women receiving oral contraception (þ0.12 mU/L), and this trend remained significant after multiple adjustments for confounding factors.19 Finally, although some studies suggested that COC could alter insulin sensitivity,20,21 the data available to date indicate that this mode of contraception does not exert significant influence on glucose metabolism.13 The influence of progestin-only contraceptives on glucose and lipid metabolism also appears weak and, in most cases, non-significant, although it depends on the specific pharmacologic characteristics of the different molecules.22,23 A complete review from the Cochrane Database recently evaluated the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk of diabetes due to overweight.24 This latter analysis confirms that current evidence indicates no major differences in glucose metabolism between different hormonal contraceptives in women without diabetes. Oral contraception and incidence of diabetes in women From epidemiological data, it can be concluded that oral contraception in healthy women is not associated with an increased risk of developing diabetes. As a first demonstration, among the 98,590 women participating in the Nurses’ Health Study, the incidence of diabetes was not increased in current or past users of oral contraceptives.25,26 After a four year follow-up, the OR for diabetes occurrence was 1.6
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(0.9–3.1) in current users, and 1.2 (0.8–1.8) in past users, after adjusting for age, body mass index, familial history of diabetes, tobacco consumption, physical activity, alcohol consumption, hypertension, previous pregnancies and dyslipidemia.25 Accordingly, a case-control study including 57,180 Chinese women (Shanghai Women’s Health Study) did not find any association between the use of oral contraception and the incidence of diabetes.27 Thus, even if some oral contraceptive combinations slightly alter insulin sensitivity, no clinical relevance has been reported in terms of diabetes incidence. Influence of oral contraception on metabolic control in women with diabetes The influence of COC appears to be non-significant in healthy women, but it was important to address their impact on glycemic control in diabetic women. A Cochrane review conducted in 2006 investigated whether progestin-only, combined or non-hormonal contraceptives differ in terms of effectiveness in preventing pregnancy, in their side-effects on carbohydrate and lipid metabolism and in long-term complications such as micro- and macrovascular disease, when used in women with diabetes.28 Although the three randomized controlled trials included in this systematic review were insufficient to provide definite conclusions, no difference was found in daily insulin requirement, glycated hemoglobin (HbA1c) or fasting blood glucose after twelve months of contraception in type 1 diabetic women. In the whole diabetic population, the analysis reported blood glucose levels to remain stable during treatment with most contraception regimens. Only high-dose COC was found to slightly impair glucose homeostasis.28 Although none of them compared the effect of different doses of EE, studies conducted in type 1 diabetic women failed to demonstrate an increase in insulin needs under estroprogestive contraception. In a Russian study including 113 premenopausal women with diabetes, combined oral contraception did not influence HbA1c nor insulin requirements, and the majority of the hormonal combinations did not exert any unfavorable effects on blood lipid profile.29 Oral contraception and microvascular complications in diabetic women In women with diabetes, one of the most important questions relates to the potential worsening effect of hormonal contraception on the occurrence or the progression of degenerative complications, especially retinopathy and glomerulopathy, through direct deleterious actions on microvascular circulation. However, this specific risk seems to be insignificant except in cases of severe and active complications. Indeed, no increase in the prevalence and/or the severity of microvascular complications, namely retinopathy and nephropathy, was reported in type 1 diabetic women using COC. A prospective study examined the progression of microvascular lesions in 86 women with type 1 diabetes (diabetes duration: 14 years, HbA1c: 12%), and found no influence of combined oral contraceptives one year after the initiation of this mode of contraception.30 In addition, COCs did not exert any worsening effect on the progression of retinopathy or on the incidence of macular edema in women with either younger onset diabetes (type 1) or older-onset diabetes (both type 1 and type 2) after a 10year or a 6-year follow-up, respectively (Table 1).31 Only one observational study reported an association between COC use and a significant increase in proteinuria level, but in a small sample of type 1 diabetic patients.32 Despite these reassuring data, it is crucial to remember that the prescription of combined contraception with estrogens and progestins, whatever their route of administration, should not be proposed, or at least with extreme caution, in diabetic patients with uncontrolled microvascular complications such as severe retinopathy (ischemic or proliferative area), active macular edema, or nephropathy with persistent proteinuria. It cannot be excluded that estroprogestives could exert deleterious effects on microvessels, and robust prospective data regarding the safety of this mode of contraception are still lacking in such pathophysiological contexts. Oral contraception and vascular risk in diabetic women In addition to these considerations on glycemic control and microvascular complications, the safety profile of oral contraceptive methods must be analyzed according to the level of cardiovascular risk, more specially in women with type 2 diabetes. The latter condition is frequently associated with
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Table 1 Influence of combined oral contraceptive (COC) use on retinopathy progression in the Wisconsin Epidemiological study of Diabetic Retinopathy (women with either younger- or older-onset diabetes). Adapted from Ref.31 Changes in complications
Progression of retinopathy Progression to proliferative retinopathy Incidence of macular edema Incidence of hypertension a b
Adjusted OR (95%CI) COC users versus non-users Younger-onset diabetesa 10-Year follow-up
Older-onset diabetesb 6-Year follow-up
1.21 (0.73–2.02) 0.54 (0.27–1.08)
1.19 (0.43–3.24) 0.28 (0.03–2.77)
0.99 (0.46–2.14) 1.05 (0.56–1.94)
0.48 (0.11–2.08) 1.91 (0.50–7.26)
Women diagnosed with diabetes before the age of 30 years (all on insulin therapy). Women diagnosed with diabetes after the age of 30 years (random sample stratified by duration of diabetes, insulin-treated or not).
