Monique Hedderson1
(1)
Kaiser Permanente Northern California’s Division of Research, Oakland, CA, USA
Monique Hedderson
Email: Monique.m.hedderson@kp.org
Abstract
Increasing parity is a risk factor for GDM. For women with a history of GDM, a subsequent pregnancy increases 3-fold the risk of progressing to type 2 diabetes. Therefore, the proper use of contraception to prevent unwanted pregnancies in young women both before and after a pregnancy complicated by GDM is essential. There are several forms of hormonal contraceptives available that offer effective contraception. Some forms of hormonal contraceptives also have unwanted metabolic side effects, and the risks associated with the use of individual contraceptives should be weighed against their benefits. Women with a history of GDM may be particularly vulnerable to metabolic side effects. This chapter summarizes hormonal contraceptive use before pregnancy and its effect on risk of GDM and reviews family planning methods in women after a GDM pregnancy, including postpartum lactational amenorrhea, barrier methods, combination oral contraceptives, progesterone-only contraception, and intrauterine devices. We will review the risks and benefits of each method, as the effect of the method in preventing unintended pregnancies may outweigh any adverse impacts on glucose tolerance and lipid metabolism.
21.1 Introduction
Gestational diabetes (GDM) is a common pregnancy complication and its prevalence has increased 35–90% during the last decade.1 Parity is a risk factor for GDM, therefore preventing unwanted pregnancies by encouraging effective contraceptive use with minimal metabolic side effects in reproductive age women is important. Women with prior GDM are at high risk of developing type 2 diabetes mellitus (T2DM), with up to 50% diagnosed with diabetes within 5 years after delivery.2 Currently, postpartum screening for T2DM among women with a history of GDM is suboptimal3 and women with prior GDM may have undiagnosed diabetes or impaired glucose tolerance after pregnancy. Pregnancy occurring in women with suboptimal glucose control increases the risk of congenital malformations and the risk has been shown to increase with increasing degree of maternal hyperglycemia.4 Therefore, contraception use in women with prior GDM is essential to ensure a planned pregnancy occurs when glucose status is normalized. Preventing an additional unwanted pregnancy may also reduce the risk of subsequent diabetes, since one additional pregnancy has been shown to be associated with a threefold increased risk of T2DM in women with previous GDM.5 Therefore, women with a history of GDM need safe and efficient methods of contraception postpartum that do not enhance their already elevated risk of developing T2DM. This chapter reviews the efficacy and effects on glucose metabolism of the various contraception options available for women with prior GDM including: postpartum lactational amenorrhea, barrier methods, combination oral contraceptives (COCs), progesterone-only contraception, intrafallopian devices, and intrauterine devices (IUDs).
21.2 Hormonal Contraceptive Use Before Pregnancy and Risk of GDM
GDM is defined as carbohydrate intolerance first recognized during pregnancy and its incidence has increased 35–90% during the last decade.1 Parity is a risk factor for GDM, therefore preventing unwanted pregnancies by encouraging effective contraceptive use in reproductive age women is important. The increase in incidence of GDM during the last decade coincided with the availability of two new forms of progestin only contraception, Norplant and Depo-Provera (depot medroxyprogesterone acetate [DMPA])6 in the U.S. The synthetic progestins used in several forms of hormonal contraceptives are structurally related to testosterone and may produce androgenic side effects. The metabolic effects of androgens include reduced glucose tolerance7 and weight gain.8 Therefore, women who have taken hormonal contraceptives, especially progestin dominant forms before pregnancy, may be more vulnerable to the metabolic stress induced by placental hormones in late pregnancy,9 and may be more likely to develop GDM.
