Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 6776

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Best Practice & Research Clinical Endocrinology & Metabolism

journal homepage: www.elsevier.com/locate/beem

Diabetes and oral contraception

Pierre Gourdy, MD, PhD, Professor a, b, *
a b

Service de Diabtologie, Maladies Mtaboliques et Nutrition, CHU de Toulouse, France INSERM U1048, Institut des Maladies Mtaboliques et Cardiovasculaires, Universit 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 specic 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 signicantly inuence the risk of developing diabetes, even in women with a history of gestational diabetes. Furthermore, although data from specic 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 prole, progestin-only contraceptives, as well as non-hormonal methods, represent alternatives according to patient wishes. 2012 Elsevier Ltd. All rights reserved.

Abbreviation: COC, combined oral contraception. * Service de Diabtologie, Maladies Mtaboliques et Nutrition, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: 33 561 323 740; Fax: 33 561 322 270. E-mail address: pierre.gourdy@inserm.fr. 1521-690X/$ see front matter 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 specic 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 rst 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 specic 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 (2079 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 specic risks related to diabetes can be minimized through preconception care including specic 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 2044 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 1.225.58]), 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 (0.590.93), OR for type 2 diabetes 0.60 (0.420.83). Furthermore, the data indicate that diabetes status signicantly inuences 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 signicantly more likely to be prescribed the latter contraception than were women without diabetes: OR 1.65 (1.262.13). Compared with non-diabetic subjects, women with type 2 diabetes were also less likely to be prescribed a combined oral contraceptive: OR 0.39 (0.240.62).9 Taken together, these observations highlight signicant 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 inuenced 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 proles of the different contraceptive modes in diabetic women. Although specic studies in diabetic women remain sparse, we will detail thereafter our current knowledge on the inuence of the two types of oral hormonal contraception, namely combined estroprogestive and progestin-only pills, on metabolic and vascular risks in this population. Inuence 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 signicant inuence on plasma glucose concentrations and insulin secretion prole.10 In most studies, no signicant changes in fasting plasma glucose were observed in women receiving such oral contraception.1113 Furthermore, following the introduction of a COC, glycemic proles in response to oral glucose challenge have been shown to remain unchanged,14 or to weakly increase, but without clinical signicance 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 modied 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 (0.12 mU/L), and this trend remained signicant 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 signicant inuence on glucose metabolism.13 The inuence of progestin-only contraceptives on glucose and lipid metabolism also appears weak and, in most cases, non-signicant, although it depends on the specic 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 conrms 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 rst 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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(0.93.1) in current users, and 1.2 (0.81.8) 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 Womens Health Study) did not nd 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. Inuence of oral contraception on metabolic control in women with diabetes The inuence of COC appears to be non-signicant 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 insufcient to provide denite 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 inuence HbA1c nor insulin requirements, and the majority of the hormonal combinations did not exert any unfavorable effects on blood lipid prole.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 specic risk seems to be insignicant 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 inuence 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 signicant 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 prole 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 Inuence 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 Adjusted OR (95%CI) COC users versus non-users Younger-onset diabetesa 10-Year follow-up Progression of retinopathy Progression to proliferative retinopathy Incidence of macular edema Incidence of hypertension
a b

Older-onset diabetesb 6-Year follow-up 1.19 (0.433.24) 0.28 (0.032.77) 0.48 (0.112.08) 1.91 (0.507.26)

1.21 (0.732.02) 0.54 (0.271.08) 0.99 (0.462.14) 1.05 (0.561.94)

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 stratied by duration of diabetes, insulin-treated or not).

obesity and multiple cardiovascular risk factors such as hypertension and dyslipidemia. Unfortunately, to date, no study specically 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 inuence of combined estroprogestive contraception on the incidence of stroke was higher in diabetic than in non-diabetic women.33 Another study reported a signicant increase in the risk of stroke (OR: 7.1 (3.516.1)) 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 conrmed 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 7.4 (3.198.1) in diabetic users and OR 4.2 (1.610.9) in diabetic non-users.35 Importantly, the identication 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 inuence of cumulative cardiovascular risk factors, a WHO case-control study included 1309 women in Europe and developing countries, and found no signicant inuence of COC on the risk of myocardial infarction in women without tobacco consumption and hypertension: OR 1.1 (0.129.69).36 In contrast, this study demonstrated a signicant 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 [3.0887.7]), smoking women without hypertension (OR: 26.6 [7.00 101]), and smoking women with hypertension (OR: 71.4 [16.5309]).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 inuence plasma lipid prole (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 prole 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 signicant changes in insulin sensitivity, lipid prole 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 specic studies have been performed to evaluate the inuence of oral contraception on blood pressure in diabetic women. In the general population, the inuence 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. Identication 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 signicant increase in venous risk has been associated to hyperglycemia itself. Although transdermal or vaginal administration of estroprogestive combinations limits their inuence 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 estradiolvalerate 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 prole, 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 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
a

Combined oral contraceptives 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

Progestin-only pills No restriction Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks Advantages outweigh theoretical/proven risks

According to the severity of the complications.

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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 prole 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 efcient modes of contraception were used by obese women with poorer medical management. Whether obesity is associated with a decrease in the efciency 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 nd 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 specic 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 510 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 inuence 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 prole 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 LatinoAmerican 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 (1.575.27) in the whole population, 2.96 (1.356.52) when women were exposed to microprogestins for 48 months, and 4.92 (1.7613.73) for an exposition to this contraceptive mode exceeding 8 months.52 However, these data have not been conrmed 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 inuence of oral contraceptives on the risk of developing type 2 diabetes seems to be non-signicant 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 specic restriction. In the absence of contraindications related to a signicant 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 specic population. Indeed, the presence of obesity, hypertension, or dyslipidaemia must inuence 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 proles, progestin-only contraceptives represent an interesting alternative thanks to their metabolic and vascular safety prole, 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 efciency. 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, rstly to immediately reinforce educative messages about contraception in diabetes, and secondly to conduct specic 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 - Specic prospective studies are needed in obese women with uncomplicated type 2 diabetes to assess the efciency and the safety of oral contraceptives. - The inuence 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 denitive conclusions regarding the safety of oral contraceptives in terms of degenerative complications associated with diabetes.

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