obesity and multiple cardiovascular risk factors such as hypertension and dyslipidemia. Unfortunately, to date, no study specifically dedicated to diabetic women has been conducted to address the cardiovascular safety of combined oral contraceptives, but data from sub-group analyses are available. For instance, in a WHO study, the influence of combined estroprogestive contraception on the incidence of stroke was higher in diabetic than in non-diabetic women.33 Another study reported a significant increase in the risk of stroke (OR: 7.1 (3.5–16.1)) in diabetic women using a COC.34 In addition, a case-controlled study analyzed the risk of myocardial infarction induced by COCs according to diabetic status. The data confirmed that diabetes represents an independent risk factor, but also show that this mode of contraception is associated with a further increase in the incidence of myocardial infarction risk in the diabetic population: OR ¼ 7.4 (3.1–98.1) in diabetic users and OR ¼ 4.2 (1.6–10.9) in diabetic non-users.35 Importantly, the identification of one or more cardiovascular risk factors associated with diabetes should lead us to reconsider the prescription of combined contraceptives in diabetic women. Illustrating the influence of cumulative cardiovascular risk factors, a WHO case-control study included 1309 women in Europe and developing countries, and found no significant influence of COC on the risk of myocardial infarction in women without tobacco consumption and hypertension: OR 1.1 (0.12–9.69).36 In contrast, this study demonstrated a significant increase in myocardial infarction incidence related to oral contraception use in women with associated cardiovascular risk factors: non-smoking women with hypertension (OR: 16.4 [3.08–87.7]), smoking women without hypertension (OR: 26.6 [7.00– 101]), and smoking women with hypertension (OR: 71.4 [16.5–309]).36 It is also important to consider the potential worsening effect of COC on cardiovascular risk factors in diabetic women. This mode of contraception has been shown to influence plasma lipid profile (increasing triglycerides and HDL cholesterol and slightly decreasing LDL cholesterol), according to both estrogen dosage and to the androgenic action of the progestin.37,38 Since dyslipidemia is a frequent feature of metabolic syndrome and type 2 diabetes, it is crucial to consider the hypertriglyceridemic effects of COCs and to prescribe this type of contraception with caution. In clinical practice, plasma lipid profile must be analyzed before and monitored after the initiation of COC. Furthermore, COCs will be contraindicated in case of persistent hypertriglyceridemia in diabetic women. In the absence of familial dyslipidemia or nephropathy, the situation appears to be quite different in type 1 diabetic patients. No significant changes in insulin sensitivity, lipid profile or coagulation parameters were observed in type 1 diabetic women after the introduction of a COC, compared with non-diabetic women.39 To our knowledge, no specific studies have been performed to evaluate the influence of oral contraception on blood pressure in diabetic women. In the general population, the influence of COCs on blood pressure is modest, although they are able to induce hypertension in less than 5% of women.40 However, the prevalence of hypertension is generally higher in women with type 2 diabetes, and also in the case of nephropathy in type 1 diabetic women. Identification of hypertension history and blood pressure measurement are thus absolutely required before prescribing hormonal contraception in diabetic women, and combined contraceptives will be contraindicated in case of uncontrolled hypertension.