To date there has been only one study examining hormonal contraceptive use before pregnancy and risk of GDM. In a nested case–control study, Hedderson et al examined the effects of hormonal contraceptives, including COCs, progestin-only oral contraceptives (POCs) and DMPA use, on subsequent risk of GDM categorized by the androgenicity of the progestin component. There was a suggestion that compared with no hormonal contraceptive use, use of a low-androgen hormonal contraceptive before pregnancy was associated with a slight (16%) reduction in risk of GDM, whereas use of a high-androgen hormonal contraceptive was associated with a modest (43%) increase in GDM risk.10 These results suggest that some forms of hormonal contraceptives may actually be beneficial and others detrimental in terms of their metabolic effects and the subsequent risk of GDM during pregnancy. It is important to understand whether hormonal contraceptives that are widely used increases the risk of GDM, especially for high risk women, such as women who are overweight or obese. It is also crucial to understand the risks and benefits of the contraceptive choices available for women with a history of GDM who are at high risk of developing GDM in a subsequent pregnancy and of progressing to T2DM.
21.3 Hormonal Contraceptive Use After Pregnancy
21.3.1 Postpartum Lactational Amenorrhea
Lactation amenorrhea method (LAM) is defined as the informed use of breastfeeding as a contraceptive method.11 LAM is a form of contraception available to women with GDM during the immediate postpartum period while breastfeeding. LAM can delay ovulation and provide 98% efficacy in protection from pregnancy in the first 6 months postpartum12,13 when practiced correctly. To practice LAM effectively, women must begin breastfeeding immediately after delivery, avoid supplementation, and breastfeed frequently (i.e., at least every 4 h during the daytime and 6 h during the night). When other contraceptive methods are used in conjunction with exclusive breastfeeding there is an extremely low failure rate. However, LAM is a transitional form of contraception, since the method is less effective when menses returns, 6 months have elapsed postdelivery, or when supplementing infant feeding is used. Therefore, it is crucial that women be educated regarding the factors affecting its efficacy if they are planning to use this as their only form of contraception. Another method of contraception should be initiated if 6 months have elapsed since delivery, menses returns, or the woman begins to supplement feed her infant.
One concern with the use of LAM for birth control in women with a history of GDM is that it is unpredictable when the return of menstruation and ovulation occurs. Breastfeeding in women with a history of GDM may have additional metabolic benefits for both mother and her infant and should be encouraged; breastfeeding is discussed in greater detail in a separate chapter in this book. Therefore, for women with GDM, a strong endorsement of breastfeeding can be coupled with LAM and recommendation of an additional barrier method, such as condoms. This option is especially good for women who are reluctant to use medications such as hormonal contraception while breastfeeding, due to concerns about hormonal effects on the quality and quantity of milk and fear of passing hormones to the infant.
21.3.2 Barrier Methods
Barrier methods include condoms, diaphragm, cervical cap, and spermicides, and can be used by women with a history of GDM since they do not affect glucose tolerance. However, when used alone, condoms have a high typical failure rate of approximately 15%.14 As mentioned above, when these methods are used in conjunction with LAM it greatly improves their success rate. The success of these methods requires proper use and strong motivation by both the patient and partner. However, when these criteria cannot be met, intrauterine or hormonal contraceptives might be preferable. The use of condoms should be recommended for women who are engaging in sexual activity with multiple partners as a means to protect against sexually transmitted diseases.
21.3.3 Combination Oral Contraceptives
COC pills contain both progestin and estrogen and are used by more than ten million women in the U.S.15 The type of progestin varies, although in the U.S., the estrogen component is always ethinyl estradiol. It is generally believed that the estrogen component, ethinyl estradiol, has no net effect on glucose tolerance and insulin sensitivity.16 However, ethinyl estradiol adversely influences hemostatic and renin-angiotensin systems to increase thrombotic risk.17Oral estrogens have also been shown to increase high-density lipoprotein (HDL) cholesterol, decrease low-density lipoprotein (LDL) cholesterol, and to increase triglycerides, globulins, and blood pressure.18 Therefore, low dose estrogen formulas are recommended and women with hypertension or other cardiovascular risk factors are contraindicated from taking COCs.
