Abstract
The incidence of pregnancies affected with neural tube defects (NTDs) has been reduced by food fortification programs and public health campaigns promoting folic acid supplementation, but the incidence of NTDs in the USA has not achieved the full potential reduction expected with adequate periconceptional folate utilization. In seeking new ways to access sexually active women at risk for pregnancy, one option would be to link folic acid supplementation to contraceptive use. Since birth control pills are the most popular method of reversible contraception in the USA, it would seem quite logical to find a way to supplement them. To this end, a very efficient folate, levomefolate calcium salt (metafolin), has been added to drospirenone-containing oral contraceptives in equimolar concentrations to the recommended supplements of folic acid to reduce the risk for pregnancy and to reduce the risk of NTDs in pregnancies that occur while women are taking the pill or shortly after they discontinue its use. This article will focus on the need for such folate supplementation and will summarize the contraceptive and noncontraceptive benefits of the 30 μg EE/3 mg drospirenone pill (Yasmin®, Bayer Healthcare, NJ, USA) to which has been added 451 metafolin (Safyral®, Bayer Healthcare). The new information about thromboembolism risks associated with use of drospirenone-containing pills is also discussed.
Keywords
Over half a century after the introduction of the birth control pill and IUDs, accidental pregnancies should be a thing of the past. However, the reality is that the goal of planned and prepared for pregnancies is still an abstract concept. Statistics are not even collected to help estimate how close the USA (or any country) is to achieving that goal. Instead, the most frequently used measure to categorize pregnancies reflects the woman's response to her pregnancy rather than her preparation for it. Pregnancies are tallied as ‘intended’ or ‘unintended.’ By definition, an unintended pregnancy is one which the woman did not want at the time of conception. Clearly, with unintended pregnancies women are not prepared. Sadly, because intended pregnancy includes all the women who are ambivalent about pregnancy and all the women who may have desired pregnancy but had not had preconceptional care, large numbers of women with intended pregnancies are also suboptimally prepared.
While an estimated 11% of sexually active women not seeking pregnancy but not using any contraception currently contribute disproportionately to the 49% unintended pregnancy rate, a significant number of pregnancies in the USA occur in women who are using contraception [1]. The first year failure rate of oral contraceptives (OCs) in typical use is 9% [2], which means in the USA alone at least 750,000 to 1 million ‘pill users’ become pregnant each year [3]. These statistics have prompted many US experts to call for more use of ‘forgettable contraceptives’, such as IUDs and implants [4]. Another approach has been to add noncontraceptive benefits to birth control pills to increase women's consistent use of birth control [1]. Another approach might be to use the pill to help women prepare for pregnancy by providing them with additional folate [5–8].
Periconceptional folate
Preconceptional care is designed to prepare a woman for pregnancy in order to optimize the pregnancy outcomes for both maternal health and infant wellbeing. However, preconceptional care has not been implemented as a standard. In part, this is because of the high rate of accidental pregnancies and because women do not understand that pregnancy is potentially hazardous and is something for which they should prepare [9]. The content of preconceptional care must be individualized to address each woman's medical problems and lifestyle issues, but one element common to the care of all women seeking pregnancy is that they must have sufficient folic acid intake for at least 1–3 months before conception and during the first trimester of pregnancy to reduce the risk of neural tube defects [10–12]. Women who accidently conceive while using the pill generally do not have adequate folate levels. Women conceiving shortly after pill discontinuation also lack adequate levels because it can take several weeks to months of folate supplementation to achieve necessary steady-state folate conditions, depending upon the woman's baseline folate levels [13–17]. Return to fertility following pill discontinuation is rapid. Estimates are that within 1 month of pill cessation, 21% of women seeking pregnancy conceive and that within 3 months, 57% of these women conceive [18,19].
Preconceptional folate supplementation to achieve therapeutic levels is important because neural tube defects (NTDs) often develop even before the woman is aware that she is pregnant. The closure of the neural crest is normally complete in the cranial pole by 21–26 days postconception and by 23–25 days in the caudal pole.
NTDs: impacts
NTDs encompass a wide range of lethal and severely debilitating birth defects, including anencephaly and spina bifida. Mortality for infants with anencephaly is 100% and for infants with spina bifida is approximately 30%. Survivors experience morbidity from neurological problems that correspond to the level in the spinal cord of their lesion. Most spina bifida results in paralysis of the lower extremities and loss of bowel and bladder function, and requires lifelong medical support. The suffering associated with NTDs among survivors can be measured in many ways. The magnitude of life-years lost to NTDs is 620.5 per 10,000 births, a number exceeded in the category of congenital anomalies only by cardiovascular congenital anomalies. Total years of impaired life have been estimated to be 248.1 per 10,000 life-years. The cost of medical care of patients with an NTD in the USA is approximately US$185,000 per patient per year [20–23]. Spina bifida and anencephaly affect 300,000 newborns worldwide each year [24].