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Corroborating data indicate that diabetic women are generally characterized by an increased risk of thromboembolic events. This trend mainly results from the fact that most women with type 2 diabetes are obese or at least overweight, whereas no significant increase in venous risk has been associated to hyperglycemia itself. Although transdermal or vaginal administration of estroprogestive combinations limits their influence on protein synthesis by the liver, the safety of both alternative routes has not been addressed to date and the contraindications remain the same that those of COCs in diabetic women. Similarly, the safety of the recent hormonal contraception formulation containing estradiol–valerate or 17-b-estradiol has not been addressed in diabetic women. Use of oral contraceptives in diabetic women Medical eligibility criteria for contraceptive use were updated in 2009 by the WHO,41 then adapted for the United States in 2010.42 These clinical guidelines include situations potentially associated with high vascular risks, such as diabetes (Table 2). Thereafter, we devised the following recommendations for the management of oral contraceptives in women with either type 1 or type 2 diabetes. Women with type 1 diabetes As previously detailed in this review, it is crucial to take into account the existence of microvascular or cardiovascular complications and/or vascular risk factors (dyslipidemia, hypertension, tobacco consumption, diabetes duration >20 years) before the introduction of any oral contraceptive in type 1 diabetic women. COC can be prescribed for type 1 diabetic women without any macrovascular or active microvascular complications, and in the absence of any cardiovascular risk factors. Poor glycemic control alone does not represent a contraindication for use of combined contraceptives, but great caution must be exercised with associated risk factors, especially tobacco consumption. In our opinion, minor or moderate non-proliferative retinopathy, as well as isolated and moderate microalbuminuria, should not be considered as contraindications to combined contraception use. In contrast, when severe degenerative complications are present, such as nephropathy with proteinuria and/or renal failure, active retinopathy (ischemic and proliferative area), cardiovascular diseases or peripheral/vegetative neuropathy, COC must be contra-indicated. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives represent an alternative, as well as non-hormonal methods, according to patient wishes. Women with type 2 diabetes The situation is quite different for type 2 diabetes since this metabolic condition is frequently associated with obesity, insulin resistance and cardiovascular risk factors. Thus, the use of COC must be
Table 2 Medical eligibility criteria for the use of combined oral contraceptives and progestin-only pills in diabetic women. Adapted from Refs.41,42 Clinical presentation
Combined oral contraceptives
Progestin-only pills
History of gestational diabetes Type 1 diabetes (absence of vascular complications) Type 2 diabetes (absence of vascular complications) Microvascular complications (retinopathy, nephropathy, neuropathy) Other vascular disease or diabetes duration >20 years
No restriction Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Theoretical/proven risks outweigh advantages to unacceptable health riska Theoretical/proven risks outweigh advantages to unacceptable health riska
No restriction Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks
a
According to the severity of the complications.
Advantages outweigh theoretical/proven risks
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restricted in type 2 diabetic women and the choice of an alternative contraception, such as progestinonly or non-hormonal contraceptives, should be systematically considered. However, the incidence of type 2 diabetes rapidly increases in women in association with overweight or obesity but in the absence of additional vascular risk factors, even in the youngest age ranges. COCs can be proposed in these cases, but only in women without obesity (Body Mass Index <30 kg/m2), additional cardiovascular risk factors or microvascular or cardiovascular complications. Choosing this contraceptive strategy systematically implies a strict monitoring of weight, glycemic control, plasma lipid profile and blood pressure. At the population level, there is no evidence that COC induces body weight gain in obese women.43 Obesity must be considered as an additional factor of complexity in women with type 2 diabetes. A recent French study demonstrated a 4-fold increase in the number of undesired pregnancies in obese women, compared with those in the normal weight range.44 Less efficient modes of contraception were used by obese women with poorer medical management. Whether obesity is associated with a decrease in the efficiency of hormonal contraception, due to an increase in distribution volume, remains a matter of debate.45,46 Two case-control studies reported an increase in undesired pregnancy in obese women.47,48 Conversely, other studies did not find any association between the failure of hormonal contraception and obesity.43 Altogether, the data available do not allow us to conclude that optimal use of oral contraceptives leads to lesser protection in obese women than in women with weight in the normal range, although no results have been provided for women with BMI values exceeding 35 kg/m2. However, COC must be avoided in obese women with type 2 diabetes. No specific studies have been conducted to address the metabolic and vascular safety of progestin-only contraception in this context. Oral contraception in women with a history of gestational diabetes Contraceptive options in women who experienced gestational diabetes also represent an important matter of discussion according to the high risk of developing type 2 diabetes in this particular population. Indeed, numerous studies reported a 7-fold increase in diabetes incidence in the 5–10 years following gestational diabetes.49 After gestational diabetes, it is crucial to systematically check the glucose tolerance status in the immediate post-partum period and to organize a systematic screening for alteration of