Alterations in carbohydrate metabolism in women using COCs are thought to be related primarily to the progestin component. The synthetic progestins used in hormonal contraception are structurally related to testosterone and may also produce androgenic side effects. The metabolic effects of androgens include reduced glucose tolerance7 and weight gain.8 The degree of androgenicity in COCs is determined by the dose and type of progestin and whether and to what degree it is opposed by estrogen. The progestin components most widely used in today’s COCs are either “second-generation” (e.g., levonorgestrel or norgestimate) or “third-generation” (desogestrel or gestoden). The third generation progestins were specifically formulated to decrease the androgenic side effects. There are also “fourth-generation” progestins, such as drospirenone, dienogest and nomegestrol acetate that have aldosterone antagonist properties, and appear to have no androgenic effects and exhibit partial anti-androgenic activity.19 The overall metabolic effects of any given COC will depend on the net of the type and dose of each hormonal component.
21.4 Effects of COC on Glucose Metabolism Use in Healthy Populations
Early metabolic studies of COCs suggested that formulations with higher doses of the more androgenic forms of progestins (such as norgestrel and levonorgestrel) were associated with greater alterations of glucose metabolism, often resulting in higher levels of fasting insulin.20–25 Newer formulations of COCs, with lower doses of progestins, have since been formulated to decrease the androgenic side effects. Since then, several studies have examined the effects of low dose formulations on glucose metabolism among women with normal glucose tolerance.
21.5 Randomized Trials
A recent Cochrane review identified all randomized controlled trials examining hormonal contraceptives and carbohydrate metabolism in women without diabetes; they identified 14 trials with enough data to analyze. Glucose values were often better among women using COCs that had desogestrel than other pills, but the insulin results were not consistent.26 However, the authors noted there have been few studies that compared specific types of contraceptives and many had small numbers of participants and large losses to follow-up. In addition, it was noted that no studies examined whether carbohydrate response to COCs is different in women who are overweight or obese. While there is limited data available on how the new fourth generation COCs (Yaz, Yasmin, etc.) affect glucose metabolism, one small RCT found that Yasmin, a combined low-dose COC with 30 μg of ethinyl estradiol and 3 mg of the novel progestogen drospirenone, as well as the reference Marvelon, containing 30 μg ethinyl estradiol and 150 μg desogestrel, had little impact on carbohydrate metabolism when used for 1 year.27 In addition, this study found that Yasmin resulted in a beneficial increase in ratio of total HDL and suggests a potential cardioprotective benefit.28
21.6 Epidemiologic Studies
Kim et al examined the cross-sectional association between current OC use and fasting glucose, fasting insulin, and diabetes in the CARDIA study, a large study (n = 1940) of young African-American and white women.29 After adjusting for extensive covariate data, current use of a COC was associated with lower fasting glucose levels and lower odds of diabetes, but higher insulin levels. They also examined the longitudinal association between COC use and incident diabetes at 10 years of follow-up but found no association, although they had extremely small numbers of participants who developed diabetes. In this study, women primarily used one type of COC and they were unable to examine whether the association varied by the progestin component of the COC. These results suggested that use of COC in healthy young women might actually be beneficial for glucose tolerance and could have important clinical implications, however, they need to be replicated, preferably in a prospective study.
There have been two large population-based prospective cohort studies in the US on COC use and T2DM risk. Both were conducted in the Nurses’ Health Study and no significant increase in risk of type 2 diabetes was observed with the older high-dose estrogen–progestin formulations30 or in the newer low-dose estrogen–progestin COCs.31 However, both of these studies were limited to predominantly white women and neither was able to examine whether the effects varied by progestin type.
One recent large population-based cohort study in Finland examined COC use and levonorgestrel-releasing IUD use compared with no use of hormonal contraceptives. They found oral contraception users were more insulin resistant, had higher lipid and insulin levels, and lower homeostatic model assessment (HOMA) and insulin sensitivity compared with IUD users32 and nonusers. They examined second vs. third-generation COC use and actually found users of third-generation COCs had higher levels of C-reactive protein (CRP), total cholesterol, HDL, triglycerides, insulin resistance, and insulin secretion compared with users of second-generation COCs, contrary to what would be expected. This latter study is the only large cohort study to date to find significant metabolic effects of COCs and it needs to be replicated in other studies.