Risk factors for NTD
NTDs occur sporadically; 90% of cases occur in women who have not experienced prior affected pregnancies [25]. NTDs are caused by both genetic and environmental factors. Identified risk factors include diabetes, obesity, hypertension, certain anticonvulsants, genetic factors, race/ethnicity and nutrition (especially folate insufficiency) [25,26]. The link between NTDs and maternal folate deficiency was established through a series of landmark studies [27–36]. It was particularly difficult to identify this link as the women did not have clinical folate deficiency, but had only folate levels that were inadequate for pregnancy.
Folates play pivotal roles in both DNA synthesis and repair [27]. They are needed for methylation, which is particularly important during the initial period of embryonic development [37,38]. Folates are derived from a wide variety of foodstuffs. Folic acid is a stable synthetic form that is used in food fortification and in medications used for supplementation. Folic acid must be reduced to its metabolically active form – tetrahydrofolate. Blood samples obtained early in pregnancy have been compared with pregnancy outcomes to determine that serum folate and red blood cell levels of at least 16 and 906 nmol/l, respectively, provided the greatest protection from NTDs [39]. Estimates are that 50–60% of primary NTDs [38] and 70% of recurrent NTDs [40] could be prevented by adequate periconceptional folic acid intake.
Approaches to folate supplementation
Several public health measures have been utilized to increase women's folate levels before pregnancy and during the first months of organogenesis. The three main approaches have included dietary improvement, folate supplementation and food fortification. Dietary improvement is difficult to achieve when so many pregnancies occur by accident. Furthermore, women's compliance with nutrition and lifestyle recommendations have been found to be inadequate [41]. Different recommendations made in different countries about the amount and duration of needed supplementation have complicated matters [10–12,16]. Strongly worded public health messages promoting the importance of folic acid supplementation have caused temporary increases in the use of folates, but little long-term impact has been found [42]. Therefore, food-stuff enrichment (supplementation) with folic acid has been adopted in many countries. For example, in the USA, grains and cereals have been fortified with 140 μg folic acid/100 g [43], which has raised the daily dietary intake of the general population by 128 μg per day [44]. Higher levels of supplementation were not adopted for fear that they might mask pernicious anemia, particularly among the elderly. This food fortification has had measurable impacts. The percentage of the population with low serum folate (<3 mg/ml) declined from 21% before food fortification to <1% in the period immediately following food fortification with folic acid [45] and the rates of pregnancies with NTDs dropped from 10.8 to 6.9/10,000 [11]. Similar success has been documented in many other countries with folic acid food fortification. Initiatives are underway to increase fortification of wheat flour with folic acid in other countries and to fortify other important food staples, such as corn and rice [11].
While food fortification reduced the numbers of US women with folate deficiency, surveys showed paradoxically that mean serum levels of folate in the USA actually fell following the introduction of food fortification [46–49]. This unfortunate finding was particularly evident among indigent women who are less likely to access early prenatal care and to have early testing to identify affected pregnancies [11,36,50,51]. Similarly in Canada, Shuaibi et al. demonstrated that, although no woman was folate deficient, only 14% had red blood cell concentrations of folate associated with significant NTD risk reduction [52].
Substantial challenges remain to further reduce NTD incidence using only these three public health approaches. Population-wide food fortification could be slightly raised in some countries, but fortification is close to its upper limit, unless vitamin B12 fortification is added [53]. Messages to young women to plan their pregnancies and to supplement their folate intake for a few months preceding conception have failed [41,43,54]. In Europe, the majority of women surveyed were not taking folic acid supplements periconceptionally. The highest utilization (above 30% of women) was found only in the Netherlands and Denmark [55]. Compounding these problems is the issue that obesity can induce abnormalities in the release of folate from body stores [56]. Attempts to urge all reproductive age women to consume additional folate on an ongoing basis until they are not at risk for pregnancy have not achieved target folate levels needed to maximally reduce NTDs. Even clinicians very aware of the problem do not advise routine supplementation at recommended levels. A survey of North American pregnancy care providers found that only 7.2% ordered folic acid and/or multivitamin supplementation for their nonpregnant, reproductive age female patients, compared with 42.8% who ordered it for pregnant patients [57].