glucose metabolism in the follow-up. Recent data indicated that a history of gestational diabetes is not associated with the use of numerous contraceptives.50 However, only a few studies addressed the question of whether oral contraception alters glucose homeostasis after gestational diabetes. No changes in glucose tolerance, and only a slight alteration of insulin sensitivity, were reported in the short-term following the prescription of oral hormonal contraception in women with a recent history of gestational diabetes.51 Accordingly, after a 7year follow-up, no increase in type 2 diabetes incidence was observed in a cohort of Hispanic women with a history of gestational diabetes who received COCs.52 Recording the data from 14 studies, BaptisteRoberts et al. further demonstrated that combined contraception does not influence the risk of developing type 2 diabetes in women who previously experienced a gestational diabetes.53 Furthermore, a single retrospective study led to discordant results, reporting that COCs led to a worsened glycemic profile compared with non-hormonal contraceptives in 590 Hispanic women followed during 2 years.54 The relationship between microprogestive contraception and type 2 diabetes incidence has been also examined, but in only one study.52 Latino–American women who experienced gestational diabetes were found to have an increased risk of developing type 2 diabetes during the post-partum period with breastfeeding: the OR was 2.87 (1.57–5.27) in the whole population, 2.96 (1.35–6.52) when women were exposed to microprogestins for 4–8 months, and 4.92 (1.76–13.73) for an exposition to this contraceptive mode exceeding 8 months.52 However, these data have not been confirmed to date, and it is important to emphasize that only breastfeeding women were considered, limiting the extrapolation for all post-partum situations. According to current knowledge, the influence of oral contraceptives on the risk of developing type 2 diabetes seems to be non-significant in women with a history of gestational diabetes. The use of combined or progestin-only oral contraception can be proposed in this clinical situation without specific restriction. In the absence of contraindications related to a significant risk of cardiovascular or thromboembolic disease, COCs are thus an excellent option according to patient wishes. However, in relation to the high risk of thromboembolism in the immediate post-partum, COCs are contraindicated
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during the 6 weeks following the delivery, as recommended in the general population. At this time, the only hormonal contraceptive option is progestin-only pills. As highlighted above, women who have had gestational diabetes mellitus must be monitored in the immediate postpartum period to ensure that blood glucose levels return to normal without further treatment. However, the choice of the contraceptive mode must also take into consideration the associated vascular risk factors, more frequent in this specific population. Indeed, the presence of obesity, hypertension, or dyslipidaemia must influence the choice of contraception towards one without cardiovascular consequences, such as progestin-only contraceptives. Conclusion Although exposed to numerous risks of complications during pregnancy, diabetic women are less likely to use contraception than non-diabetic women. As an explanation, oral hormonal contraceptives, mainly estroprogestive pills, are prescribed less in diabetic women, probably as a result of the fear of vascular side effects. However, available data strongly suggest that COCs represent a safe and effective option for preconception care in diabetic women, at least in those with uncomplicated diabetes. Recent guidelines underline the need to avoid the use of estroprogestive pills in case of associated cardiovascular risk factors, cardiovascular diseases or severe microvascular complications, such as nephropathy with proteinuria or active proliferative retinopathy. Furthermore, the number of type 2 diabetic women in the reproductive age range is dramatically higher nowadays, and COCs must be used with caution in this population due to the frequent association with obesity and vascular risk factors which increases both thromboembolic and arterial risks. Facing these high-risk profiles, progestin-only contraceptives represent an interesting alternative thanks to their metabolic and vascular safety profile, as well as non-hormonal methods, according to patient wishes. Importantly, the poor tolerance of microprogestins, particularly due to frequent uterine bleeding, must also be kept in account to guide the choice of contraception, aiming to an optimal adherence and efficiency. Improving the management of contraception will be a crucial step to limit the burden of unplanned pregnancy in women suffering from diabetes mellitus. To this aim, it is crucial that endocrinologists and gynecologists, as well as general practitioners, join forces, firstly to immediately reinforce educative messages about contraception in diabetes, and secondly to conduct specific prospective studies in the diabetic population, including new formulations without EE. Practice points - Diabetic women are exposed to numerous complications during pregnancy. - Diabetic women are less likely to use contraception, especially combined hormonal contraceptives, than non-diabetic women. - Combined oral contraception represents a safe and effective option in diabetic women, at least in those with uncomplicated diabetes. - Progestin-only contraceptives represent an interesting alternative in case of associated cardiovascular risk factors, cardiovascular diseases or severe microvascular complications.
Research agenda - Specific prospective studies are needed in obese women with uncomplicated type 2 diabetes to assess the efficiency and the safety of oral contraceptives. - The influence of the more recent combined oral contraceptives (low EE dosage, estradiol– valerate, 17b-estradiol) has to be investigated in the diabetic population. - Long-term prospective trials would provide definitive conclusions regarding the safety of oral contraceptives in terms of degenerative complications associated with diabetes.
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