21.7 Effects of COCs in Women with Diabetes
In general, the few studies examining short-term use of low-dose COC use in diabetic women suggest the changes in insulin sensitivity, glucose tolerance, lipid metabolism, and the coagulation/thrombotic system are minimal and similar to findings in healthy women.33, 34 However, these studies were conducted more than a decade ago and more information examining how the various forms of COCs effect glucose metabolism and diabetic women are needed.
21.8 Effects of COCs Among Women with a History of GDM
There have been a few studies examining the effects of low-dose COCs compared with nonhormonal contraception in women with a history of GDM. Kjos et al conducted a randomized-controlled trial of Hispanic women with a history of GDM and found no difference in glucose tolerance and no adverse effects on lipids with short-term use of two low-dose COCs compared with noncontraceptive users.35Skouby found no effects of low-dose triphasic COC (ethinyl estradiol and levonorgestrel) on glucose tolerance in 16 women with previous GDM and in 19 normal women after treatment for 2 and 6 months.36In another small study with 6 women with a history of GDM and 6 women without GDM history, Skouby et al found a slight decrease in insulin sensitivity among women with previous GDM after using a low-dose triphasic COC for 6 months, but the effects were not sufficient to alter glucose tolerance.37
In another large prospective observational cohort study of Latino women with prior GDM, Kjos et al found that COC use was not associated with risk of T2DM compared with women not using hormonal contraception during 7 years of follow-up.38 To further our understanding of the effects of COCs in women with a history of GDM, more long-term studies are needed of COC use, preferably in ethnically diverse populations with detailed information on baseline metabolic risk factors and outcomes, and with attention to the specific types of OC and the androgenicity of the progestin component.
In general, evidence from existing studies of COCs in healthy populations, women with diabetes, and women with a history of GDM suggest that the use of low-dose COCs can be prescribed to women with prior GDM. However, formulations with the lowest dose ethinyl estradiol and the lowest dose and least androgenic progestin should be prescribed. If women have coexisting hypertension or other CVD risk factors than consideration should be given to nonestrogen containing methods. More information is needed to clarify whether certain types of COC are actually beneficial and others detrimental in terms of carbohydrate metabolism; this could have clinical implications for recommendations as to what types of COC to prescribe, especially for high risk women such as women with diabetes or a history of GDM. More studies are needed with large enough numbers to compare different types of COC and to examine whether the effects vary among obese vs. normal weight women.
21.9 Progestin-Only Oral Contraceptives
POCs are commonly used by women who are breastfeeding and women with contraindications to taking synthetic estrogens. POCs have no effects on maternal coagulation factors or blood pressure and do not affect milk supply in lactating women. However, POCs are more likely to cause break through bleeding which, in turn, could affect their acceptability and lead to poor compliance and hence higher pregnancy rates. POC efficacy has been estimated to be between 1.4 and 4.3 pregnancies per 100 woman-years of use.39
In a landmark study, Kjos et al examined a large cohort of 904 postpartum women with a recent history of GDM and found a threefold increased risk of developing type 2 diabetes among lactating women who were using POCs (0.35 mg of norethindrone) compared with low-dose COC and nonhormonal methods.38 The magnitude of this risk increased with duration of uninterrupted use and was highest among women who used POCs for more than 8 months. Only breastfeeding women were prescribed POCs and therefore the question of whether nonbreastfeeding women with prior GDM also have any increased risk with POC use could not be examined. The authors concluded that the observed adverse effects of unopposed progestins, may have been due to the combination of the hormonal effects of lactation, whereby endogenous estrogen is suppressed and combined with the underlying insulin resistance and a β-cell dysfunction in women with GDM.38 There is currently no data available to determine whether POCs have similar adverse effects in nonlactating women. These findings have yet to be confirmed in other populations or ethnic groups or to see if these associations vary by obesity status in women with a history of GDM. Therefore, POCs may be a good contraceptive option for women with contraindications to COCs, such as women with hypertension, but more information is needed to confirm their safety in lactating women with a history of GDM.