OCs as a source of folate
A more modest approach that targets sexually active women of reproductive age is being offered by the addition of metafolin to two drospirenone (DRSP)-containing OC pills (Beyaz® and Safyral®, Bayer Healthcare, NJ, USA). These two pills have been approved by the US FDA for use by women who choose to use OCs as their method of birth control, to raise their folate levels for the purpose of reducing their risk of a NTD developing in a pregnancy conceived while the woman is taking the pills or shortly after discontinuing one of these methods. Of interest, new studies have suggested other potential pregnancy benefits. Low folate levels in early pregnancy are also associated with vascular deficiencies in the placenta, which in turn, have been linked to significantly higher rates of prematurity, small for gestational age at birth and pre-eclampsia [5–7].
The purpose of this article is to provide a comprehensive overview of the 30 μg ethinylestradiol (EE)/3 mg drospirenone (DRSP) pill with 451 mg levomefolate calcium (Safyral). The components of the formulation, as well as the contraceptive and noncontraceptive benefits of the parent contraceptive pill (Yasmin®) will be briefly summarized. The logic of utilizing metafolin as a source of folate will also be described. The new product labeling describing venous thromboembolism (VTE) risk will be presented to guide clinicians in counseling women.
Overview of the market
Currently, there are two OCs available with a folate supplementation. One pill has added 451 mg metafolin to a 30 μg EE formulation (Yasmin) and is marketed as Safyral; the second adds the same amount of metafolin to the 20 μg EE formulation (Yaz®) and is marketed as Beyaz. The Beyaz pill has been discussed in another article in this series [58].
Description of product
Overview of Safyral
Safyral is available in a blister pack containing 21 active pills and seven hormone-free pills. Each of the 21 active pills contains 30 μg EE and 3 mg DRSP (Yasmin), as well as 0.451 mg levomefolate calcium (metafolin). The seven hormone-free pills contain 0.451 mg metafolin in each pill.
DRSP
The progestin in this pill, DRSP, is an analog of the aldosterone antagonist, spironolactone [59]. DRSP is synthesized from androstenolone and has both antimineralocorticoid and antiandrogenic activity [60–62]. The 3 mg dose of DRSP used in Safyral is roughly equivalent to 25 mg of spironolactone in terms of antimineralocorticoid activity. Using in vitro transactivation assays, the effects of DRSP have been found to be very similar to progesterone on androgen-, glucocorticoid- and mineralocorticoid-receptor-mediated induction of transcription. Compared with other progestins used in OCs, such as levonorgestrel (LNG), norgestimate (NGM), gestodene, dienogest, desogestrel (DSG) and cyproterone acetate (CPA), the pharmacologic profile of DRSP most closely matches that of progesterone in all dimensions [63,64]. DRSP counteracts estrogen-induced stimulation of the renin–angiotensin–aldosterone system [63] and blocks testosterone from binding to androgen receptors [58,63]. As with all hormonal contraceptives, most of the contraceptive action is provided by the progestin which thickens the cervical mucus to prevent sperm entry into the upper genital tract and suppresses ovulation.
EE
EE is a long-acting, synthetic estrogen, which is used in virtually all modern combination birth control pills. The estrogen in OCs provides cycle control and contributes to contraceptive action by having a mild negative impact on follicle-stimulating hormone in the first half of the cycle, which delays follicle development.
Levomefolate calcium
Levomefolate calcium is a synthetic calcium salt of L-5-methyletrahydrofolate (L-5-methyl-THF). The 0.451 μg dose of metafolin contains 0.416 mg L-5-methyl-THF, which is equimolar to 0.4 mg of folic acid. It is a metabolite of vitamin B9. L-5-methyl-THF is the predominant folate form (98% of folates) found in the human circulation and is equivalent to the synthetic levomefolate calcium on an equimolar basis [14,63]. DNA methylation is required for gene expression during embryogenesis. 5-methyl-THF is the form of folate that provides methyl groups for the formation of S-adenosyl methionine, the universal methyl donor needed for DNA methylation. Genetic variations associated with folate metabolism can significantly reduce the level of 5-methyl-THF and these transfers. In particular, one polymorphism is the 677C→T variant of the MTHFR gene, which results in decreased serum folate [65] and has been associated with a disproportionately increased risk of NTDs [66]. Administration of the end product of folate metabolism (5-methyl-THF) eliminates the possibility that women with these variants will fail to raise body stores of usable folate adequately.
Pharmacokinetics
DRSP
Studies demonstrate that absorption of DRSP is rapid and complete. Plasma concentrations peak 1–2 h after ingestion. Absolute bioavailability of DRSP averaged 76% [63]; steady-state levels were achieved after 8 days. Maximum levels ranged between 60 and 87 ng/ml, and trough levels ranged between 20 and 25ng/ml. There was a two- to three-fold accumulation in serum Cmax and area under the curve (0–24 h) values of DRSP following multiple dose administration of Yasmin. Approximately 95% of DRSP is serum protein bound. DRSP binds to albumin, but not to sex hormone-binding globulin or corticosteroid-binding globulin. It does not dampen the increases that EE induces in these proteins.