21.10 Long-Acting Progestin Only Methods
Long-acting progestin contraceptive methods can be administered intramuscularly or subcutaneously. The subcutaneous levonorgestrel implant, Norplant, is no longer marketed in the US and will not be discussed. Little information is available on Implanon, an etonogestrel implant, although this implant contains much lower doses of progestin, suggesting it should have minimal effects on glucose metabolism and data from two small observational studies, one in diabetic women40 and one in healthy women,41 found it did not have meaningful effects on carbohydrate metabolism. DMPA is administered intramuscularly. It delivers a plasma concentration of 1 ng/mL medroxyprogesterone and its effects last 3 months.42 DMPA is highly effective (≤0.3% pregnancies with typical use in the first year.43 Similar to POCs, DMPA has no effects on maternal coagulation or blood pressure. However, a review of the effects of injectable or implantable POCs on insulin-glucose metabolism found 7 out of 8 studies with data from an oral glucose tolerance test found an approximately doubling of insulin at 2- or 3-h postchallenge test6; the effects on fasting, half-hour, or 1-h postchallenge insulin levels were less consistent. DPMA use has also been associated with increases in mean weight,44, 45 which appears to be due to changes in adipose mass rather than fluid or lean tissue.46
The studies examining the effects of DMPA in populations at high risk for T2DM suggest that it may substantially increase the risk of progression to T2DM. In a case–control study of 284 women with diabetes and 570 controls conducted among a high-risk Navajo population, Kim found that T2DM was 3.6 times more common in women who used DMPA compared with women who used COCs. Kim also found a dose–response association with longer duration of use, women who used DMPA for 1 year or more had an almost eightfold increased risk of diabetes compared with combination OC-users.47 In an observational cohort study Xiang and colleagues48 examined DMPA use compared with use of COCs on the risk of T2DM among Latino women with a history of GDM. After adjusting for covariates and weight gain during follow-up there was no increased risk of T2DM among DMPA users. However, in stratified analyses, use of DMPA among women with high baseline triglycerides or during breastfeeding did increase the risk of diabetes. Xiang and colleagues49 also found that 1–2 years of treatment with DMPA was associated with greater weight gain compared with nonhormonal or COC users, but there were no significant differences in changes in lipids among the groups and women taking COCs experienced greater increases in systolic blood pressure. In general, data suggests that DMPA may cause adverse metabolic effects, which may be particularly concerning in women at high risk of T2DM or while breastfeeding. Therefore, it would not be recommended as a first-line choice for most women with a history of GDM. However, since DMPA has the advantage of requiring very little active involvement from the patient and since an additional pregnancy in women with prior GDM is associated with a threefold increased risk of developing T2DM,5 it may be an option for patients who have a hard time with the compliance required to take daily medication and who do not desire an additional pregnancy. However, these women should be clinically monitored for adverse metabolic changes.
21.11 Intrauterine Devices
IUDs are a very effective form of reversible contraception. The two forms of IUDs currently used in the U.S. are predominantly copper (TCu380A) or levonorgestrel-releasing. The levonorgestrel-releasing IUD and to a slightly lesser extent the TCu380A IUD are extremely effective, with a cumulative pregnancy rate at 5 years of <0.5% for the levonorgestrel-releasing IUD and between 0.3 and 0.6% for the TCu380A IUD.50 The currently available IUDs may be an ideal form of contraceptive for women with a history of GDM, because they do not appear to have substantial metabolic effects, especially the nonhormonal copper IUD. According to medical guidelines of the World Health Organization, the copper IUD is advised for women with diabetes mellitus with or without comorbidity.51 However, side effects of copper IUDs including bleeding and pain cause removal of the device within the first year in up to 15% of users.52 Therefore, the levonorgestrel IUD may be preferred in some women with a history of GDM as it has a low frequency of bleeding disturbances.
There have been no studies of IUD use in women with a history of GDM. A randomized trial of women with type 1 diabetes comparing levonorgestrel-releasing IUD to a copper T 380A IUD with respect to effects on glucose metabolism after 12 months of use found the levonorgestrel-releasing IUD had no effects on fasting glucose, glycosylated hemoglobin, or daily insulin doses.53 One study54 of levonorgestrel IUD use among 48 perimenopausal women suffering from menorrhagia found mean fasting plasma glucose levels increased, whereas mean diastolic blood pressure decreased after 12 months of use, however, this study was not a randomized trial and not a representative sample. In general, data to date suggest that both levonorgestrel and copper IUDs can be used in women with a history of GDM, however more studies on the effects of IUD use in women with a history of GDM are needed.
21.12 Contraceptive Vaginal Ring
The contraceptive vaginal ring is a flexible ring composed of ethinyl vinyl acetate and releases 15 μg of ethniyl estradiol and 120 μg of the third-generation progestin, etonogestrel, per day.55 The delivery system had the advantage of avoiding first-pass metabolism through the liver and a once a month insertion. NuvaRing is the only vaginal ring available in the US and it is highly efficacious with an efficacy of 99.1%.55 While there is limited information on the metabolic effects of the vaginal ring, the one small study to date found that the NuvaRing had less impact on carbohydrate metabolism and greater reduction in free androgen levels than a low dose COC pill.56
21.13 Surgical Sterilization
Operative sterilization is a nonreversible form of contraceptive that is an excellent choice for women with a history of GDM who have decided they do not want to have any more children. This option should be offered to parous women and can be performed during delivery among women who are undergoing cesarean section. Vasectomy is also a nonreversible form of contraceptive that can be performed with comparatively less morbidity and lower cost than either bilateral tubal ligation or microinsert coil insertion (Essure), both of which require a hysteroscopic or laparoscopic procedure.
21.14 Obesity and Contraception Use
Obesity is the strongest modifiable risk factor for GDM identified to date. Unfortunately, most of the studies to date on the metabolic effects of hormonal contraceptives were unable to examine whether the effects varied by obesity. Recent studies suggest that increased weight and body mass index (BMI) may affect steroid hormonal metabolism or sequestration in fat and can alter hormonal contraceptive effectiveness.57,58 A study of health plan enrolees who became pregnant while using hormonal contraceptives found that among consistent users (women who missed no pills in the reference month), the risk of pregnancy was more than doubled in women with a BMI greater than 27.3. More information is needed to clarify whether the metabolic effects of hormonal contraceptives vary by obesity status and to further clarify how obesity affects contraceptive efficacy in order to determine if overweight women need additional contraceptive methods.
21.15 Conclusions
Effective contraception with minimal metabolic side effects is essential for women both before and after a pregnancy complicated by GDM. Table 21.1 summarizes the recommendations in this chapter. In general, women with prior GDM have many contraception options and the benefits of most forms of contraception seem to outweigh the risks of an unwanted pregnancy. Existing evidence suggests progestin-only methods during lactation should be used with caution. Women with prior GDM should be given contraceptive options that meet their lifestyle and does not further increase their risk of developing diabetes. More rigorous studies examining the metabolic effects of the various hormonal contraceptive methods currently available could help clarify if some forms are actually beneficial and other detrimental to glucose metabolism.
Table 21.1
Summary of the types of contraception and the current recommendations based on their effects on glucose metabolism
|
Type of contraception |
Recommendation |
|
Combination OCPs |
Safe; little known regarding fourth generation |
|
Progestin-only OCPs |
May increase glucose intolerance, particularly during breastfeeding |
|
Depo-Provera (depot medroxyprogesterone acetate [DMPA]) |
May increase glucose intolerance, particularly during breastfeeding |
|
Etonogestrel implants |
Limited data, but appear to be safe |
|
NuvaRing |
Safe |
|
IUDs(levonorgestrel, copper) |
Safe |
|
Condoms/diaphragm |
Safe, although efficacy rates not as high as other methods |
|
Lactation amenorrhea method |
Safe temporary method while exclusively breastfeeding, but must be used accurately and it is recommended to use barrier method in addition for added efficacy |
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