EE
Serum concentrations of EE reached peak levels within 1–2 h after administration of Yasmin. Steady-state conditions developed during the second half of the treatment cycle. Following daily administration, serum Cmax and AUC (0–24 h) values of EE accumulate by a factor of approximately 1.5–2. The absolute bioavailability of EE when administered is approximately 40% as a result of presystemic conjugation and first-pass metabolism. Interestingly, the rates of absorption of DRSP and EE are slower under fed (high fat meal) conditions.
Levomefolate calcium
Levomefolate calcium (metafolin) is absorbed rapidly and incorporated into the body folate pool. Peak plasma concentrations rise by approximately 50 nmol/l 0.5–1.5 h after a single oral administration. Steady-state levels in the serum are seen after 8–16 weeks, depending upon baseline levels. Steady-state levels in red blood cells take longer to achieve because of the slow turnover of older blood cells. Folates have both fast and slow turnover pools. The fast pools represent newly absorbed folate, whereas the slower turnover pool reflects folate polyglutamate, which has a mean residence time of at least 100 days. Bioavailability of L-5-methyl-THF following single doses is at least as high as that of folic acid [14]. For individuals with genetic mutations that limit folic acid conversion to L-5-methyl-THF and in people who use medications that inhibit dihydrofolate reductase, administration of the final product (metafolin) results in higher serum levels of L-methyl-THF [14,67]. Several studies of varying durations (8–24 weeks) have demonstrated that in women given 5-methyl-THF compared with those given folic acid, serum folate levels and red blood cell folate levels were generally higher with the 5-methyl-THF supplements [13,68–70].
In one clinical trial, women were randomized into two arms in a double-blind, double-dummy trial comparing Safyral to folic acid supplements [15]. In one arm, the patients were given Safyral and a dummy pill; in the second they were given Yasmin and a tablet with 0.4 mg of folic acid for 24 weeks. After this period, they were entered into a 20-week open-label study of Yasmin alone to observe washout. At each point in time during the trial, the women with Safyral had higher levels of folate in both serum and red blood cells compared with the women in the 0.4-mg folic acid arm. Almost half of the subjects remained at or above the red blood cell folate level of 906 nmol/l 10 weeks after stopping Safyral – the level thought to be needed to provide protection against folate-deficiency-induced NTD (
Clinical uses on label
Contraception
In early preclinical studies, Yasmin was shown to effectively inhibit ovulation, as measured by blood testing for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone, and by ultrasonic monitoring of ovarian cyst development [72]. In addition, cervical mucus thickens, with reductions in spinnbarkeit and ferning tests.
Yasmin has been used for over a decade in the EU and USA as an effective contraceptive. In an open-label, multicenter clinical trial in the USA, the uncorrected Pearl Index was 0.406 per 100 women-years based on one pregnancy in 3201 cycles of 326 subjects. The pregnancy ratio, based on 220 women completing 13 cycles without the use of alternative contraception, was 0.455 per 100 women-years [73]. In comparative efficacy trials, the DRSP pill provided pregnancy protection equivalent to a 30 μg EE/150 μg DSG (EE/DSG) formulation [74]. In a Chinese efficacy trial, the EE/DRSP formulation Pearl Index was 0.208/100 women-years, which was lower than the Pearl Index of the EE/DSG group (0.601/100 women-years) [71]. Many of the clinical trials demonstrated considerable patient satisfaction with Yasmin, which is important for continued use and successful contraception [75].
Due to its potassium-sparing properties, labeling clearly indicates that Safyral is not for use by women with underlying medical conditions that would predispose them to hyperkalemia. Women who chronically use medications on a daily basis that could potentially cause hyperkalemia should have their potassium levels measured approximately 2 weeks after starting any DRSP-containing contraceptive. Similarly, patients who are being evaluated for vitamin B12 deficiency must understand that metafolin might mask their pernicious anemia.
Potential reduction in NTDs
The impact that the addition of 0.451 mg metafolin taken on a daily basis may have on NTD risk reduction has not been directly measured, but has now been modeled. Assuming that all oral contraception users switch to pill formulations containing levomefolate for at least 6 months, that 5–8% of pill users would experience an accidental pregnancy and that 23% of users would discontinue pill use, the authors concluded that the number of cases of anencephaly and spina bifida would decline by 23.7–31.4%, depending on the baseline folate levels of the women switching from unfortified pills [76].
Postmarketing findings: other applications
There have been no postmarketing findings for Safyral, but important information has been published since the launch of the parent contraceptive product, Yasmin. These findings are discussed in the following sections.
Other clinical applications
In the USA, the parent compound, Yasmin, is approved only for protection from pregnancy. Several studies have noted that Yasmin has favorable impacts on skin conditions and wellbeing (including premenstrual and menstrual symptoms) reflecting the antiandrogenic and antimineralocorticoid properties of DRSP.
Treatment for androgen excess conditions
In a double-blind study, the efficacy and tolerability of Yasmin as a treatment for acne vulgaris was compared with a triphasic pill formulation that had FDA approval as a treatment for moderate cystic acne (Ortho Tri-Cyclen®, Janssen Pharmaceuticals, NJ, USA). Over 1100 women were randomized to receive EE/DRSP (n = 568) or EE/NGM (n = 586) for six treatment cycles. EE/DRSP was superior for the reduction in total lesion count (p = 0.020) and for the investigators’ assessments of therapeutic effect on facial acne (p = 0.006), as well as subjects’ assessments. The two pills were comparable in the decrease in inflammatory lesion counts [77]. For the treatment of severe papular and nodulocystic acne, the combination of 30 μg EE/3 mg DRSP and 100 mg of spironolactone has been shown to be very effective and well tolerated [78]. The impact of EE/DRSP on both acne and seborrhea was compared in a randomized double-blind, nine-cycle trial study with a 35 mg EE/2 mg cyproterone acetate pill. Each compound reduced median total acne lesion count by approximately 60% and also reduced sebum production and hair growth on the upper lip and chin [79]. In a trial comparing the DRSP pill to a 30 μg EE/150 mg LNG pill, the proportion of subjects with acne declined by 10% in the DRSP group, but remained unchanged in the LNG pill group [80]. Both DRSP and DSG pills with 30 μg of EE were found to improve preexisting acne and seborrhea [79]. In a prospective comparative trial of a 30 μg EE/DRSP versus a 30 μg EE/DSG pill in women who have polycystic ovary syndrome (PCOS), the DRSP pill users had better outcomes in terms of persistent regular cycles, a persistent decrease in hirsutism, a fall in BMI and blood pressure, a better lipid profile, and favorable glycemic effects [81].
In a randomized study of women with PCOS, pill formulations with DRSP and CPA resulted in greater reduction in serum androgens (total testosterone, free testosterone and androstenedione) and progressive increases in sex hormone-binding globulin (SHBG) compared with third-generation formulations (DSG and gestodene), with equivalent amounts of EE [82].
Menstrual symptoms
The clinical significance of DRSP in blocking estrogen-induced changes in the renin–angiotensin–aldosterone system has been explored in many trials. One study evaluated menstrual symptoms using the Women's Health Assessment Questionnaire (WHAQ) at baseline and at each follow-up visit for three phases of the menstrual cycle [83]. This study found that with Yasmin, there was a significant decline in mean WHAQ scores during the premenstrual phase, especially in problems with impaired concentration, water retention, negative affect, increased appetite and undesirable hair changes. In the menstrual phase, mean WHAQ symptoms declined with Yasmin for impaired concentration, negative effect and hair changes [83]. In another prospective study using the Psychological General Well-being Index, Yasmin users showed a significant reduction in both the incidence and severity of several physical symptoms associated with menstruation, especially abdominal bloating and breast tenderness [84]. Improvements were noted by cycle three and were sustained through to the end of the 6-month trial. In another randomized, placebo-controlled study of Yasmin in women with premenstrual dysphoric disorder (PMDD), a consistently greater reduction was found in all 22 premenstrual symptoms assessed [85]. For the cluster of appetite, acne and food cravings, the difference was statistically significant. In a study conducted in European, Middle Eastern and Canadian women, a reduction of almost 50% was seen in the frequency of abdominal bloating, breast tenderness and dysmenorrhea [81]. In Chinese trials using the Menstrual Distress Questionnaire, the DRSP group showed better scores in water retention and general wellbeing during scheduled bleeding episodes compared with the EE/DSG group [80]. In a comparative open-label trial of EE/DRSP versus EE/DSG pills, the incidence of premenstrual symptoms was higher in the 6-month baseline period in the DRSP group, but lower on treatment [86]. Dysmenorrhea scores were also better in the DRSP group. A statistically significant difference was seen in weight gain in those on EE/DSG, with gain seen in mean weight at all in the DRSP group. More subjects using DRSP pills reported improved physical wellbeing compared with women in a LNG comparison group [86].
Other interesting findings
In a study of healthy users of a variety of combined OCs, users of Yasmin, but not LNG-containing pills, demonstrated a significant increase in endothelium-dependent vasodilation in both large vessels and peripheral microvasculature [87]. A second study found that with Yasmin, endothelial-dependent vasodilation was greater for active pills compared with placebo pills, but no changes were seen in endothelial-independent dilation across the menstrual phases [88].
Postmarketing findings: thromboembolism
The possibility that DRSP may be associated with increased risk of VTE and/or for arterial thromboembolism (ATE) has been investigated by many researchers using a variety of data sources, study designs and outcome measures (i.e., total VTE vs idiopathic VTE). It is known that DRSP does not temper the EE-induced changes in hepatic protein production as do the more androgenic progestins, such as LNG. For example, high-density lipoprotein and triglyceride levels show a greater increase with DRSP-containing combination pills compared with LNG pills. Similarly, EE-induced production of extrinsic clotting factors and other procoagulation proteins may be greater with DRSP pills than with LNG pills, which could lead to an increased risk of thromboembolism. However, experience has taught the error in using such surrogate measures to predict important clinical events, such as VTE risk [89].
Summary of studies investigating VTE risk
Primarily because of concerns about potential problems with hyperkalemia, the FDA initially required as a condition of product approval that extensive postmarketing surveillance be established to study all clinical manifestations of this problem. Later concerns about thrombosis prompted regulatory authorities to require that surveillance studies in both the USA and EU be expanded to study possible VTE risks.
In the EU, a large-scale, prospective, cohort comparative trial was established to provide large-scale data comparing Yasmin with all other progestins used in the EU and also specifically with LNG [90]. In the USA, a retrospective cohort study utilizing electronic medical data from United Healthcare-affiliated health centers, compared the risks associated with Yasmin with all other US pills [91]. Those studies were designed in conjunction with each of the regulatory authorities and were conducted by independent investigators. The results of the studies were reviewed by the regulatory authorities every 6 months until, after 3 years, sufficient numbers of women had been studied to determine that there was no excessive increase in use of DRSP-containing pills with 30 μg of EE.
The absolute rate of VTE per 10,000 women-years in the EU study was found to be very similar among the various progestins: DRSP 9.1; LNG 8.0; all other OCs 9.9. After adjusting for risk factors, the hazard ratio (HR) for DRSP versus LNG was 1.0 (95% CI: 0.6–1.8). When only the 30 μg EE/LNG pills were used as the comparator pill, the adjusted HR was 0.8 (95% CI: 0.5–1.5). The highest rate for VTE risk was during the first 3 months of OC use. Obese women had approximately a threefold higher VTE risk compared with normal weight women.
Following publication of these postmarketing surveillance study results, two large retrospective studies reported that DRSP-containing pills were associated with increased risk of VTE, especially when compared with LNG-containing pills [92,93]. Although the FDA determined that these studies were seriously flawed and that their conclusions were unreliable, the findings prompted the FDA to commission its own study. While that FDA-commissioned study was underway (vide infra), two subsequent studies demonstrated increased risk of VTE with DRSP-containing pills. In one nested case–control study comparing DRSP and LNG for first-episode idiopathic VTE in new combined oral contraceptive (COC) users without any major risk factors, controls were matched for age, duration of recorded information and ‘general practice’ [94]. The age-adjusted incidence rate ratio comparing DRSP to LNG formulations was 2.7 (95% CI: 1.5–4.7) and adjusted for BMI, and the HR was 3.3 (95% CI: 1.4–7.6). Another nested case–control and cohort study from a claims-based database of 186 idiopathic cases of VTE found that the age-adjusted incidence rate ratio for VTE for current use of DRSP-containing pills versus LNG-containing pills was 2.8 (95% CI: 2.1–3.8) [95]. Interestingly, this study found that women under the age of 30 years had higher relative risks (RRs) of VTE compared with older women. In response to these studies, in 2011, the EMA added a warning to the product labels of DRSP-containing OC products: “Epidemiologic studies have shown that the risk of VTE for DRSP-containing OCs is higher than for LNG containing OCs (so-called second-generation progestins) and may be similar to the risk for DSG/gestodene-containing OCs (so-called third-generation progestins)” [201]. Lidegaard added another cohort study for nonfatal idiopathic thromboembolic events from national registries that reported the RR of DRSP-containing pills versus LNG formulations was 2.2 (1.3–3.9) [96].
More recently, the FDA published the results of a large-scale claims-based database study that it commissioned using Kaiser Permanente northern and southern California claims databases, as well as Washington and Tennessee State Medicaid claims databases [202]. These electronic databases include demographic data, ambulatory prescriptions from pharmacy records or claims, diagnoses from health plan records or claims, and mortality from state files. Outcomes for Yasmin were compared with those of a mixed comparator group of pills and, separately, with a 30 μg LNG pill. When these data were presented at the FDA Advisory Board meeting in December 2011, the staff stated that without access to medical records, the investigators could not control for the other major risk factors for VTE including weight, tobacco use and family history. They referred to the findings of this study as ‘Phase I’ findings. ATE rates and cardiovascular disease mortality rates were not increased in more DRSP users compared with users of other pills. Overall, the age-adjusted and site-adjusted incident rate ratio for VTE with Yasmin was 1.69 (1.39–2.06) compared with the entire comparator group of pills, and was 1.49 (1.19–1.87) compared with the 30 μg EE/150 mg LNG pill. VTE-adjusted rates were higher for new users than for all users.
Subsequent to publication of the FDA report, a large population-based cohort study was published of first-time VTE and ATE events in 819,749 women-years of OC follow-up based on a medication, primary care and hospital databases of the largest healthcare provider in Israel [97]. The risk of thrombosis was highest in the first month of use. Within the third-generation pills, there was no difference between formulations with 20 μg EE and those within 30–35 μg EE. The DRSP-containing pill was not associated with any increased risk of arterial thrombosis events (transient ischemic attack or cerebrovascular accident) relative to the use of second- or third-generation agents. On the other hand, after adjusting for risk factors on a multivariable analysis, the risk of VTE was significantly greater among DRSP pill users compared with users of pills of third-generation formulation (RR: 1.43; 95% CI: 1.15–1.78). Compared with second-generation formulations, the VTE risk of Yasmin was greater (RR: 1.65; 95% CI: 1.02–2.65). In contrast to the FDA study, the VTE risks were more consistent with prior studies; the risk of VTE increased progressively with increasing age, and was increased with reported hypertension, cancer and obesity, but, interestingly did not increase with diabetes or smoking [97]. It should be recognized that there are several important differences among the studies in the outcome measures (total VTE events vs idiopathic VTE events) in the definition of ‘exposure’, in the ability to verify the diagnoses of VTE and in the ability to control for significant confounding variables [98].
FDA labeling: 2012
The FDA published its new labeling for DRSP-containing pills in April 2012. In the warnings and precautions section for all DRSP-containing pills, the FDA advised “DRSP-containing COCs may be associated with higher risk of VTE than COCs containing the progestin LNG or some other progestins. Epidemiologic studies that compared the risk of VTE report that the risks ranged from no increase to a threefold increase” [203]. The labeling highlights the findings of the three studies that were required or sponsored by the regulatory agencies, including the two postmarketing surveillance studies and the Kaiser study (
Estimates (hazard ratios) of venous thromboembolism risk in current users of Yasmin® (drospirenone/ethinylestradiol) compared with users of oral contraceptives that contain other progestins.
‘New users’ – no use of combination hormonal contraception for at least the prior 6 months.
Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone or ethynodiol diacetate.
Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinoneacetate, gestodene, cyproterone acetate, norgestimate or norethindrone.
Includes low-dose COCs containing the following progestins: norgestimate, norethindrone or levonorgestrel.
COC: Combined oral contraceptive; EE: Ethinylestradiol.
Conclusion
Safyral provides good contraceptive efficacy and it provides an ongoing source of folate to reduce a woman's risk of conceiving a pregnancy affected by NTDs while she is using the pill or shortly after discontinuing its use. Several noncontraceptive benefits of the parent contraceptive compound of Safyral have been documented in a variety of postmarketing studies, including improvement in acne and seborrhea (resulting from antiandrogenic activity of DRSP) and improved wellbeing, especially a reduction of the premenstrual symptoms of bloating, breast tenderness and mood change (resulting from antimineralocorticoid activity of DRSP). Large-scale prospective postmarketing studies mandated by the FDA and EMA found little or no increase in VTE risk with the parent pill, Yasmin. Subsequently, case–controlled studies and claims database studies have consistently reported increased risk of VTE with this formulation. There may be many explanations for the variability seen in the VTE risk in different types of studies, but regulatory agencies have recently amended the labeling of all DRSP-containing pills to advise that DRSP-containing COCs may be associated with a greater risk of VTE than the VTE risks with LNG formulations and with some other progestins [203]. This is very similar to the warnings and cautions found in the labeling of products containing the so-called ‘third-generation’ progestins. It would be prudent to first emphasize to potential users (and women reconsidering their choice of pill) that Safyral is safer than pregnancy, but that there are pill formulations that may have lower risks for venous thrombosis than Safyral. If the patient is using the pill strictly for contraception, she may benefit from using a LNG-containing formulation. If she selects a formulation without levomefolate, it is strongly urged to plan for pregnancy and to start folic acid supplements 1–3 months prior to pill cessation. If the patient is using Safyral for its additional noncontraceptive benefits or to avoid side effects of LNG-formulations, the physician should have her consider the increase in risk of VTE. They should be sure to factor in all of her comorbidities (e.g., BMI, smoking and family history) when estimating the magnitude of the increased risk and have her compare the absolute risk of thrombosis against the benefits she expects to achieve with Safyral.
Some experts have suggested that the addition of levomefolate is unnecessary; that from a societal and public health perspective, clinician time would be better spent counseling women on more effective contraceptive methods and that pill users considering pregnancy should be urged to continue their current pill and start taking folic acid at least 1 month prior to pill discontinuation [58]. Clearly, more women should be encouraged to use the top tier, ‘forgettable’ contraceptive methods, but OCs remain the most popular reversible method in many parts of the world. Providers should always urge women to plan and prepare for each pregnancy. However, the reality persists that most pregnancies are not prepared for. The argument has also been made that many pregnancies occur due to inconsistent pill use, which could diminish the rise of folate resulting from fortified pills. However, occasional inconsistent pill use that may put a woman at risk of pregnancy would not completely negate a substantial folate benefit. If there is no significant increase in cost associated with the use of the levomefolate-containing pills and the patient is otherwise a good pill candidate, this formulation provides many attractive features that may encourage more consistent pill use and provide an important safety net in case inconsistent pill use results in failure. Until other formulations (including those with LNG) provide folate, the DRSP-containing pills are unique in providing this benefit.
Future perspective
Unplanned and unprepared for pregnancies may well continue to outnumber the pregnancies that are prepared for, unless there is a major change in the perception of the health hazards of pregnancy and benefits of pregnancy planning. Even the Healthy People 2020 objectives have very modest targets: to increase the percentage of pregnancies that are intended to 56% and to reduce the pregnancy rate of contraceptive users to 9.9% [204]. Until ambivalence is replaced by deliberate decision-making and action, and until women are provided the tools to control their own fertility, unplanned families will continue to outpace family planning. Education and reeducation is of paramount importance. At least in the USA, women do not know the health hazards of pregnancy [9]. They underestimate their own fertility and overestimate the risks of contraception.
Continued expansion in the use of ‘forgettable contraceptives’ can safely and effectively provide the pregnancy protection that women need. As many of these methods require clinician action to discontinue their use (i.e., implant and IUD removal), clinicians often have an opportunity to encourage short-term use of folates prior to method cessation. Women can and often do discontinue OC methods without any intervention from clinicians. It is very appropriate to have a safety net to reduce the risk of NTDs as women transition between methods or prepare for pregnancy. To this end, it would be hoped that folate supplements would be added whenever possible to all reversible contraceptives. It may well take repeated, large-scale public health campaigns to teach women about the safety of contraceptives and about the importance of preparing for pregnancy. Until then, we must all continue to share these messages one woman at a time.
Financial & competing interests disclosure
AL Nelson declares that she has received honoraria from Bayer Healthcare for her work on some of their contraceptive advisory boards and for serving on their speakers' bureaus for their contraceptive products. Her clinic has received grants from Bayer Healthcare to conduct Phase III clinical trials for new contraceptives. She also serves on advisory boards for Agile, Merck and Teva, and on speakers' bureaus for Agile, Teva and Watson. Her clinic has received grants from Merck and Teva. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Executive summary
Neural tube defects affect 300,000 pregnancies worldwide each year.
Accidental pregnancies are very common.
First-year failure rate with birth control pills in typical use is 9%.
Food fortification with folic acid has been maximized, but serum and red blood cell folate levels of sexually active, reproductive age women still fall below the level needed to minimize neural tube defects.
One in five women seeking pregnancy conceives in the first month following pill discontinuation.
A new oral contraceptive formulation, which adds 0.451 mg levomefolate calcium (L-5-methyltetrahydrofolate) to the 30 μg ethinylestradiol/3 mg drospirenone (DRSP) pill, Yasmin®, is marketed under the name Safyral®.
Both serum and red blood cell folate levels rise to protective levels in less than 24 weeks of Safyral use and remain elevated for weeks following pill cessation. Over half of women maintain protective for red blood cell folate levels for over 10 weeks. All women have folate levels above baseline level for 20 weeks.
Because its DRSP has both antimineralocorticoid and antiandrogenic properties, Safyral has been shown to have benefits for both skin conditions (acne, seborrhea and hirsutism) and for wellbeing, especially for perimenstrual problems.
DRSP-containing pills may be associated with higher risk of venous thromboembolism than pills containing levonorgestrel or some other progestins.